Addiction. Hales Et Al (2011) American Psychiatric Publishing Textbook of Substance Abuse Management, 4th Ed

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The American Psychiatric Publishing Textbook of Substance Abuse Treatment, 4th Edition Edited by Marc Galanter, M.D., and Herbert D. Kleber, M.D. DOI: 10.1176/appi.books.9781585623440 What is this?

CONTENTS

Part 1: The Basis of Addictive Disorders Chapter 1. Neurobiology of Addiction Chapter 2. Genetics of Addiction Chapter 3. Epidemiology of Addiction Chapter 4. Cross-Cultural Aspects of Addiction

Part 2: The Nature of Treatment Chapter 5. Assessment of the Patient Chapter 6. Patient Placement Criteria Chapter 7. Evolution in Addiction Treatment Concepts and Methods

Part 3: Specific Drugs of Abuse Alcohol Chapter 8. Neurobiology of Alcohol Chapter 9. Clinical Management of Alcohol Abuse and Dependence Stimulants Chapter 10. Neurobiology of Stimulants Chapter 11. Clinical Management: Cocaine Chapter 12. Clinical Management: Methamphetamine Hallucinogens and Club Drugs Chapter 13. Neurobiology of Hallucinogens Chapter 14. Hallucinogens and Club Drugs Other Substances Chapter 15. Nicotine and Tobacco Chapter 16. Benzodiazepines and Other Sedatives and Hypnotics Chapter 17. Treatment of Anabolic-Androgenic Steroid–Related Disorders Opioids Chapter 18. Neurobiology of Opiates and Opioids Chapter 19. Detoxification of Opioids Chapter 20. Opioid Maintenance Treatment Chapter 21. Buprenorphine Maintenance Chapter 22. Antagonists of Opioids

Part 4: Treatment Modalities

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Chapter 23. Psychodynamics Chapter 24. Cognitive-Behavioral Therapies Chapter 25. Motivational Enhancement Chapter 26. Twelve-Step Facilitation: An Adaptation for Psychiatric Practitioners and Patients Chapter 27. Contingency Management Chapter 28. Network Therapy Chapter 29. Group Therapy Chapter 30. Family Therapy

Part 5: Rehabilitation Settings Chapter 31. Inpatient Treatment Chapter 32. Therapeutic Communities Chapter 33. Community-Based Treatment Alcoholics Anonymous and Other 12-Step Programs Chapter 34. Psychological Mechanisms in Alcoholics Anonymous Chapter 35. The History of Alcoholics Anonymous and the Experiences of Patients Chapter 36. Outcome Research on 12-Step and Other Self-Help Programs

Part 6: Special Populations Chapter 37. Adolescent Substance Abuse Chapter 38. The Mentally Ill Substance Abuser Chapter 39. Women and Addiction Chapter 40. Perinatal Substance Abuse: Drug Dependence, Motherhood, and the Newborn Chapter 41. HIV/AIDS and Hepatitis C Chapter 42. Prescription Drug Abuse Chapter 43. Substance Use Disorders Among Physicians Chapter 44. Gay Men and Lesbians Chapter 45. Minorities

Part 7: Special Topics Chapter 46. Testing to Identify Recent Drug Use Chapter 47. Medical Education Chapter 48. Prevention of Substance Abuse Chapter 49. Forensic Addiction Psychiatry

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Editors Marc Galanter, M.D. Professor of Psychiatry, Department of Psychiatry; Director of the Division of Alcoh olism and Drug Abuse, New York University School of Medicine, New York, New York Herbert D. Kleber, M.D. Professor of Psychiatry and Director, Division of Substance Abuse, Columbia University, New York, New York

Contributors Sudie E. Back, Ph.D. Assistanct Professor, Division of Clinical Neuroscience, Medical University of South Carolina, Charleston, South Carolina Monica Barros, M.D. Chief Resident, Department of Psychiatry, Georgetown University Hospital, Washington , DC Steven L. Batki, M.D. Department of Psychiatry, University of California, San Francisco; Director, Addiction Psychiatry Research Program, San Francisco VA Medical Center, San Francisco, California Adam Bisaga, M.D. Associate Professor of Clinical Psychiatry, Department of Psychiatry, Columbia University College of Physicians and Surgeons; Research Psychiatrist, New York State Psychiatric Institute, New York, New York J. Wesley Boyd, M.D., Ph.D. Associate Director, Physician Health Services, Massachusetts Medical Society; Assistant Clinical Professor of Psychiatry, Harvard Medical School; Staff Psychiatrist, Cambridge Health Alliance, Cambridge, Massachusetts Kathleen T. Brady, M.D., Ph.D. Professor of Psychiatry, Division of Clinical Neuroscience, Medical University of South Carolina, Charleston, South Carolina David W. Brook, M.D. Professor of Psychiatry, New York University School of Medicine, New York, New York Judith S. Brook, Ed.D. Professor of Psychiatry, New York University School of Medicine, New York, New York Kirk J. Brower, M.D. Associate Professor of Psychiatry, Department of Psychiatry; Executive Director, University of Michigan Addiction Treatment Services, University of Michigan, Ann Arbor, Michigan Robert Paul Cabaj, M.D. Director, San Francisco Department of Public Health Community Behavioral Health Services; Associate Clinical Professor in Psychiatry, University of California, San Francisco, San Francisco, California Kathleen M. Carroll, Ph.D. Professor of Psychiatry, Division of Substance Abuse, Yale University School of Medi cine, West Haven, Connecticut Crystal A. Caudill, M.P.H. Director, Wedco District Health Department, Cynthiana, Kentucky Harvey L. Causey III, M.D. Medical Director, Morris Village Alcohol and Drug Addiction Treatment Center, South Carolina Department of Mental Health; Clinical Assistant Professor of Psychiatry, Department of Neuropsychiatry, University of South Carolina School of Medicine, Columbia, South Carolina

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Chapter 1. Neurobiology of Addiction

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George F. Koob: Chapter 1. Neurobiology of Addiction, in The American Psychiatric Pu blishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.344000. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Neurobiology of Addiction George F. Koob, Ph.D.

CONCEPTUAL FRAMEWORK, DEFINITIONS, AND ANIMAL MODELS Drug add ction, also known as substance dependence, is a chron c, relapsing disorder characterized by 1) compulsion to seek and take the drug, 2) loss of control in limiting intake, and 3) emergence of a negative emotional state (e.g., dysphoria, anxiety, irr tabil ty) when access to the drug is prevented (defined here as dependence) (Koob and Le Moal 1997). Addiction and substance dependence, as currently defined in DSM-IV-TR (American Psychiatr c Association 2000), will be used interchangeably throughout this chapter and refer to a final stage of a usage process that moves from drug use to addict on. Clinically, the occas onal but limited use of a drug w th the potential for abuse or dependence is distinct from escalated drug use and the emergence of a chronic drug-dependent state. An important goal of current neurobiolog cal research is to understand the neuropharmacolog cal and neuroadaptive mechanisms within specific neurocircuits that mediate the trans tion from occasional, controlled drug use to the loss of behav oral control over drug seeking and drug taking that defines chronic addiction. Addict on has been conceptualized as a chronic, relapsing disorder with roots in both impulsiv ty and compulsivity and w th neurob ological mechanisms that change as an indiv dual moves from one domain to the other. Subjects w th impulse control disorders experience an increasing sense of tension or arousal before comm tting an impulsive act; pleasure, gratif cat on, or relief at the time of comm tting the act; and, finally, regret, self-reproach, or guilt following the act. In contrast, individuals with compulsive disorders experience anxiety and stress before comm tting a compulsive, repetitive behavior and then relief from the stress by performing the compulsive behav or. In addict on, drug-taking behavior progresses from impulsivity to compulsivity in a three-stage cycle: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. As individuals move from an impulsive to a compulsive disorder, the drive for the drug-taking behav or shifts from pos tive to negative reinforcement (Figures 1–1 and 1–2). Impulsivity and compulsivity can coexist in different stages of the addict on cycle. FIGURE 1–1. Diagram showing stages of impulse control disorder and compulsive disorder cycles related to the sources of reinforcement.

In impulse control disorders, an increasing tens on and arousal occurs before the impulsive act, with pleasure, gratificat on, or relief during the act. Following the act there may or may not be regret or guilt. In compulsive disorders, there are recurrent and persistent thoughts (obsessions) that cause marked anxiety and stress followed by repet tive behaviors (compulsions) that are aimed at preventing or reducing distress (American Psychiatr c Association 1994). Positive reinforcement (pleasure/gratif cat on) is more closely associated with impulse control disorders. Negative reinforcement (relief of anxiety or relief of stress) is more closely associated with compulsive disorders. Source. Reprinted from Koob GF: "Allostatic View of Motivat on: Implications for Psychopathology," in Motivational Factors in the Etiology of Drug Abuse (Nebraska Symposium on Motivat on, Volume 50). Lincoln, NE, Univers ty of Nebraska Press, 2004. Used w th permiss on. FIGURE 1–2. Diagram describing the addiction cycle—preoccupation/anticipation, binge/intoxication, and withdrawal/negative affect—from a psychiatric perspective with the different criteria for substance dependence incorporated from DSM.

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Much of the recent progress in understanding the neurob ology of add ction has derived from the study of animal models of add ction that have focused on specific drugs such as opiates, psychostimulants, and alcohol (Shippenberg and Koob 2002). Although no animal model of addiction fully emulates the human condition, animal models do permit investigation of specific elements of the process of drug add ct on. Such elements can be categorized by models of different stages of the add ction cycle. Much of the focus in animal studies has been on the synaptic sites and transductive mechanisms in the nervous system on wh ch drugs with dependence potential act initially to produce their positive reinforcing effects (binge/intoxication stage). But components of new animal models that comprise the negative reinforcing effects of dependence (withdrawal/negative affect stage) and the craving stage (preoccupation/ant cipat on) have been developed and are beginning to be used to explore how the nervous system adapts to drug use (Shippenberg and Koob 2002) (Table 1–1). The neurobiolog cal mechanisms of addiction involved in various stages of the add ction cycle have a specif c focus on certain brain circuits and the molecular/neurochemical changes associated with those circu ts during the transition from drug taking to drug add ct on and how those changes persist in the vulnerability to relapse (Koob and Le Moal 2001). Research was supported by National Institutes of Health grants AA06420 and AA08459 from the National Institute on Alcohol Abuse and Alcoholism, DA04043 and DA04398 from National Institute on Drug Abuse, and DK26741 from the National Institute of Diabetes and Digestive and Kidney Diseases. Research was also supported by the Pearson Center for Alcoholism and Addiction Research at The Scripps Research Institute. The author would like to thank Mike Arends for his assistance with manuscript preparation. This is publication number 18781 from The Scripps Research Institute.

NEUROBIOLOGICAL MECHANISMS OF THE BINGE/INTOXICATION STAGE It has long been hypothesized that a key element of drug add ction is that drugs of abuse activate brain reward systems and that understanding the neurobiological bases for acute drug reward is v tal to understanding how these systems change during the development of add ction (Koob 2004; Koob and Le Moal 1997). Research on the neurobiology of the pos tive reinforcing effects of drugs with addict on potential has focused principally on the origins and terminal areas of the mesocorticolimbic dopamine system. Indeed, there is compelling evidence indicating the importance of this system in psychostimulant reward. However, study of the specific circuitry associated w th drug reward has been broadened to include the many neural inputs and outputs that interact with the basal forebrain. More recently, research on specific components of the basal forebrain that have been dentified as associated with drug reward has focused on both the nucleus accumbens and amygdala (Koob and Le Moal 2001; Koob et al. 1998) (see Figure 1–3). As our understanding about the neural circuits involved in the reinforcing effects of drugs with dependence potential has evolved, so too has our understanding of the role of neurotransmitters/neuromodulators. Five of those systems have been dentified as having a role in the acute reinforcing effects: dopamine, opio d peptides, -aminobutyric ac d (GABA), serotonin, and endocannabinoids (Table 1–2). FIGURE 1–3. Sagittal section through a representative rodent brain illustrating the pathways and receptor systems implicated in the acute reinforcing actions of drugs of abuse.

Cocaine and amphetamines activate the release of dopamine in the nucleus accumbens and amygdala via direct act ons on dopamine terminals. Opioids activate op o d receptors in the ventral tegmental area, nucleus accumbens, and amygdala via direct act ons on interneurons. Opioids facil tate the release of dopamine in the nucleus accumbens via an act on e ther in the ventral tegmental area or the nucleus accumbens, but are also hypothesized to activate elements independent of the dopamine system. Alcohol activates -aminobutyr c ac dA (GABAA) receptors in the ventral tegmental area, nucleus accumbens, and amygdala via either direct actions at the GABAA receptor or through indirect release of GABA. Alcohol is hypothesized to facilitate the release of opioid pept des in the ventral tegmental area, nucleus accumbens, and central nucleus of the amygdala. Alcohol facil tates the release of dopamine in the nucleus accumbens via an action either in the ventral tegmental area or the nucleus accumbens. Nicotine activates nicotinic acetylcholine receptors in the ventral tegmental area, nucleus accumbens, and amygdala, either directly or indirectly, via actions on interneurons. Nicotine may also activate op o d pept de release in the nucleus accumbens or amygdala, independent of the dopamine system. Cannabinoids activate cannabino d type 1 (CB1 ) receptors in the ventral tegmental area, nucleus accumbens, and amygdala via direct actions on interneurons. Cannabinoids facil tate the release of dopamine in the nucleus accumbens via an action either in the ventral tegmental area or the nucleus accumbens, but are also hypothesized to activate elements independent of the dopamine system. Endogenous cannabinoids may interact with postsynapt c elements in the nucleus accumbens involving dopamine and/or opioid pept de systems. The blue arrows represent the interactions within the extended amygdala system hypothesized to have a key role in psychostimulant reinforcement. AC = anterior commissure; AMG = amygdala; ARC = arcuate nucleus; BNST = bed nucleus of the stria terminalis; Cer = cerebellum; C-P = caudate-putamen; DMT = dorsomedial thalamus; FC = frontal cortex; Hippo = hippocampus; IF = inferior colliculus; LC = locus coeruleus; LH = lateral hypothalamus; N Acc = nucleus accumbens; OT = olfactory tract; PAG = periaqueductal gray; RPn = reticular pontine nucleus; SC = super or colliculus; SNr = substantia nigra pars ret culata; VP = ventral pall dum; VTA = ventral tegmental area.

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Source. Reprinted from Koob GF: "The Neurocircuitry of Add ct on: Implications for Treatment." Clinical Neuroscience Research 5:89–101, 2005. Used with permission. The mesolimb c dopamine system is well established as having a cr t cal role in the activating and reinforcing effects of indirect sympathomimetics such as cocaine, methamphetamine, and nicotine. However, although all drugs of abuse acutely activate the mesolimb c dopamine system, particularly in the medial shell reg on of the nucleus accumbens, the role of dopamine becomes less cr t cal w th opioid drugs, alcohol, and

9

-tetrahydrocannabinol (

9

-THC). Here, other neurotransm tter

systems such as op o d peptides, GABA, and endocannabinoids may play key roles e ther in series or independent of activation of the mesolimb c dopamine system. For example, a particularly sens tive site for blockade of the acute reinforcing effects of alcohol w th opioid and GABAergic antagonists appears to be the central nucleus of the amygdala (Koob 2003). Op o d peptide antagonists also block the reinforcing effects of

9

-THC, a key active ingredient in marijuana.

Serotonin receptors at specif c subtypes modulate psychostimulant and alcohol reward. Moreover, endocannabinoid mechanisms have been implicated in psychostimulant, op oid, alcohol, and cannabino d reward. For example, serotonin type 1B (5-HT1B) receptor agonists facilitate cocaine reward (Parsons et al. 1998) and decrease alcohol reward (Tomkins and O'Neill 2000). Cannabinoid type 1 (CB1 ) antagonists block op o d, alcohol, and cannabino d reward (Justinova et al. 2004, 2005). In summary, multiple neurotransmitters are implicated in the acute reinforcing effects of drugs of abuse. Key players in the nucleus accumbens and amygdala are dopamine, opioid peptide, and GABA systems with modulation via serotonin and endocannabinoids.

NEUROBIOLOGICAL MECHANISMS OF THE WITHDRAWAL/NEGATIVE AFFECT STAGE The neural substrates and neuropharmacological mechanisms for the negative motivational effects of drug withdrawal may involve disrupt on of the same neural systems implicated in the positive reinforcing effects of drugs but also involve recruitment of anti-reward systems. Measures of brain reward funct on during acute abstinence from all major drugs w th dependence potential have revealed increases in brain reward thresholds as measured by direct brain-stimulat on reward (Epping-Jordan et al. 1998; Gardner and Vorel 1998; Markou and Koob 1991; Paterson et al. 2000; Schulteis et al. 1994, 1995). These increases in reward thresholds may reflect decreases in the activity of reward neurotransmitter systems in the midbrain and forebrain implicated in the positive reinforcing effects of drugs. Changes at the neurochem cal level that reflect changes in the neurotransmitter system impl cated in acute drug reward are called within-system neuroadaptations to chronic drug exposure. These neuroadaptations include decreases in dopaminerg c and serotonerg c transmiss on in the nucleus accumbens during drug withdrawal as measured by in vivo microdialysis (Parsons and Justice 1993; Weiss et al. 1992), increased sens tiv ty of opioid receptor transduction mechanisms in the nucleus accumbens during opioid w thdrawal (Stinus et al. 1990), decreased GABAerg c and increased N-methyl-D-aspartate (NMDA) glutamatergic transmission during alcohol withdrawal (Dav dson et al. 1995; Morrisett 1994; Roberts et al. 1996; Weiss et al. 1996), and differential regional changes in n cotinic receptor function (Collins et al. 1990; Dani and Heinemann 1996). It is hypothesized that decreases in reward neurotransm tters reflect a w thin-system neuroadaptation and contribute significantly to the negative motivational state associated w th acute drug abstinence. In a within-system neuroadaptation, "the primary cellular response element to the drug would itself adapt to neutralize the drug's effects; persistence of the opposing effects after the drug disappears would produce the withdrawal response" (Koob and Bloom 1988, p. 720). The decreased reward system function may persist in the form of long-term biochemical changes that contribute to the clinical syndrome of protracted abstinence and vulnerabil ty to relapse. The emot onal dysregulation associated w th the w thdrawal/negative affect stage may also involve a between system neuroadaptation, in which neurochem cal systems other than those involved in positive rewarding effects of drugs of abuse are recru ted or dysregulated by chronic activation of the reward system (Koob and Bloom 1988). In addition, brain neurochem cal systems involved in stress modulation may be engaged w thin the neurocircu try of the brain stress systems in an attempt to overcome the chronic presence of the perturbing drug and to restore normal funct on desp te the drug's presence. Both the hypothalamic-pituitary-adrenal axis and the brain stress system mediated by corticotropin-releasing factor (CRF) are dysregulated by chronic administration of all major drugs with dependence or abuse potential, resulting in the common response of elevated adrenocort cotrop c hormone, corticosterone, and amygdala CRF during acute withdrawal (Delfs et al. 2000; Koob et al. 1994; Merlo-Pich et al. 1995; Olive et al. 2002; Rasmussen et al. 2000; Rivier et al. 1984). Acute withdrawal from drugs may also increase the release of norepinephrine in the bed nucleus of the stria terminalis (BNST) and decrease levels of neuropept de Y (NPY) in the central and medial nuclei of the amygdala (Roy and Pandey 2002). During the development of dependence, these results suggest not only a change in the function of neurotransmitters associated with the acute reinforcing effects of drugs (dopamine, opioid peptides, serotonin, GABA, and endocannabino ds) but also recru tment of the brain stress system (CRF and norepinephrine) and dysregulat on of the NPY brain anti-stress system (Koob and Le Moal 2001) (Table 1–3). Moreover, activat on of the brain stress systems may not only contribute to the negative motivational state associated w th acute abstinence but may also contribute to the vulnerability to stressors observed during protracted abstinence in humans. The neuroanatomical ent ty termed the extended amygdala (Heimer and Alhe d 1991) may represent a common anatom cal substrate for acute drug reward and a common neuroanatom cal substrate for the negative effects on reward function produced by stress that help drive compulsive drug administrat on. The extended amygdala is composed of the BNST, the central nucleus of the amygdala, and a transition zone in the medial subreg on of the nucleus accumbens (shell of the nucleus accumbens). Each of these regions has cytoarchitectural and circuitry similarities (Heimer and Alheid 1991). The extended amygdala receives numerous afferents from limbic structures such as the basolateral amygdala and hippocampus and sends efferents to the medial part of the ventral pallidum and a large project on to the lateral hypothalamus. Thus, the specific brain areas that link class cal limb c (emot onal) structures with the extrapyram dal motor system are further defined (Alhe d et al. 1995). The concept of an anti-reward system has been recently formulated to accommodate the signif cant changes in brain emot onal systems associated with the development of dependence (Koob and Le Moal 2005). The anti-reward concept is based on the hypothesis that there are brain systems in place to limit reward (Koob and Bloom 1988), an opponent-process concept that forms a general feature of biological systems. The concept of an anti-reward system is derived from the hypothesis that between-system neuroadaptations result from activat on of the reward system at the neurocircu try level. A between-system neuroadaptat on is a circu try change in which circuit B (anti-reward circuit) is activated by circuit A (reward circuit). This concept has ts origins in the theoretical pharmacology that predates opponent-process theory (Martin 1967). Thus, the activation of brain stress systems such as CRF, norepinephrine, and dynorphin w th concom tant dysregulat on of the NPY system may represent the recruitment of an anti-reward system in the extended amygdala that produces the motivational components of drug withdrawal and provides a baseline hedon c shift that facilitates craving mechanisms (Koob and Le Moal 2005).

NEUROBIOLOGICAL MECHANISMS OF THE PREOCCUPATION/ANTICIPATION STAGE The preoccupation/ant cipat on stage of the add ct on cycle has long been hypothesized to be a key element of relapse in humans, and t contributes to the definit on of addict on as a chron c, relapsing disorder. Although often linked to the construct of craving, craving per se has been difficult to measure in human clinical studies (Tiffany et al. 2000) and often does not correlate with relapse. Nevertheless, the stage of the add ct on cycle when the individual reinstates drug-seeking behavior after abstinence remains a challenge for researchers who focus on neurobiological mechanisms and med cat on development for treatment. Animal models of craving can be divided into two domains: craving type 1 involves drug seeking induced by stimuli paired w th drug taking; craving type 2 features drug seeking induced by an acute stressor or a state of stress (Table 1–4). Craving type 1 animal models emphasize the use of drug-primed reinstatement and cue-induced reinstatement. Craving type 2 animal models are characterized by stress-induced reinstatement in animals that have acquired drug self-administrat on and then have been subjected to extinction of responding for the drug. Most evidence from animal studies suggests that drug-induced reinstatement is localized to the medial prefrontal cortex/nucleus accumbens/ventral pall dum circuit mediated by the neurotransmitter glutamate (McFarland and Kalivas 2001). In contrast, neuropharmacological and neurobiological studies using animal models for cue-induced reinstatement include the basolateral amygdala as a crit cal substrate, with a possible feed-forward mechanism through the prefrontal cortex system involved in drug-induced reinstatement (Ever tt and Wolf 2002; Weiss et al. 2001). Neurotransmitter systems involved in drug-induced reinstatement are characterized by a glutamatergic project on from the frontal cortex to the nucleus accumbens that is modulated by dopamine activ ty in the frontal cortex. Cue-induced reinstatement involves dopamine modulation in the basolateral amygdala and a glutamatergic project on to the nucleus accumbens from both the basolateral amygdala and ventral sub culum (Everitt and Wolf 2002; Vorel et al. 2001). In contrast, stress-induced reinstatement of drug-related responding in animal

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models appears to depend on the activat on of both CRF and norepinephrine in elements of the extended amygdala (central nucleus of the amygdala and BNST) (Shaham et al. 2003; Shalev et al. 2002). Protracted abstinence, largely described in alcohol dependence models, appears to involve overactive glutamaterg c and CRF systems (De Witte et al. 2005; Valdez et al. 2002).

OVERALL NEUROCIRCUITRY OF ADDICTION In summary, three neurob olog cal circuits have been dentified that have heuristic value for the study of the neurobiological changes associated with the development and persistence of drug dependence (Figure 1–4). The acute reinforcing effects of drugs of abuse that make up the binge/intox cat on stage most likely involve actions with an emphasis on the extended amygdala reward system and inputs from the ventral tegmental area and arcuate nucleus of the hypothalamus. In contrast, the symptoms of acute w thdrawal that are important in add ct on, such as negative affect and increased anxiety associated with the w thdrawal/negative affect stage, most likely include decreases in function of the extended amygdala reward system but also a recruitment of brain stress neurocircuitry. The craving stage, or preoccupat on/anticipation stage, features key afferent projections to the extended amygdala and nucleus accumbens, specifically the prefrontal cortex (for drug-induced reinstatement) and the basolateral amygdala (for cue-induced reinstatement). Compulsive drug-seeking behavior is thought to be driven by ventral striatal–ventral pallidal–thalamic-cortical loops. FIGURE 1–4. Key common neurocircuitry elements in drug-seeking behavior of addiction.

Three major circu ts that underlie addict on can be distilled from the literature. A drug reinforcement circuit (reward and stress) is composed of the extended amygdala, including the central nucleus of the amygdala, the bed nucleus of the stria terminalis, and the transition zone in the shell of the nucleus accumbens. Multiple modulator neurotransmitters are hypothesized, including dopamine and opioid peptides for reward; and cort cotropin-releasing factor and norepinephrine for stress. The extended amygdala is hypothesized to mediate integration of rewarding stimuli or stimuli with positive incentive salience and aversive stimuli or stimuli with negative aversive salience. During acute intox cat on, valence is weighted on processing rewarding stimuli, and, during the development of dependence, aversive stimuli come to dominate function. A drug- and cue-induced reinstatement (craving) neurocircuit is composed of the prefrontal (anter or cingulate, prelimb c, orb tofrontal) cortex and basolateral amygdala, w th a primary role hypothesized for the basolateral amygdala in cue-induced craving and a primary role for the medial prefrontal cortex in drug-induced craving, based on animal studies. Human imaging studies have shown an important role for the orbitofrontal cortex in craving (see text). A drug-seeking circu t (compulsive) circuit is composed of the nucleus accumbens, ventral pallidum, thalamus, and orbitofrontal cortex. The nucleus accumbens has long been hypothesized to have a role in translating motivation to action and forms an interface between the reward funct ons of the extended amygdala and the motor functions of the ventral striatal–ventral pallidal–thalam c-cort cal loops. The striatal-pallidal-thalamic loops reciprocally move from prefrontal cortex to orb tofrontal cortex to motor cortex—ultimately leading to drug-seeking behavior. Note that, for the sake of simplic ty, other structures are not included, such as the hippocampus (which presumably mediates context-specific learning, including that associated with drug act ons). Also note that dopamine and norepinephrine both have w despread innervat on of cort cal reg ons and may modulate function relevant to drug add ction in those structures. CRF = cort cotropin-releasing factor; DA = dopamine;

-END = -endorphin; ENK = emkephalin; NE = norepinephrine; VTA = ventral tegmental area.

Source. Reprinted from Koob GF, Le Moal M: Neurobiology of Addiction. London, Academic Press, 2005. Used with permiss on.

MOLECULAR AND CELLULAR MECHANISMS IN THE BRAIN CIRCUITS ASSOCIATED WITH ADDICTION Determining which genetic and environmental factors produce the vulnerability to add ction has become one of the most exciting pursuits in the study of the neurobiology of addiction. One hypothesis is that molecular changes at the gene or gene transcript on level will provide the key to understanding such vulnerabil ty. The search at the molecular level has led to an examinat on of how repeated perturbation of intracellular signal transduction pathways leads to changes in nuclear function and altered rates of transcript on of particular target genes. Altered expression of such genes would lead to altered activ ty of the neurons where such changes occur and, ultimately, to changes in the function of neural circuits in which those neurons operate. Two transcription factors in particular have been impl cated in the plast city associated with add ction: cyclic adenosine monophosphate (cAMP) response elementbinding protein (CREB), and

FosB. CREB regulates the transcript on of genes that contain a cAMP response element site within the regulatory reg ons and can be

found ubiqu tously in genes expressed in the central nervous system such as those that encode neuropeptides, synthetic enzymes for neurotransmitters, signaling proteins, and other transcript on factors. CREB can be phosphorylated by protein kinase A and by protein kinases regulated by growth factors, putting it at a point of convergence for several intracellular messenger pathways that can regulate the expression of genes. Much work in the add ction field has shown that activation of CREB in the nucleus accumbens is a consequence of chron c exposure to opiates, cocaine, and alcohol, and deactivation of CREB in the central nucleus of the amygdala w th alcohol and nicotine. The activat on of CREB is linked to the activat on of the dysphoria-inducing op o d receptor that binds the opioid peptide dynorphin. Up-regulat on of the cAMP pathway and CREB in the nucleus accumbens is thus believed to represent a mechanism of motivat onal tolerance and dependence. More specifically, these molecular adaptat ons may decrease an individual's sens tiv ty to the rewarding effects of subsequent drug exposures (tolerance) and impair the reward pathway (dependence) so that after removal of the drug the individual is left in an amotivational, dysphoric, or depressed-like state (Nestler 2004). In contrast, decreased CREB phosphorylat on has been observed in the central nucleus of the amygdala during alcohol w thdrawal and has been linked to decreased NPY function and, consequently, the increased anxiety-like responses associated w th acute alcohol withdrawal (Pandey 2004). Increased CREB in the nucleus

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accumbens and decreased CREB in the central nucleus of the amygdala are not necessarily mutually exclusive. Furthermore, these effects point to transduction mechanisms that could produce neurochemical changes in the neurocircu ts outlined above as being important for breaks w th reward homeostasis in addict on. The molecular changes associated w th long-term changes in brain function as a result of chron c exposure to drugs of abuse have also been linked to changes in transcript on factors, which can change gene expression and produce long-term changes in protein expression and, as a result, neuronal function. Although acute administration of drugs of abuse can cause a rap d (hours) activation of members of the Fos family, such as c-fos, FosB, Fra-1, and Fra-2, in the nucleus accumbens, other transcript on factors, isoforms of activated

FosB, accumulate over longer per ods of time (days) with repeated drug administration (Nestler 2004). Animals w th

FosB have exaggerated sensitivity to the rewarding effects of drugs of abuse. Therefore,

and maintain a state of addict on. How changes in

FosB may be a sustained molecular trigger that helps to initiate

FosB that can last for days can also translate into vulnerability to relapse remains a challenge for future work

(Nestler 2004). Genetic and molecular-genetic animal models have prov ded a molecular basis to support the neuropharmacolog cal substrates dentified in neurocircuitry studies. Alcohol-preferring rats have been bred that show particularly high levels of voluntary consumpt on of alcohol, increased anxiety-like responses, and numerous neuropharmacological phenotypes, such as decreased dopaminergic activity and decreased NPY activity (McBr de et al. 1990; Murphy et al. 2002). In an alcoholpreferring and -nonpreferring cross, a quantitative trait locus was dentified on chromosome 4, a reg on on which the gene for NPY has been mapped. In the inbred preferring- and nonpreferring-quant tative trait loci analyses, loci on chromosomes 3, 4, and 8 have been dentified that correspond to loci near the genes for the dopamine D2 and serotonin 5-HT1B receptors (Carr et al. 1998). Advances in molecular biology have given researchers the ability to systemat cally inactivate genes that control the express on of proteins that make up receptors or neurotransmitters/neuromodulators in the central nervous system using the gene knockout approach. "Knockout" m ce have a gene inactivated by homologous recombinat on. A knockout mouse deficient in both alleles of a gene is homozygous for the deletion and is termed a null mutation (–/–). A mouse that is deficient in only one of the two alleles for the gene is termed a heterozygote (+/–). Transgen c knockin m ce have an extra gene introduced into their germline. An addit onal copy of a normal gene is inserted into the genome of the mouse to examine the overexpress on effects of the product of that gene. Alternatively, a new gene, not normally found in the mouse, can be added, such as a gene associated w th a specif c pathology in humans. Wild-type controls are animals bred through the same breeding strategies involving mice that receive the transgene injected into the fertilized egg (transgenics) or a targeted gene construct injected into the genome via embryonic stem cells (knockout) but lacking the mutation on either allele of the gene in question. Although such an approach does not guarantee that these genes are the vulnerable ones in the human population, the genes do prov de viable candidates for exploring the genet c basis of endophenotypes associated with add ct on (Koob et al. 2001). Notable positive results with gene knockout studies in mice have focused on knockout of the

opioid receptor, wh ch eliminates opioid, nicotine, and cannabinoid

reward and alcohol drinking in m ce (Contet et al. 2004). Op o d (morphine) reinforcement as measured by cond t oned place preference or self-administrat on is absent in

knockout mice, and there is no development of somat c signs of dependence to morphine in these mice. Indeed, to date, all morphine effects tested,

including analgesia, hyperlocomotion, respiratory depress on, and inhib tion of gastrointestinal transit, are abolished in

knockout m ce (Gaveriaux-Ruff and Kieffer

2002). Selective delet on of the genes for express on of different dopamine receptor subtypes and the dopamine transporter has revealed significant effects to challenges with psychomotor stimulants. D1 receptor knockout m ce show no response to D 1 agonists or antagonists and show a blunted response to the locomotor-activating effects of cocaine and amphetamine. When compared with wild-type m ce, D 1 knockout mice are also impaired in their acquis tion of intravenous cocaine self-administration (Caine et al. 2007). D2 knockout m ce have severe motor def cits and blunted psychostimulant responses to psychostimulants and opiates, but the effects on psychostimulant reward are less consistent. Dopamine transporter knockout mice are dramatically hyperactive but also show a blunted response to psychostimulants. Although developmental factors must be taken into account for the compensatory effect of deleting any one or a combination of genes, t is clear that D1 and D2 receptors and the dopamine transporter play important roles in the actions of psychomotor stimulants (Caine et al. 2002, 2007).

BRAIN IMAGING CIRCUITS INVOLVED IN HUMAN ADDICTION Brain imaging studies using magnet c resonance imaging techn ques or positron emission tomography w th ligands for measuring oxygen utilizat on or glucose metabolism are providing dramatic insights into the neurocircu try changes in the human brain associated w th the development of, maintenance of, and vulnerability to addiction. Overall, these imaging results show a striking resemblance to the neurocircu try identified in studies in animals. During acute intox cation with alcohol, n cotine, or cocaine, there is an activat on of the orbitofrontal cortex, prefrontal cortex, anter or cingulate, extended amygdala, and ventral striatum. This activation is often accompanied by an increase in availability of the neurotransm tter dopamine. During acute and chronic withdrawal there is a reversal of these changes accompanied by decreases in metabol c activ ty, particularly in the orbitofrontal cortex, prefrontal cortex, and anter or cingulate, and decreases in basal dopamine activity as measured by decreased D2 receptors in the ventral striatum and prefrontal cortex. Cue-induced reinstatement appears to involve a reactivation of these circu ts, much like that of acute intox cat on (Bonson et al. 2002; Bre ter et al. 2001; Childress et al. 1999). Craving or cues associated w th cocaine and nicotine produce activat on of the prefrontal cortex and anterior cingulate gyrus (Lee et al. 2005; Risinger et al. 2005). Imaging studies also show evidence that cues associated w th cocaine craving increase dopamine release in the striatum as well as op o d peptides in the anterior cingulate and frontal cortex (Gorel ck et al. 2005; Volkow et al. 2006; Wong et al. 2006). Craving in alcoholic individuals appears to be correlated with higher opio d peptide activity in the striatum but lower dopaminerg c activ ty (Heinz et al. 2004, 2005). Thus, imaging studies to date reveal baseline decreases in orbitofrontal function and dopamine function during dependence, but a reactivat on of the dopamine and reward system function during acute craving episodes consistent w th the early formulat on of different neural substrates for craving type 1 and type 2 (see above).

CONCLUSION Much progress in neurob ology has provided a useful neurocircu try framework w th which to dentify the neurobiolog cal and neuroadaptive mechanisms involved in the development of drug add ction. The brain reward system implicated in the development of addict on is composed of key elements of the basal forebrain, w th the nucleus accumbens and central nucleus of the amygdala playing part cularly important roles. Neuropharmacolog cal studies in animal models of add ct on have provided evidence that ind cates the activat on of specif c neurochemical mechanisms in specific brain reward neurochemical systems in the basal forebrain (dopamine, opioid peptides, GABA, serotonin, and endocannabinoids) during the binge/intoxication stage. During the withdrawal/negative affect stage, there is a dysregulat on of the same brain reward neurochem cal systems in the basal forebrain. There is also recruitment of brain stress systems (CRF and norepinephrine) and dysregulat on of brain anti-stress systems (NPY) that contribute to the negative motivational state associated w th drug abstinence. During the preoccupation/ant cipation stage, neurob ological circuits that engage the frontal cortex glutamatergic project ons to the nucleus accumbens are crit cal for drug-induced reinstatement, whereas basolateral amygdala and ventral subiculum glutamatergic project ons to the nucleus accumbens are involved in cue-induced reinstatement. Stress-induced reinstatement appears to be mediated by changes in the anti-reward systems of the extended amygdala. The changes in craving and anti-reward (stress) systems are hypothesized to remain outs de of a homeostat c state. As such, these changes convey the vulnerabil ty for development of dependence and relapse in add ction. To date, genetic studies in animals suggest roles for the genes encoding the neurochemical elements involved in the brain reward (dopamine, op o d peptide) and stress (NPY) systems in the vulnerability to addiction. Molecular studies have dentified transduction and transcription factors that may mediate the dependence-induced reward dysregulation (CREB) and chron c-vulnerability changes ( FosB) in neurocircuitry associated with the development and maintenance of addiction. Human imaging studies reveal similar neurocircu ts involved in acute intoxication, chronic drug dependence, and vulnerabil ty to relapse. Although no exact imaging results necessarily predict addiction, two salient changes in established and unrecovered substance-dependent individuals that cut across different drugs are decreases in orb tofrontal/prefrontal cortex funct on and in brain D2 receptors. No molecular markers are suff ciently specific to predict vulnerabil ty to addict on, but changes in certain intermediate early genes with chron c drug exposure in animal models show promise of long-term changes in specific brain regions that may be common to all drugs of abuse. The continually evolving knowledge base of biolog cal and neurob ological aspects of substance use disorders provides a heurist c framework to better develop the diagnoses, prevention, and treatment of substance abuse disorders.

KEY POINTS The brain reward system impl cated in the development of addict on comprises key elements of the basal forebrain such as the ventral striatum, the extended

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amygdala, and ts connections. Neuropharmacolog cal studies in animal models of addict on have provided evidence to indicate that there are decreases of specif c neurochemical mechanisms in specif c brain reward neurochemical systems in the ventral striatum and amygdala (dopamine, op o d peptides, -aminobutyric ac d, and endocannabinoids; light side of addiction). Recruitment of brain stress systems (cort cotropin-releasing factor and norepinephrine; dark side of addiction) and dysregulation of brain anti-stress systems (neuropept de Y) provide the negative motivat onal state associated with drug abstinence. Changes in the reward and stress systems are hypothesized to maintain hedonic stabil ty in an allostatic state (altered reward set point), as opposed to a homeostatic state and, as such, convey the vulnerability for the development of dependence and relapse in add ction. Similar neurochem cal systems have been implicated in animal models of relapse, with dopamine and opioid peptide systems (and glutamate) being impl cated in drug- and cue-induced relapse, possibly more in prefrontal cortical and basolateral amygdala projections to the ventral striatum and extended amygdala than in the reward system tself. The brain stress systems in the extended amygdala are directly implicated in stress-induced relapse. Genet c studies to date in animals using knockouts of specif c genes suggest roles for the genes encoding the neurochemical elements involved in the brain reward (dopamine, op o d pept de) and stress (neuropept de Y) systems in the vulnerability to add ction.

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SUGGESTED READING

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Koob GF: Allostatic view of motivation: impl cat ons for psychopathology, in Motivat onal Factors in the Et ology of Drug Abuse (Nebraska Symposium on Motivat on, Vol 50). Ed ted by Bevins RA, Bardo MT. Lincoln, Univers ty of Nebraska Press, 2004, pp 1–18 Koob GF, Le Moal M: Drug add ction, dysregulation of reward, and allostasis. Neuropsychopharmacology 24:97–129, 2001 Koob GF, Le Moal M: Plasticity of reward neurocircuitry and the "dark s de" of drug addict on. Nat Neurosci 8:1442–1444, 2005 Koob GF, Le Moal M: Neurobiology of Addiction. London, Academic Press, 2006 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 2. Genetics of Addiction

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Joel Gelernter, Henry R. Kranzler: Chapter 2. Genetics of Addiction, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.344402. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Genetics of Addiction Joel Gelernter, M.D. Henry R. Kranzler, M.D.

GENETICS OF ADDICTION: INTRODUCTION Like other important psychiatric traits, substance dependence (SD) is genetically influenced, and this genetic influence is complex. This means that the genetic influence plays out in something other than a Mendelian mode (i.e., dominant, recessive, or X-linked), and, practically speaking, this means there are many genes involved—none of which ever fully determines that a person will be affected. Moreover, as with other complex traits, SD risk is influenced by both genetic and environmental factors. But in the case of SD risk there is a special twist: there is a necessary component of gene-by-environment interaction. A person cannot become substance dependent without exposure to the substance, regardless of genetic constitution. This places a trait like cocaine dependence (you cannot be cocaine dependent if you do not have access to cocaine) in contrast to a trait like schizophrenia, in which, as far as we know, special environmental exposure is not required for the condition to develop. Although this is of obvious inherent interest to geneticists, we also need to ask, what are the clinical implications of the genetic contribution to SD? This is important for several reasons. First, it can help us to appreciate that, if different individuals experience different levels of risk, the nature of some part of this risk is purely biological. Second, once specific genetic factors—alleles at particular genetic loci, or genes—are identified, our understanding of the biology of the addiction process is increased substantially. Knowledge of new mechanisms can reasonably be expected to lead to the identification of novel pharmacological targets and new treatments. Finally, as we learn more about the genetic factors influencing risk, course, and biological treatment of SD, we become better able to elucidate the environmental contributors to risk, as well as the nature of the interactive effects of genes and environment in determining risk. In this chapter, we review the progress made in identifying genes and alleles that influence risk for SD. Because genetic epidemiological studies have provided clear evidence of the genetic influence on SD, we first briefly discuss the evidence from such studies, examining the genetic contribution to major forms of SD. We also discuss results from genetic linkage analyses in which the entire genome was searched in order to identify regions of chromosomes that contain susceptibility genes. We then explore some of the evidence supporting the relationship of specific candidate genes to phenotype. In addition, we review current methodological advances that carry the prospect of accelerating the already rapid pace of gene identification in the next few years. Recent years have already seen remarkable developments in our understanding of the genetic influence on risk of several kinds of SD. A series of consistent and replicated findings have emerged that are already providing new insight into the biological mechanisms of these disorders. This work was supported in part by National Institute on Drug Abuse grants R01 DA12849, R01 DA12690, and K24 DA15105; National Institute on Alcohol Abuse and Alcoholism grants R01 AA11330 and K24 AA13736; and funds from the U.S. Department of Veterans Affairs (the VA Medical Research Program, and the VA Connecticut-Massachusetts Mental Illness Research, Education and Clinical Center).

IMPORTANCE OF GENES FOR DRUG DEPENDENCE RISK Four types of SD are among the greatest public health problems in the United States: alcohol

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dependence (AD); cocaine dependence (CD); opioid dependence (OD); and nicotine, or tobacco, dependence (ND). All of these disorders cut across geography, race, ethnicity, and socioeconomic status and adversely affect the individual and those around him or her, as well as society at large. These disorders are of varying importance internationally; since alcohol and tobacco are the most consistently available substances, AD and ND are the most consistent problems worldwide. Family studies may show the range of related phenotypes and may indicate that disorders are familial, but they cannot demonstrate the heritability of a disorder per se. Support for the importance of genetic factors in risk for a disorder usually comes from twin and adoption studies.

Heritability of Alcohol Dependence Familial, and specifically genetic, factors are important for the development of AD, as established by twin, family, and adoption studies. The largest twin studies have yielded heritability estimates in the range of 50%–60%, indicating that half or more of the risk for AD is genetic (e.g., Kendler et al. 1992, 1997; Prescott and Kendler 1999). Kendler et al. (1997) considered the intersection between the Swedish Twin Registry, which logged almost all twins born in Sweden from 1902 to 1949 (about 9,000 male pairs), and temperance board registrations in that country from 1929 to 1974 (about 2,500 twin pairs). Subjects came to the attention of temperance boards mostly through physicians and law enforcement agencies because of alcoholism or crimes related to alcohol consumption. Temperance board registration served as a proxy measure for the diagnosis of AD. Because multiple cohorts of twins were assessed in this study, it was possible to consider not only the heritability of AD per se but also the stability of the heritability over time in a sample drawn from the general population. These authors found that, although the prevalence of AD was similar overall in monozygotic (MZ) and dizygotic (DZ) twins, the concordance rate was significantly higher among the former. Moreover, in this sample, heritability was stable over time, suggesting that the environmental contributions to the risk for AD were consistent as well (in magnitude, if not in their exact nature) and that major social and historical changes did not affect environmentally determined AD risk. Thus, in this study, the diagnostic constructs used for AD, for which genetic liability can be estimated, appeared to be valid and meaningful in terms of consequences and outcomes for individuals.

Heritability of Drug Dependence Tsuang et al. (1996) analyzed data from the Vietnam Era Twin Registry, which includes more than 3,000 male twin pairs. In the analysis, abuse of a particular substance was defined as at least weekly use of the drug in question. This study yielded detailed and comprehensive information regarding the heritability of abuse of a variety of substances. Significant pairwise concordance rates showed a familial basis for all of the drugs considered. A significant pairwise difference in concordance rates between MZ and DZ twins was seen for abuse of or dependence on marijuana, stimulants, cocaine, and all drugs combined. For OD, the additive genetic heritability was 0.43. Despite the large number of twin pairs, there were relatively few with OD; MZ concordance for this disorder was 13.3% and DZ concordance 2.9% (based on about 30 pairs of each type of twin). For stimulant abuse, the estimated heritability was 0.44, with MZ concordance being 14.1% (21/149) and DZ concordance 5.3% (6/113). A significant difference among proportions was evident. Using the same twin registry, Tsuang et al. (1998) also examined genetic risk for the co-occurrence of different forms of substance abuse. They determined that genetic factors exist that are both specific to certain individual drugs of abuse, including stimulants, and general to multiple forms of abuse or dependence. Kendler and Prescott (1998) published twin study data showing unexpectedly high heritability for cocaine use disorders. In a sample of female twins, heritabilities for cocaine abuse and dependence were estimated at 0.79 and 0.65, respectively. A similar estimate for CD was obtained in a sample of male twins, for whom the heritability was 0.79 (Kendler et al. 2000a). The twin samples used in these studies were large. However, because the samples were drawn from the general population, in which the prevalence of the disorders is low, the number of twin pairs from which heritabilities were estimated was considerably smaller. Nonetheless, to date, these findings provide the best and most specific

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evidence of heritability and are the most specific in addressing the genetic liability for cocaine abuse and dependence. Many behaviors related to ND have been shown to be heritable. For example, research based on the Vietnam Era Twin Registry estimated that the heritability of ND was >60% (True et al. 1999). The heritability of AD was estimated as 0.55 in the same sample, with the genetic correlation between ND and AD shown to be 0.68. Madden et al. (2000) also found the genetic risk for these disorders to be correlated. Heritability of regular tobacco use was estimated to be >60%, based on comparison of a large sample of Swedish twin pairs who were reared either together or apart (Kendler et al. 2000b). For this investigation, the phenotype was defined by the subject's response that he or she smoked or used snuff regularly. In a large Finnish twin study, the heritability for the age at which smoking was initiated was 0.59 for males and 0.36 for females, for the amount smoked it was 0.54 in males and 0.61 in females, and for smoking cessation it was 0.58 in males and 0.50 in females (Broms et al. 2006). A meta-analysis of twin studies for phenotypes related to ND showed that smoking initiation heritability could be estimated at 0.37 for males and 0.55 for females, while smoking persistence heritability was estimated to be 0.59 for males and 0.46 for females (Li et al. 2004).

Summary Alcohol and drug dependence are both familial and genetically influenced. A suitable model for these disorders is one in which there are both general and specific risk factors—that is, some genetic loci act generally to influence risk for dependence on any substance, and others appear to influence risk for specific kinds of SD. Establishing the genetic bases for these disorders through twin and adoption studies provides a clear rationale for efforts to identify the specific genes that underlie risk for their development.

GENOMEWIDE LINKAGE AND ASSOCIATION STUDIES Because we do not fully understand the biology of SD, the genes that are involved are not known a priori. There are now two general methods that can be used to identify risk genes without a priori knowledge of risk mechanisms. These methods both query the entire genome and use statistical (rather than biological) methods of inference. Genomewide linkage studies are the traditional approach to identifying risk loci. These are family-based studies that require the investigation of markers that map throughout the entire genome, allowing the identification of chromosomal regions where markers are coinherited with the phenotype of interest. Genomewide linkage scans have been completed for AD, CD, OD, ND, and for related traits. Genomewide association studies feature a newer methodology in which very closely spaced markers—at least 100,000 and sometimes more than 1,000,000—are studied in an effort to discover those that vary in frequency in cases compared to controls. The goal of this type of study is to genotype enough markers such that there is at least one marker within linkage disequilibrium—distance of any point in the genome. There has been one genomewide association study addressing a specific SD diagnosis, ND, with individual genotyping of subjects. Successful genomewide linkage studies give the chromosomal locations of risk loci but generally do not identify specific genes. In contrast, successful genomewide association studies can implicate specific genes and alleles.

Linkage Studies Studies of alcohol dependence Genome scan linkage mapping projects have identified promising chromosomal locations for AD susceptibility loci, which in some cases have led to discovery of disease-influencing loci. Linkage studies of AD by investigators in the Collaborative Studies on Genetics of Alcoholism (COGA) (Foroud et al. 2000; Reich et al. 1998) and in the intramural program of the National Institute on Alcohol Abuse and Alcoholism (Long et al. 1998) have yielded promising logarithm of odds scores (lod scores; a measure of the likelihood that loci mapping to the region are linked to the disorder under study) for several

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chromosomal locations influencing risk of AD. Both groups reported that loci influencing risk for AD map close to an alcohol dehydrogenase (ADH) gene cluster on the long arm of chromosome 4. Several other linkage peaks, even ones that did not meet standard criteria for genomewide significance, have led to the identification of likely disease-influencing loci for AD. Analyses of the COGA data set using the transmission disequilibrium test and related family-based methods have revealed several additional areas of interest (Camp and Bansal 1999; Page et al. 1999; Nielsen and Zaykin 1999; Sun et al. 1999). Wilhelmsen et al. (2003) reported a genomewide linkage study for a low level of response to alcohol, which, like a family history of AD, has been identified as a risk factor for the subsequent development of AD (Schuckit et al. 2006). Although this study considered only 139 sibling pairs, several suggestive linkages were identified. Ehlers et al. (2004) conducted a linkage analysis in a sample of 243 Mission Indians in the southwest United States. Although there were no lod scores suggestive of linkage for the diagnosis of AD, several lod scores in excess of 2.0 (i.e., suggestive of linkage) were identified for the phenotypes of severity of alcohol consumption (chromosomes 4 and 12) and for alcohol withdrawal (chromosomes 6, 15, and 16). A recent large study focused on a set of 474 small families recruited in Ireland (Prescott et al. 2006) and reported strongest results (up to a multipoint lod score of 4.59) on chromosome 4.

Studies of drug dependence There have been numerous genomewide linkage scans for ND and related traits (e.g., Beirut et al. 2004; Gelernter et al. 2004; Li et al. 2006; Straub et al. 1999), one for CD (Gelernter et al. 2005), and two for OD (Gelernter et al. 2006a; Glatt et al. 2006). Uhl (2004) noted convergence among many of these and other linkage studies that considered substance dependence traits on a set of chromosomal regions of interest.

Studies of nicotine dependence and related traits In their 2004 review, Li and colleagues noted that putative linkages in numerous genomewide linkage scans for cigarette smoking and related phenotypes had been identified on at least 12 chromosomes. Since then, additional linkage studies have been reported (Bierut et al. 2004; Ehlers and Wilhelmsen 2006; Gelernter et al. 2004; Li et al. 2006; Swan et al. 2006; Vink et al. 2004; Wang et al. 2004). Many studies have used patient samples recruited for an index trait other than ND. We reported genomewide significant linkage of score on the Fagerström Test for Nicotine Dependence, which measures the severity of tobacco dependence, to chromosome 5 markers in African American subjects (Gelernter et al. 2007).

Study of cocaine dependence Gelernter et al. (2005) conducted a genomewide linkage scan in a sample of small nuclear families ascertained through two siblings affected with CD. The sample included 528 full- and 155 half-sibling pairs, of whom 45.5% were European American and 54.5% were African American. The phenotypes of CD diagnosis, cocaine-induced paranoia, and six cocaine-related subtypes that were derived using cluster analytical methods were examined. For the diagnosis of CD, the authors found evidence suggestive of linkage on chromosome 10 in the full sample, and at different locations on chromosome 3 in the European American families. The cluster-derived subtypes yielded the strongest results, including a lod score of 4.66 on chromosome 12 (in European Americans only) for membership in the cluster characterized as "heavy use–cocaine predominant" and a lod score of 3.35 for membership in the cluster characterized as "moderate cocaine and opioid abuse" on chromosome 18. A genomewide significant lod score of 3.65 on chromosome 9 was obtained for African American families for the trait of cocaineinduced paranoia, which is reported by a substantial proportion of heavy users of cocaine.

Studies of opioid dependence Using a sample overlapping with the one studied in the CD linkage study, Gelernter et al. (2006a) conducted a genomewide linkage scan in a sample of small nuclear families (393 families, including 250

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full-sibling pairs and 46 half-sibling pairs) ascertained through two siblings affected with OD. We examined linkage of the DSM-IV diagnosis of OD, and, analogous to the CD study, the two clusterdefined phenotypes represented by at least 250 families: a "heavy opioid users" cluster and a "nonopioid users" cluster. Further exploratory analyses were completed for three other cluster-defined phenotypes. As with the CD linkage study, the strongest statistical results were obtained for the cluster-defined traits: for the heavy opioid users we observed a lod score of 3.06, among European American and African American subjects combined, on chromosome 17 (empirical pointwise P = 0.0002); and for the nonopioid users, we obtained a lod score of 3.46 (empirical pointwise P = 0.00002) elsewhere on chromosome 17, among European American subjects only. Glatt et al. (2006) reported the initial results from a genomewide linkage scan of heroin dependence in a sample of Han Chinese subjects from Yunnan Province (which is near the "Golden Triangle," a region known for opium poppy production in the past century). This study included information from 194 independent affected sibling pairs (ASPs). The result from this study that showed greatest statistical significance for possible linkage was a region on chromosome 17q (P = 0.009, uncorrected); this was not the same region of chromosome 17 as that identified as linked by Gelernter et al. (2006a).

Association Studies Studies using pooling strategies exclusively Deoxyribonucleic acid (DNA) pooling provides a relatively economical way to complete a genomewide association analysis, but with serious compromises made that affect accuracy, the ability to identify specific genotype/phenotype correlations, and haplotype reconstruction. This approach has been used several times to address SD phenotypes (Johnson et al. 2006; Liu et al. 2005, 2006). These studies have produced results of interest, and have identified novel candidates for future study, but require future studies with individual genotyping, for validation.

Study of nicotine dependence The only genomewide association study for a specific SD trait published to date that involved genotyping subjects individually focused on ND (Bierut et al. 2007). A two-stage design was implemented: first, pooled DNA was used to screen 2.4 million single nucleotide polymorphisms (SNPs); second, >30,000 SNPs, selected on the basis of the first stage, were screened individually in 1,050 cases and 879 controls. Numerous genes were identified as possibly associated with ND, including both novel genes (e.g., neurexin 1, NRXN1, and vacuolar protein sorting 13 homolog A, VPS13A) and genes that were previously considered candidates based on known physiology (e.g., cholinergic receptor, nicotinic, beta 3, CHRNB3). This work is of great interest and has the potential to identify new biological pathways important for addiction, but replication is extremely important. In the presence of a very high level of multiple testing, it would be expected that many of the results from this study (as for all studies of this design) are actually false positives.

CANDIDATE GENE STUDIES The following review summarizes some of the notable candidate gene studies in SD. Many of the genes discussed below are associated with both AD and drug dependence (DD).

Alcohol Dependence Candidate Gene Studies Alcohol-metabolizing enzymes Influence of genetic polymorphism at some loci encoding the acetaldehyde dehydrogenases and ADHs on risk of AD in some populations is well established. The mechanism for these effects is very clear. Ethanol is metabolized to acetaldehyde by ADHs, with the most important loci for AD research being ADH1B (previously known as ADH2) and ADH1C (previously known as ADH3). Acetaldehyde is metabolized primarily by acetaldehyde dehydrogenases, the relevant locus for which is ALDH2. Acetaldehyde, a toxic intermediate in the metabolic pathway, produces a "flushing reaction"

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characterized by a set of uncomfortable symptoms including flushing, lightheadedness, palpitations, and nausea. Thus, deviation from the normal metabolism of ethanol that results in increased exposure to acetaldehyde, such as that produced by the medication disulfiram or that which occurs due to genetic variation, produces an aversive effect of ethanol consumption, which might decrease the behavior and thereby the risk of AD (Goedde et al. 1979). A genetic variant that greatly reduces or eliminates acetaldehyde dehydrogenase function, thereby decreasing the elimination of acetaldehyde (which occurs mostly in Asian populations), has long been known to be protective against AD; ADH variants that increase function, yielding elevated acetaldehyde concentrations, may also be protective (e.g., see Hasin et al. 2002; Konishi et al. 2003; Thomasson et al. 1991). As noted earlier in this chapter, several genomewide linkage scans have implicated a region of chromosome 4q that contains an ADH gene cluster, which has prompted more intensive investigation of the ADHs. ADH4 (Edenberg et al. 2006; Luo et al. 2005a, 2005b, 2006a) is one of several diseaseinfluencing loci in this cluster. In adults, the

subunit encoded by ADH4 mainly contributes to ADH

activity in the liver (Edenberg et al. 1999; Li and Bosron 1987; Li et al. 1977). Edenberg et al. (1999) demonstrated that a variant that could affect

subunit regulation, the –75A allele, has promoter activity

that is more than twice that of the –75C allele. Despite the important role of ADH4 in alcohol metabolism, it has, until recently, been largely overlooked in relation to AD. Luo et al. (2005a), (2005b) reported strong associations of ADH4 markers to AD using a variety of methods. Variants in the ADH gene and in ALDH2 are associated with AD (Luo et al. 2006b). Sixteen markers within the ADH gene cluster were genotyped, with four markers within ALDH2 and 38 unlinked ancestryinformative markers in a case-control sample. All markers were found to be in Hardy-Weinberg equilibrium (HWE) in controls, but some markers showed Hardy-Weinberg disequilibrium (HWD) in specific cases. Genotypes of many markers were associated with AD. Diplotype trend regression analysis showed that ADH5 genotypes, and diplotypes of ADH1A, ADH1B, ADH7, and ALDH2, were associated with AD in European Americans, African Americans, or, in some cases, both. In this study, fine mapping of the risk-influencing alleles showed them to coincide with some well-known functional variants. Edenberg et al. (2006) similarly genotyped SNPs across the ADH gene cluster on chromosome 4q in a set of families with high risk for alcoholism from COGA. They found the most consistent evidence of association with AD for ADH4, extending into the 3' untranslated region of that gene bordering on ADH5. Haplotype analysis consisting of tag SNPs covering the entire ADH4 gene together with both upstream and downstream regions of the gene also showed significant evidence for association. These investigators also obtained suggestive evidence of association with AD for ADH1A and ADH1B.

GABRA2 Work reported by the COGA group (Porjesz et al. 2002) demonstrated, first, linkage of electroencephalogram beta frequencies (considered to be an AD-related endophenotype) to chromosome 4p; then, linkage disequilibrium to a -aminobutyric acid (GABA)A receptor gene cluster in this same chromosomal region, in a sample ascertained through extended pedigrees with multiple AD individuals. Fine mapping showed strongest association to GABRA2, one of four GABAA genes in this region (Edenberg et al. 2004). Several groups of investigators, using case-control samples, have replicated this major finding, with evidence of association of AD to a haplotype at GABRA2 in multiple populations (Covault et al. 2004; Fehr et al. 2006; Lappalainen et al. 2005). Enoch et al. (2006) also found an association of GABRA2 in Plains Indians and Finnish Caucasians. As in prior studies, these investigators identified two common haplotypes, which differed markedly in frequency in the populations being studied. Using harm avoidance, a dimensional measure of anxiety, they found haplotype linkage to alcoholism with high and low dimensional anxiety, and to harm avoidance itself, in both populations. They interpreted the results as suggesting that, within the 3' portion of GABRA2, there is a functional locus (or loci) that differs by population and alters risk for alcoholism via the mediating action of anxiety. Although the AD association has been replicable, no specific causative variant has been

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reported, and we must consider the possibility that the origin of the association signal is in a gene or regulatory region adjacent to GABRA2 rather than in GABRA2 itself. Further, Pierucci-Lagha et al. (2005) found an association of GABRA2 with subjective response to alcohol in healthy subjects. Two other genes encoding GABAA receptor subunits, GABRA1 and GABRAG3, have also been shown to be associated with AD, although the evidence supporting these loci is presently substantially weaker than that for GABRA2 (Dick et al. 2004, 2006).

CHRM2 Two reports have provided moderately strong support for muscarinic acetylcholine receptor M2 (genetic locus CHRM2) as an AD risk locus (Luo et al. 2005b; Wang et al. 2004). As for the ADH cluster and GABRA2,CHRM2 maps into a chromosomal region that had been identified as putatively linked to AD linkage (Reich et al. 1998). Several CHRM2 SNPs were reported to be significantly associated to AD; different CHRM2 SNPs were associated with major depression. Luo et al. (2005c) found evidence of association of markers at this locus with the same two phenotypes. It is therefore reasonable to ask exactly what phenotypes are influenced by polymorphic variation at the locus of interest. Is this variation related to diagnosis per se, or is it some intermediate phenotype, or both? Luo et al. (2007) have shown that CHRM2 variation is related to personality measures, and this suggests one possible mechanism for effects on diagnosis traits.

Opioid receptor genes The

opioid receptor has been implicated in the pathogenesis of dependence on many abusable

substances. At first, studies examining association of the

opioid receptor gene (genetic locus OPRM1)

with SD focused on the A118G polymorphism, which encodes an Asn40Asp amino acid substitution and has been shown to be functional. Arias et al. (2006) used meta-analysis to examine the association of Asn40Asp with SD in 22 published articles describing 28 distinct samples and over 8,000 subjects. These studies considered OD and AD, predominantly. Nearly equal numbers of studies showed significantly higher frequency of the Asp40 allele among SD cases than among controls. Overall, there was no significant association between Asn40Asp and SD (odds ratio = 1.01; 95% confidence interval = 0.86–1.19), nor was there substantial evidence of a moderator effect (e.g., AD vs. OD). In a more comprehensive study of the locus, Zhang et al. (2006) examined 13 SNPs spanning the OPRM1 coding region among 382 European Americans affected with AD and/or DD and 338 healthy controls. Two haplotype blocks were identified. Genotype distributions for all SNPs were consistent with HWE expectations in controls, but in cases, SNPs mapping to both Block I and Block II showed deviation from HWE; this can be an indicator of association with phenotype. Significant differences were found between cases and controls in allele and/or genotype frequencies for SNPs mapping in both blocks. Frequency distributions of haplotypes differed significantly for cases and controls (P <0.001 for both AD and DD). Population structure analyses excluded population stratification artifact. Additional supporting evidence for association between OPRM1 and AD was obtained in a smaller replication sample of Russian subjects. These findings suggest that OPRM1 intronic variants (or other variants in linkage disequilibrium with them) play a role in susceptibility to AD and DD in populations of European ancestry. Although the OD subsample was relatively small, some of the most robust associations were observed in that sample. In contrast to the positive reinforcing effects of the

and

opioid receptors, stimulation of the

opioid

receptor produces aversive effects and, by counterbalancing the reinforcing effects of alcohol, may play a role in the development of AD. Using a sample from COGA, Xuei et al. (2006) examined the association of SNPs in OPRK1, the gene encoding the

opioid receptor, and PDYN, which encodes its

peptide ligand prodynorphin. Family-based analyses showed associations of AD with multiple SNPs mapping to PDYN, and in intron 2 of OPRK1. Haplotype analyses also supported the association of PDYN to AD.

Drug Dependence Candidate Gene Studies Dopa decarboxylase 7 of 14

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Dopa decarboxylase is an enzyme of major importance for dopamine synthesis; it also plays a role in serotonin biosynthesis. Ma et al. (2005) studied DDC, the gene encoding this protein, in ND, based both on its physiology and its map location in an ND linkage peak they identified. They showed association between long-range DDC haplotypes and three correlated quantitative traits of smoking behavior using family-based association tests (FBATs) in families, each ascertained through an affected sibling pair for ND. Yu et al. (2006) replicated and extended these results, and reported an association of alleles and haplotypes at DDC with the DSM-IV diagnosis of ND or Fagerström Test for Nicotine Dependence score. They genotyped 18 SNPs spanning a region including DDC and the genes immediately flanking it, in the affected sibling pair sample recruited for opioid or cocaine dependence (i.e., the linkage sample described above). Evidence of association was observed with several SNPs for both traits. The most significant result was obtained for the relationship of Fagerström Test for Nicotine Dependence score to an SNP that maps to the same intron as an important DDC splice site. These findings were consistent with those of Ma et al. (2005), and served to localize the causative variants to the 3' end of the coding region.

DRD2/ANKK1/TTC12 The possible association of variants that map at or near the DRD2 locus with drug or alcohol dependence has provoked a long-running controversy. Although there are many articles published on the issue, there is still no clear consensus regarding a possible effect of this locus on phenotype. Gelernter et al. (2007) identified a modest linkage peak (lod score = 1.97) for ND in the European American part of the sample at the region of chromosome 11 that includes the NCAM1-TTC12-ANKK1-DRD2 gene cluster. One possible explanation for the inconsistent results generated in the study of DRD2 is that the findings reflect an indirect effect that is actually mediated through variation at a nearby locus. To investigate this possibility, the authors genotyped 43 SNP markers in a region, including DRD2 and the three adjacent genes noted above, in the previously described SD linkage sample of >1,600 subjects. DRD2 and NCAM1 are clearly functional candidate genes for SD, but the TTC12 and ANKK1 loci are not well characterized. Weak evidence was found for association of the flanking DRD2 and NCAM1 markers to ND, but very strong evidence was found for the association of multiple SNPs at TTC12 and ANKK1 in both European American and African American populations (minimal P =0.0007 in African Americans and minimal P =0.00009 in European Americans), as well as strong evidence for highly significant association of a single haplotype spanning TTC12 and ANKK1 to ND in the pooled sample (P = 0.0000001). It was concluded that a risk locus for ND maps to a region that spans TTC12 and ANKK1 and that functional studies of these loci are warranted. These results support the explanation that the DRD2 findings could be attributable to variants in nearby loci, which could reflect either functional variations that affect those loci or relatively distant regulatory regions important for DRD2 function. It is noteworthy that several of the genes analyzed in the present discussion (GABRA2 and DDC as well as ANKK1/TTC12) map in proximity to linkage peaks identified in genomewide linkage analysis.

Array-based candidate gene study for nicotine dependence Modern array-based genotyping methodologies allow the query of orders-of-magnitude more variants than previous methodologies, and, as a result, we are starting to see studies with much more extensive genotyping. Saccone et al. (2007) reported on an extensive candidate gene study for ND, including 3,713 SNPs spanning 348 candidate genes that were chosen based on prior pathophysiological hypotheses. It is of interest that some of the strongest results from this rather diverse set of candidates were concentrated in systems previously thought to be important for ND genetics; that is, cholinergic receptor genes, especially CHRNB3 (a locus also suggested to be important in the genomewide association study from this same group [Bierut et al. 2007]) and GABRA4.

GENE-BY-ENVIRONMENT INTERACTION Gene-by-environment interaction refers to the situation where environmental effects on a phenotype differ depending on underlying genotype. Gene-by-environment interaction is an important factor in

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modulating risk for psychiatric phenotypes. Perhaps surprisingly, the magnitude of such effects can be large enough to be detected reliably. In a prospective, longitudinal study of a representative birth cohort, Caspi et al. (2003) found that individuals with one or two copies of the "short" allele of a common functional polymorphism, 5-HTTLPR, in the serotonin transporter protein gene (SLC6A4) reported more symptoms related to depression in relation to stressful life events than individuals homozygous for the "long" allele. Kaufman et al. (2004) reported similar results, but in an adolescent population. Covault et al. (2007) reported finding a similar gene-by-environment interaction in which the 5-HTTLPR polymorphism, together with negative life events, moderated drinking and drug use in college students. In findings that are consistent with earlier results showing that this allele increases risk for depression under conditions of increased stress, individuals homozygous for the short 5-HTTLPR allele who experienced multiple negative life events reported more frequent and heavy drinking and greater nonprescribed drug use. Kaufman et al. (2007) also examined genetic and environmental predictors of early alcohol use, but in this study the subjects were adolescents; predictors of early alcohol use included maltreatment, SD family loading, and 5-HTTLPR genotype. Maltreated children and matched community controls participated; the rate of alcohol use in the maltreated children was more than seven times the rate observed in controls, and maltreated children also initiated drinking, on average, more than 2 years earlier than controls. Consistent with the Covault et al. (2007) report, early alcohol use was predicted by maltreatment, 5-HTTLPR, and a gene-by-environment interaction, with increased risk for early alcohol use associated with the short allele.

GENES THAT INFLUENCE RISK, AND THE NATURE OF THEIR EFFECTS Studies in genetic epidemiology have shown that alcohol and drug dependence, like other important traits in neuropsychiatry, are genetically influenced. Since SD traits are genetically complex, identifying some of the many risk genes involved has been a difficult task. Nevertheless, chromosomal locations for risk genes for both alcohol and drug dependence have been identified through use of genetic linkage studies, and risk genes have been found based on the linkage peaks. Many linkage peaks have been observed in multiple studies of multiple SD traits. Additionally, candidate genes based on known physiology have been identified reliably as risk genes for AD, DD, or both. There are numerous cases now where replications have been published. In fact, and perhaps contrary to initial expectations, SD traits present some of the more encouraging examples of in-progress genetic dissection of sets of complex traits. Still, the task of gene identification is just beginning, and the majority of the genetic variance for these traits is still unaccounted for. In addition to the identification of other specific loci that contribute to the risk of these disorders, work is needed to elucidate the mechanisms by which the genes that are identified exert their effects. We can reasonably expect that such knowledge, when attained, will provide a firm basis for efforts at prevention, early identification, and treatment of these common and often destructive disorders.

KEY POINTS The major forms of substance dependence (alcohol, nicotine, opioid, and cocaine dependence, for example) are all heritable. Genes that influence heritable traits may be identified. Linkage studies point to chromosomal locations; association studies, and other methods of analysis that make use of linkage disequilibrium relationships, point to specific genes. Replicable gene–phenotype relationships have been identified for many kinds of substance dependence. The best-known, and best-replicated, findings so far in substance dependence genetics involve alcohol metabolism genes. Polymorphic variation in numerous genes that encode enzymes important for alcohol metabolism influences risk for alcohol dependence.

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Lately, methodological progress in genetics has been extremely rapid. New methodologies that make it possible to acquire orders-of-magnitude more genetic information than was possible even a few years ago all but guarantee an enhanced pace for progress in the future. Gene-by-environment interaction is an important area of research in psychiatric genetics. Recently, examples of such interaction have been demonstrated for substance dependence genetics.

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muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. Hum Mol Genet 13:1903–1911, 2004 [PubMed] Wilhelmsen KC, Schuckit M, Smith TL, et al: The search for genes related to a low-level response to alcohol determined by alcohol challenges. Alcohol Clin Exp Res 27:1041–1047, 2003 [PubMed] Xuei X, Dick D, Flury-Wetherill L, et al: Association of the kappa-opioid system with alcohol dependence. Mol Psychiatry 11:1016–1024, 2006 [PubMed] Yu Y, Panhuysen C, Kranzler HR, et al: Intronic variants in the DOPA decarboxylase (DDC) gene are associated with smoking behavior in European-Americans and African-Americans. Hum Mol Genet 15:2192–2199, 2006 [PubMed] Zhang H, Luo X, Kranzler HR, et al: Association between two opioid receptor gene (OPRM1) haplotype blocks and drug or alcohol dependence. Hum Mol Genet 15:807–819, 2006 [PubMed]

SUGGESTED READING Bierut LJ, Madden AF, Breslau N, et al: Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet 16:1:24–35, 2007 Edenberg HJ, Dick DM, Xuei X, et al: Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations. Am J Hum Genet 74:705–714, 2004 Gelernter J, Yu Y, Weiss R, et al: Haplotype spanning TTC12 and ANKK1, flanked by the DRD2 and NCAM1 loci, is strongly associated to nicotine dependence in two distinct American populations. Hum Mol Genet 15:3498–3507, 2006 Kendler KS, Prescott CA, Neale MC, et al: Temperance board registration for alcohol abuse in a national sample of Swedish male twins, born 1902 to 1949. Arch Gen Psychiatry 54:178–184, 1997 Luo X, Kranzler HR, Zuo L, et al: Diplotype trend regression (DTR) analysis of the ADH gene cluster and ALDH2 gene: multiple significant associations for alcohol dependence. Am J Hum Genet 78:973–987, 2006 Tsuang MT, Lyons MJ, Meyer JM, et al: Co-occurrence of abuse of different drugs in men: the role of drug-specific and shared vulnerabilities. Arch Gen Psychiatry 55:967–972, 1998 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 3. Epidemiology of Addiction

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Judith S. Brook, Kerstin Pahl, Elizabeth Rubenstone: Chapter 3. Epidemiology of Addiction, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.344608. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Epidemiology of Addiction Judith S. Brook, Ed.D. Kerstin Pahl, Ph.D. Elizabeth Rubenstone, B.A.

DEFINITIONS OF ADDICTION Addiction has been defined as "a chronic relapsing disease characterized by compulsive drug-seeking and abuse and by long-lasting chemical changes in the brain" (National Institute on Drug Abuse 2002). It is generally understood as a disease with genetic, psychosocial, and environmental underpinnings, all of which influence its development and the way in which it expresses itself in the individual. In this chapter, we examine both substance abuse and dependence, which together are referred to as substance use disorders, as delineated in DSM-IV-TR (American Psychiatric Association 2000). According to DSM-IV-TR, substance dependence is characterized by the following symptoms: 1) tolerance, as indicated by the need for a markedly increased amount of the substance to achieve the desired effect or a markedly diminished effect with continued use of the same amount; 2) withdrawal symptoms, or use of the substance to avoid withdrawal symptoms; 3) greater intake of the substance or use over a longer period of time than intended; 4) a persistent desire or unsuccessful attempts to cut down on substance use; 5) a great deal of time spent on activities related to obtaining the substance, using the substance, or recovering from its effects; 6) giving up or reducing important social, occupational, or recreational activities because of substance use; and 7) continued use of the substance despite knowledge of its having persistent negative physiological or psychological effects. In order to receive a diagnosis of substance dependence according to DSM-IV-TR, a person must meet a minimum of three out of these seven criteria within a 12-month period. After a diagnosis of substance dependence is ruled out, substance abuse is assessed using the following four criteria: 1) recurrent substance use resulting in failure to fulfill major role obligations at work, school, or home; 2) recurrent substance use in situations in which it is physically hazardous; 3) recurrent substance-related legal problems; and 4) continued substance use despite persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (American Psychiatric Association 2000). In order to receive a diagnosis of substance abuse, an individual must have at least one of these symptoms within a 12-month period. This work was supported by National Institute on Drug Abuse grants 2R01DA03188 and 7R01DA05702 and by National Cancer Institute grants 5R01CA94845 and 7R01CA84063. We would like to thank Dr. Patrick O'Malley, who made many helpful suggestions; Jonathan Koppel, for review of some of the literature; and Elyse Bento, for manuscript preparation.

THE STUDY OF EPIDEMIOLOGY The study of epidemiology deals with the patterns, causes, and control of diseases in a population (National Cancer Institute 2005). Thus, the epidemiology of substance use disorders (SUDs) focuses on how many people are affected by these disorders, who these people are (i.e., gender, race/ethnicity, age), and what other characteristics (e.g., personal attributes) are common to individuals with substance abuse or dependence. Epidemiologists distinguish between estimates of prevalence and incidence of a particular disease.

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Lifetime prevalence rates refer to cumulative estimates of the disease's occurrence in the lifetimes of the sampled individuals, up to the point in time at which the study is conducted. Period prevalence rates estimate the proportion of active cases of the disease within a circumscribed period (frequently 1 year), up to the point at which the study is conducted. Finally, incidence of a particular disease is an estimate of the first-time occurrence of the disease within a defined time frame, usually a year. Thus, annual incidence estimates describe the risk of developing the particular disease for the first time within the population from which a study sample is drawn (Anthony and Helzer 2002). Below, we first summarize findings about the lifetime prevalence of alcohol and illicit drug use disorders from epidemiological studies conducted between 1980 and 1992, and from a more recent study conducted between 2001 and 2003; next, we look at findings about past-year prevalence of alcohol and illicit drug use disorders from more recent large-scale epidemiological studies conducted between 2000 and 2004; and, finally, we highlight some prevalence estimates of tobacco dependence in the United States.

Lifetime Prevalence Estimates From Large-Scale Epidemiological Studies The first large epidemiological study to be conducted in the United States was the Epidemiologic Catchment Area (ECA) study. It was carried out in the early 1980s in five large metropolitan areas and sampled approximately 20,000 people (age 18 years and older). In an assessment of SUDs, instruments based on DSM-III (American Psychiatric Association 1980) were used to construct SUD diagnoses. Findings from the ECA study included a 7.9% lifetime prevalence of alcohol dependence and a 5.8% lifetime prevalence of alcohol abuse (Helzer et al. 1991). For both abuse and dependence, men greatly outnumbered women (6:1 for abuse; 5:1 for dependence). Lifetime prevalence of alcohol abuse peaked in people between the ages of 18 and 29 years. With regard to illicit drugs, including marijuana, cocaine, amphetamines, sedatives, opioids, and hallucinogens, findings from the ECA study revealed that marijuana abuse and dependence were most common, with a lifetime prevalence of 4.4%. All other illicit drug use disorders had a lifetime prevalence of less than 2% of the population (Anthony and Helzer 2002). The National Comorbidity Survey was conducted between 1990 and 1992 and sampled approximately 8,000 people, ages 15–54 years, in 48 states. Diagnoses were based on DSM-III-R criteria (American Psychiatric Association 1987). Findings from this study revealed a lifetime prevalence of alcohol abuse of 6.4% in women and 12.5% in men. Lifetime prevalence of alcohol dependence was estimated at 8.2% in women and at 20.1% in men (Anthony et al. 1994; Kessler et al. 1994; Warner et al. 1995). Lifetime dependence on marijuana was estimated at 4.2%. The National Longitudinal Alcohol Epidemiologic Survey sampled over 42,000 people (age 18 years and older) in 1992 and assessed alcohol and other SUDs according to DSM-IV (American Psychiatric Association 1994; Grant 1997). Lifetime alcohol dependence was estimated at 13.3% for the total sample, at 8.4% for women, and at 18.6% for men (Grant 1997). Lifetime prevalence rates of alcohol dependence were highest in the youngest cohort (ages 18–24 years; 25%). Lifetime prevalence of illicit drug dependence was 2.1% in women and 3.7% in men (Grant 1996). Between 2001 and 2003, the National Comorbidity Survey Replication Study was undertaken and more than 9,200 individuals were sampled (Kessler and Merikangas 2004). Drug use disorders were defined according to DSM-IV among a subsample of more than 5,600 participants. Results from this study indicated a lifetime prevalence of alcohol abuse of 13.2% and a lifetime prevalence of alcohol dependence of 5.4%. Lifetime drug abuse was estimated at 7.9%, whereas lifetime drug dependence was estimated at 3.0%. Unlike results from earlier studies, lifetime prevalence estimates were higher among participants between the ages of 30 and 44 years than in any other cohort, including those between the ages of 18 and 29 years. In the past few years, a growing epidemic of the nonmedical use of prescription drugs has been recognized (e.g., Compton and Volkow 2006). According to findings of the National Epidemiologic

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Survey on Alcohol and Related Conditions (NESARC) in 2006, the lifetime prevalence of sedative, tranquilizer, opioid, and amphetamine use disorders, as assessed by DSM-IV criteria, were 1.1%, 1.0%, 1.4%, and 2.0%, respectively (Huang et al. 2006). The mean age at onset for nonmedical drug use disorders was 21.2 years for sedatives, 21.9 years for tranquilizers, 22.8 years for opioids, and 20.7 years for amphetamines (Huang et al. 2006). For each category of nonmedical prescription drug, men were more likely than women to have a lifetime drug use disorder (Huang et al. 2006).

Past-Year Prevalence Estimates From Recent Epidemiological Studies Findings from more recent (2000–2006) large-scale epidemiological studies are summarized in Table 3–1. Based on these results from the National Survey on Drug Use and Health (NSDUH) and the NESARC, it appears that approximately 3%–4% of the U.S. population met criteria for past-year dependence on alcohol, and close to 5% met criteria for alcohol abuse (Grant et al. 2004a; SAMHSA 2006). Past-year prevalence of illicit drug dependence, according to NESARC, was estimated at 0.63%, whereas the NSDUH estimated it at 1.8%–2.0% (for 2003 and 2004, respectively). Past-year marijuana dependence was estimated at 1.1% in the NSDUH for both 2003 and 2004 (SAMHSA 2006). As in the lifetime prevalence estimates, men's dependence estimates were higher for all categories of past-year prevalence of SUDs than those for women. Past-year prevalence of substance use dependence was highest among those between the ages of 18 and 25 years (SAMHSA 2006). Finally, in one large-scale study called Monitoring the Future, Johnston et al. (2006a, 2006b) used a complex longitudinal design to follow multiple panels over time, with new panels being added each year. Although the investigation did not assess diagnoses of SUDs, it does provide information on initiation, use, and heavy use of a wide range of substances, including tobacco, alcohol, and illicit drugs. The project's design allows for differentiation of age, period, and cohort effects. This approach allows us to examine disparate influences on the use of different substances. As a broad generalization, for instance, cigarette smoking appears to be heavily influenced by cohort, alcohol use tends to follow a largely maturational pattern, and the use of illegal drugs tends to be influenced by period effects (O'Malley et al. 1988). However, changes in the use of alcohol and illegal drugs (in contrast to cigarettes) are also influenced heavily by changes in the individual's social environment, (e.g., leaving secondary school, work, marriage) (O'Malley et al. 2004). The study also tracks trends in the use of various substances over time, such as a decline in smoking by African American youth during the 1980s, which continues today. It seems likely that substance dependence would follow roughly similar epidemiological patterns.

Nicotine Dependence Approximately 20%–25% of the adult population of the United States is considered nicotine dependent at some point during their lifetimes (Hughes et al. 2006). Breslau et al. (2001) reported a lifetime prevalence of nicotine dependence, as defined by DSM-III-R, of 24.1% in their representative population sample of approximately 4,000 individuals. With regard to the prevalence of nicotine dependence, NESARC reported that between 2001 and 2002, 13% of the U.S. population was considered to be dependent on nicotine (Grant et al. 2004c). There is growing evidence that a greater percentage of adolescents and young adult smokers than older adult smokers are addicted to nicotine. Kandel and Chen (2000), using a proxy measure for DSM-IV diagnoses, found that almost one-third (28.5%) of monthly smokers between the ages of 12 and 17 years were dependent on nicotine. The investigators also found that, compared with adults who reported the same levels of nicotine intake, adolescents were more likely to be dependent. Similarly, Breslau et al. (2001) found that although the youngest cohort of participants in their study (ages 15–24 years) were at the lowest risk of smoking on a daily basis, when compared with three older cohorts, the ever daily smokers in the youngest cohort were seven times more likely to become dependent than ever daily smokers in the oldest cohort (ages 45–54 years).

Developmental Trends in Alcohol and Illicit Drug Use, Abuse, and Dependence

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Substance use increases during adolescence and peaks in young adulthood (Johnston et al 2006a; Johnston et al. 2006b). Thus, by late adolescence, a small percentage of youths meets the criteria for substance abuse and dependence. According to Young et al. (2002), 10% of adolescents from a large community sample met criteria for alcohol abuse, 3.5% met criteria for alcohol dependence, and 4.3% met criteria for marijuana dependence. Evidence from a large-scale epidemiological study has provided information regarding the developmental timing of the onset of SUDs. Kessler et al. (2005) found that among participants in the National Comorbidity Replication Survey, the median age at onset for SUDs was 20 years, within a relatively narrow range of 18–27 years. Wagner and Anthony (2002), using data from the National Comorbidity Survey, reported that the highest risk for initiating alcohol and marijuana use occurs at around age 18 years, and the highest risk for cocaine initiation occurs at around age 20 years. In addition, a greater percentage of the population is at risk for alcohol initiation than for marijuana and cocaine initiation, and this risk is spread out over a longer age span (Wagner and Anthony 2002). The highest risk for meeting dependence criteria, as defined by DSM-III-R, for the entire population was estimated to occur between ages 20 and 21 years for alcohol, between ages 17 and 18 for marijuana, and between ages 24 and 26 years for cocaine. The developmental period for developing marijuana dependence was completed by age 30 years, for developing cocaine dependence by age 35 years, while the risk of developing alcohol dependence extended through midlife (Wagner and Anthony 2002). Thus, the developmental period for becoming alcohol dependent seems to be substantially longer than the developmental period for marijuana and cocaine dependence. When the risk of dependence was estimated only for those who had already initiated use (i.e., had used the substance at some point in their lives) and as a function of years since first use, Wagner and Anthony (2002) found that the cumulative risk for developing cocaine dependence within 10 years of first use was 15%–16%, whereas the cumulative risks for developing marijuana dependence or alcohol dependence were 8% and 12%–13%, respectively, during the same time interval. Thus, the development of cocaine dependence among users seems to occur much more rapidly than the development of dependence among marijuana or alcohol users. In fact, Wagner and Anthony found that an estimated 5%–6% of cocaine users developed dependence within 1 year of first use.

Developmental Trends in Nicotine Dependence Nicotine dependence is closely associated with daily smoking (Breslau et al. 2001). According to Breslau et al. (2001), individuals tend to become dependent on nicotine at least 1 year after they start smoking on a daily basis. This suggests that nicotine dependence represents a later stage of heavy smoking involvement (Hu et al. 2006). Unlike the onset of smoking and daily smoking, both of which typically occur before age 25 years, the onset of nicotine dependence appears to continue into the 40s (Breslau et al. 2001). However, there is growing evidence that nicotine dependence among adolescents develops at a much faster rate than previously assumed (DiFranza et al. 2000; DiFranza et al. 2002; Gervais et al. 2006).

Developmental Trajectories of Substance Use Several investigators have recently identified prototypical patterns of substance use during adolescence, or from adolescence into adulthood (e.g., J. S. Brook et al. 2006a; Chassin et al. 2000; Orlando et al. 2004; White et al. 2002). The goal of these analyses has been to identify homogeneous subgroups of substance users that display distinct patterns of use over time, instead of basing the investigation on the assumption of a uniform developmental pattern of change among all substance users. Thus, the principal assumption of these analyses is that there are distinct subpopulations that are characterized by differential substance use patterns over time. These methods can be used to determine distinct trajectories of substance use (i.e., different subgroups of substance users) empirically rather than a priori (White et al. 2002).

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Such trajectories of substance use can then be linked to predictors and/or outcomes. Consequently, the patterns can provide information regarding the antecedents and consequences of developmental patterns of use over time (e.g., of early onset, heavy use vs. moderate use). In one such analysis, J. S. Brook et al. (2007) found that early-onset, continuous smokers faced a sevenfold increased risk of developing alcohol dependence and an elevenfold increased risk of developing illicit drug dependence, compared with nonsmokers. Early-onset, continuous smokers were also more likely to develop drug and alcohol dependence than maturing-out smokers (quitters) and late-starting smokers.

DEVELOPMENTAL EPIDEMIOLOGY The etiology of substance use, abuse, and dependence is considered to be multidetermined; several domains of psychosocial risk and protective factors have been identified to date. Risk factors increase the probability of substance abuse and dependence, whereas protective factors reduce this probability. Protective factors may also serve two other functions. First, they may offset risk factors; for example, personality vulnerability in an adult may be buffered by protective factors in the family. Second, protective factors may augment the effects of other protective factors, thus affording increased protection; for example, close family bonds in childhood may be enhanced by marital harmony, leading to a decreased likelihood of substance abuse or dependence in the individual. Risk and protective factors include the following features: 1) individual characteristics, such as comorbid psychiatric disorders; 2) developmental influences, such as genetic and gene–environment effects, familial factors, the peer group, and adult roles; and 3) contextual influences, which can include experiences of racial discrimination and school and neighborhood influences. In addition, research suggests that psychosocial factors within each of these domains may operate differentially with respect to both the severity (i.e., use vs. abuse or dependence) as well as the type (e.g., opiate vs. nicotine) of substance involvement (Conrod et al. 2000).

Individual Characteristics Three dimensions of an individual's personality and psychiatric disorders have been found to be related to substance use, abuse, and dependence. The first personality dimension encompasses an orientation toward risk-taking and sensation- or novelty-seeking behavior (Agrawal et al. 2005; Sher et al. 2000). Cloninger et al. (1988), for example, reported that preadolescents who scored high on novelty-seeking behavior were almost 20 times more likely, on average, to abuse alcohol as adults. Masse and Tremblay (1997) also demonstrated that high levels of novelty-seeking behavior in boys, assessed at both ages 6 and 10 years, predicted the early onset of alcohol abuse, cigarette smoking, and other illegal drug use. Drug abusers who scored high on measures of novelty-seeking behavior also had poorer long-term retention rates in addiction treatment programs (Helmus et al. 2001). The second personality dimension consists of a relative lack of emotional control (J. S. Brook et al. 1990). Individuals who are impulsive and lacked emotional control are more likely to abuse or be dependent on alcohol or drugs (Nigg et al. 2006; Sher and Trull 1994). In a related vein, investigators in several studies have recorded less emotional control in the children of drug abusers, irrespective of whether or not the children later developed an SUD (e.g., Elkins et al. 2004, King et al. 2006). The third personality dimension associated with drug use, abuse, and dependence is interpersonal relatedness. Individuals who have problems establishing or maintaining relationships with others are at elevated risk for drug abuse or dependence (J. S. Brook et al. 1990). Although there is a dearth of literature on the link between drug abuse and dependence and interpersonal problems, research suggests that two aspects of these problems, insecure attachment and avoidant personality, are associated with increased alcohol or drug abuse and dependence in adulthood (Mickelson et al. 1997). Psychopathology is also associated with substance use, abuse, and dependence. Research has found that SUDs are highly related to antisocial syndromes such as child and adolescent conduct disorder, antisocial personality disorder in adulthood, and antisocial behaviors (i.e., aggression, deviance) (Compton et al. 2005a; Dierker et al. 2007). Fergusson et al. (2005), for instance, demonstrated that childhood conduct disorder was predictive of both nicotine dependence and illicit drug dependence in young adulthood.

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Cohen et al. (2007) also demonstrated that conduct disorder at age 13 years predicted alcohol, marijuana, and illicit drug abuse or dependence in young adulthood, as well as trajectories of these SUDs until age 38 years. Attention-deficit/hyperactivity disorder (ADHD) has also been related to substance abuse and dependence in clinical and community samples of both adolescents and adults (Biederman et al. 2006; Wilson and Levin 2005). ADHD has been shown to predict nicotine dependence, even after statistically controlling for conduct disorder (Wilens et al. 1997). However, some studies have found that comorbid ADHD and conduct disorder is a more powerful predictor of substance use or abuse than either disorder alone (Flory et al. 2003). In addition to the antisocial syndromes, several affective disorders (e.g., major depressive disorder, bipolar disorder, dysthymic disorder, and depressed mood) are highly comorbid with SUDs, including alcohol, tranquilizers, opiates, cocaine, marijuana, and stimulants (Conway et al. 2006; Crum et al. 2005). The findings of some investigations suggest that depression precedes SUDs. In a study of adult twins, for example, Kuo et al. (2006) showed that prior major depressive disorder increased the risk for alcohol dependence but that alcohol dependence did not predict major depression. Conversely, there is an increasing body of research indicating that SUDs precede depression. For instance, D. W. Brook et al. (2002c) determined that alcohol, marijuana, and other illegal drug use during adolescence and young adulthood each predicted major depressive disorder in adulthood, even with control on prior depressive episodes. It is also possible that both SUDs and depression stem from some of the same genetic and/or environmental vulnerabilities (Volkow 2004). Furthermore, comorbid depression and SUDs are also associated with greater functional impairment (Leventhal et al. 2006) and worse treatment outcomes (Dodge et al. 2005). Finally, comorbid drug addiction (polydrug abuse and dependence) is common, such that having an SUD with any drug confers an elevated risk of use of, abuse of, or dependence on another (Tsuang et al. 1998).

Developmental Influence Gene–environment interplay Genetic factors may have an impact on the development of SUDs. Presently, however, the exact mechanisms through which genes affect substance use are not clear, but evidence suggests a combination of several genes may be involved. Numerous possible candidate genes have been identified (see Chapter 2, "Genetics of Addiction," this volume). In this section, we present research pertinent to the interplay between genes and the environment, based on the work of Sir Michael Rutter and his colleagues (2006). By way of illustration, we present three types of gene–environment interplays. The first type of interplay refers to gene–environment interactions, which are based on the premise that drug addiction is the end result of a series of processes that interact to produce a particular outcome, above and beyond the separate genetic and/or environmental factors involved. Caspi et al. (2002), for instance, demonstrated that maltreated children with a genotype encoding high levels of monoamine oxidase A expression were less likely to develop antisocial behaviors in adulthood than maltreated children who did not have this genotype. A second type of interplay, referred to as epigenetic, involves environmental cues that influence genetic expression. In this case, genes can be conceived of as dependent variables "switched on or off" by nongenetic influences. A third type of gene–environment interplay involves the individual's genes partially influencing the environments to which he or she is exposed, and it suggests that certain individuals may behaviorally alter and/or seek out risky environments. For example, youth who are prone to sensation or novelty seeking, a trait that has a genetic underpinning and has been associated with addiction (Chakroun et al. 2004), may seek out drug-using friends.

Family factors Research has identified several aspects of the family environment that are consistently related to substance use, abuse, or dependence. In youth, these factors primarily consist of the following characteristics: 1) parental substance abuse/dependence; 2) parental personality, including

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psychopathology; 3) the parent–offspring relationship (especially parental warmth and monitoring) as well as family cohesion; and 4) sibling influences (Boyle et al. 2001; J. S. Brook et al. 1990; J. G. Johnson et al. 2006; Su et al. 1997). With regard to parental factors, parental substance abuse/dependence has been linked with SUDs in offspring (Biederman et al. 2000; Merikangas et al. 1998). In addition, numerous investigations have demonstrated that parental depression, anxiety, antisocial tendencies, or poor coping skills are each related to offspring substance use or SUDs (Biederman et al. 2000; D. W. Brook et al. 2002a; J. S. Brook et al. 1990; Nurco et al. 1999; Su et al. 1997). The parent–offspring relationship has been shown to act as a mediator between parental drug abuse/dependence and offspring involvement with substances of abuse (e.g., J. G. Johnson et al. 2001). Similarly, the relationship between parental personality attributes and offspring substance use or SUDs may be mediated by the parent–offspring relationship (J. G. Johnson et al. 2001). That is, parental emotional and behavioral problems may undermine the establishment of a close and supportive relationship with offspring, thus increasing the likelihood of the latter's substance use or SUDs (Conger et al. 2002; Pilowsky et al. 2006). In accordance with family interactional theory (J. S. Brook et al. 1990), youth with a strong parental mutual attachment are more likely to identify with conventional aspects of the parents (e.g., non–drug use) and therefore to refrain from drug use. Furthermore, longitudinal research has shown that family factors present during childhood and adolescence, such as the parent–child relationship, continue to influence substance use behaviors even when the child reaches adulthood (Fagan et al. 2005).

Peer influences Another important factor in addiction is the individual's association with peers who use drugs. Two mechanisms may be operative with respect to peer factors: The individuals who are prone to drug use, abuse, or dependence may select a reinforcing substance-using peer group. On the other hand, the peer group may influence a susceptible individual through modeling and social reinforcement of drug-use behaviors. In addition, drugs are more likely to be available to individuals involved with drug-using peers.

Marital/Partner relations and occupational status In adulthood, there is high concordance between individuals' substance use and that of their partners (Vanyukov et al. 1996), possibly due to assortative mating (i.e., the selection of partners based on shared behaviors) (Yamaguchi and Kandel 1997). Individuals who are divorced, single, or who experience marital dissatisfaction are more likely to have SUDs (Fu and Goldman 2000; Whisman 1999). Women who have been the victims of intimate-partner violence are also at elevated risk for substance use and abuse (Martin et al. 2003), although this relationship may be bidirectional; that is, substance abuse may precede as well as follow domestic violence (El-Bassel et al. 2005). Relatively little research has examined factors related to employment and substance abuse and dependence. However, findings suggest that the formula developed by Karasek et al. (1981) with respect to job characteristics and health outcomes may also apply to the individual's substance abuse. Specifically, high work demand combined with low control over the work has been shown to induce greater stress, as well as to predict higher rates of SUDs among employees (Reed et al. 2006).

Trajectories: risk factors as predictors of drug use over time As previously noted, there is a growing recognition of the importance of identifying trajectories that define the progression of substance use in particular subgroups of users over a span of time. Some trajectory analyses have also examined the earlier risk factors associated with membership in each trajectory subgroup. For instance, in a longitudinal study, J. S. Brook et al. (2006b) found that adolescents who were unconventional (e.g., more rebellious), who experienced greater intrapersonal distress, or who used illegal drugs in adolescence were more likely to belong to one of the smoking trajectory groups in adulthood. Furthermore, the early-starting, continuous smokers demonstrated the highest rates of prior personality risk factors, compared with the other subgroups of smokers. Flory et

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al. (2004) also showed that marijuana nonusers in adolescence were significantly less likely to abuse or be dependent on alcohol or marijuana in young adulthood as compared with early- or late-onset marijuana users. Furthermore, trajectory analyses generally have found that the greater the earlier risk factors and adverse outcomes, the more likely the individual is to belong to the most severe substance use subgroup.

Contextual Influences Since the 1980s, the role of contextual factors in substance use, abuse, and dependence has been increasingly recognized. Low socioeconomic status (including income and education) is an important factor in the development of substance use and SUDs (Poulton et al. 2002). Several studies have found that low socioeconomic status includes a number of factors found to be conducive to substance abuse/dependence, such as 1) residence in impoverished and stressful neighborhoods; these findings are in line with the stress reduction hypothesis, which posits that drug abuse/dependence is a maladaptive form of coping with hostile environments and negative life events (Sinha 2001); 2) a drug-salient milieu, which includes more drug abusers and drug-abusing social networks (Schroeder et al. 2001); and 3) neighborhood social disorganization. Neighborhood social disorganization, which refers to a lack of cooperation of local residents toward common goals, has been assessed by a variety of different constructs (e.g., residential instability, lack of collective efficacy) (Sampson et al. 1997) and has also been associated with higher rates of local gang activity (Tolan et al. 2003), which, in turn, is a predictor of drug abuse and dependence (De la Rosa et al. 2005). Experiences of discrimination in racial/ethnic minorities have also been linked with increased tobacco and drug use (Gibbons et al. 2004; Landrine and Klonoff 2000). Research findings suggest that substance use (e.g., smoking) may be, in part, a response to the stress and possible emotional dysregulation induced by discrimination (Guthrie et al. 2002). In the preceding section, we identified some risk factors for drug abuse and dependence. Although there are ethnic differences in SUDs, the majority of risk factors are not appreciably different across ethnic groups. Furthermore, it is important to note that ethnic identification serves as a protective factor in offsetting risk factors for drug abuse and dependence.

CONSEQUENCES OF SUBSTANCE USE DISORDERS There are numerous psychosocial, physiological, and medical sequelae of SUDs, which may vary according to the substance type, quantity, and duration of use (Galea et al. 2004; Gossop et al. 2002). Recent advances in neuroimaging and the mapping of the human genome have led to a greater understanding of the cellular adaptations and alterations of gene expression resultant from chronic alcohol or drug administration (e.g., Rhodes and Crabbe 2005). This section presents an overview of the adverse consequences of substance abuse or dependence on psychosocial functioning and on mental and physical health.

Health Problems Worldwide, injection drug use is a major risk factor for HIV transmission, accounting for almost one-third of all new HIV cases outside of sub-Saharan Africa (UNAIDS 2006). Coinfection of HIV and hepatitis C is also common in drug abusers (Hagan et al. 2005). The most frequently injected illicit drugs—heroin, cocaine, and methamphetamine—are also related to other health problems, such as pulmonary (Sheu et al. 2006) and cardiovascular (Bruno 2003; Neiman et al. 2000; Sheu et al. 2006) incidents. Interestingly, in an investigation by Price et al. (2001), prior opiate addiction was found to predict premature mortality 25 years after cessation of use. Because 99% of alcohol is metabolized in the liver, alcohol use disorders are associated with hepatic disease, such as cirrhosis and hepatitis B and C (Baigent 2003; Stein 1999). Increased rates of cancers and cardiovascular problems have also been reported among heavy drinkers (Bruno 2003; Stein 1999). In addition, neurocognitive deficits have been associated with alcohol abuse or dependence, and recent findings indicate that the volume of the hippocampal region of the brain is decreased in alcoholic

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individuals (Beresford et al. 2006). Smoking marijuana is associated with airway inflammation and pulmonary carcinoma (Kalant 2004). Cigarette smoking and nicotine addiction are widely recognized as having a causative role in pulmonary and other cancers (Khuder 2001; Kumra and Markoff 2000; Kuper 2002), as well as in the development of lung diseases (Ryu et al. 2001) (e.g., emphysema, chronic obstructive pulmonary disease; Kumra and Markoff 2000) and cardiovascular events (e.g., atherosclerosis, infarction, or stroke) (Ambrose and Barua 2004). Furthermore, the results of some recent investigations suggest that health problems attributable to smoking may manifest at relatively young ages. J. S. Brook et al. (2004), for instance, showed that daily smoking at mean ages 14, 16, 22, and 27 years was associated with increased risk for respiratory ailments, neurobehavioral and cognitive problems, and general malaise by age 30 years (see Table 3–2).

Effects on Academic Achievement and Employment Substance abuse and dependence may have an impact on both academic achievement and employment. Several studies have found, for example, that adolescent substance use/abuse is related to diminished educational attainment, including school dropout (e.g., Johnson and Kaplan 1990; Myers and Andersen 1991). Approximately 6% of full-time employees and 7% of part-time employees in the United States are dependent on alcohol and/or illicit drugs, and most persons with an SUD are employed (SAMHSA 1999). The effects of SUDs on employment include lower vocational level (Friedman et al. 1996), decreased productivity (Mangione et al. 1999), greater absenteeism (e.g., related to health problems [Roberts and Fallon 2001]), more on-the-job injuries (Roberts and Fallon 2001), greater vocational instability (SAMHSA 1999; Tam et al. 2003), and more workplace-related violence (Greenberg and Barling 1999). Although we have focused on the effects of substance abuse/dependence on employment, there is evidence of a reciprocal relationship between employment and SUDs.

Antisocial Behaviors As previously noted, comorbidities may precede or be consequent to SUDs. Drug abuse/dependence and alcohol use disorders are also associated with violence and other criminal behaviors (Cartier et al. 2006; Newcomb et al. 2001). This linkage may be due to the intra-individual clustering of antisocial and problem behaviors (Fergusson et al. 1993), the disinhibitory effects of some substances (BaskinSommers and Sommers 2006), and/or neurobehavioral damage as a result of chronic substance use (Baskin-Sommers and Sommers 2006; Jentsch and Taylor 1999). Furthermore, many drug addicts engage in criminal behaviors in order to obtain illicit drugs or the capital needed for their procurement (Newcomb et al. 2001). Other mechanisms in the drug-crime nexus include family conflict stemming from substance abuse (e.g., intimate-partner violence), association with other addicts who are more likely to commit crimes, and aggressive behavior as a form of maladaptive coping.

Effects on Children and the Family Substance abuse or dependence is associated with both short- and long-term teratogenic effects. There is increasing evidence that many addictive substances (e.g., alcohol, nicotine, morphine, cannabinoids, and cocaine) can cross the placental barrier, resulting in intrauterine exposure to the developing fetus (Huestis and Choo 2002). Maternal substance use, abuse, or dependence during pregnancy has also been linked with child psychopathology, such as ADHD and aggression (Heilbronner 2005), as well as cognitive and motor deficits in neonates and infants (Lester et al. 2002; Singer et al. 2002). Both maternal and paternal preconception cigarette smoking and gestational marijuana use are associated with increased rates of certain childhood cancers in the offspring (Chang et al. 2006; Hashibe et al. 2005). Drug abuse/dependence also has a psychosocial impact on the family. Children of substance abusers have higher rates of emotional (e.g., depression, anxiety [Drucker et al. 1997; Nunes et al. 2000]) and behavioral (e.g., disruptive behavior disorders [Cooke et al. 2004; Nunes et al. 2000]) problems, as well as poorer coping skills (D. W. Brook et al. 2002b). Finally, substance abusers are at risk for conflict

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with their partners (Fals-Stewart et al. 1999) and greater marital dissatisfaction (Whisman 1999).

FUTURE DIRECTIONS A more complete understanding of the etiology of drug abuse and dependence requires a greater understanding of the psychosocial factors that influence the development of substance use and dependence. One direction for future investigations rests on the need for more extensive data on personal risk factors in children that are linked with later drug abuse and dependence in adulthood. In-depth studies of the mutual attachment relationship between parent and child and how the relationship is linked with the child's later drug abuse and dependence are greatly needed. Future research on drug abuse and dependence will benefit greatly from including broader orientations in a more complete, interdisciplinary approach. Increasing attention has been paid to the comorbidity between psychiatric disorders and drug dependence. As noted, evidence supports the existence of a reciprocal relationship between these disorders. It remains necessary to identify a) the specific mechanisms that operate between psychiatric disorders and drug dependence and b) some common underlying factors that explain the relationship between psychiatric disorders and drug dependence. There is also an urgent need for further research into the epidemic of prescription drug abuse. Much remains to be understood about this growing problem, such as the predictors of addiction to prescription medication and its effect on other drug use, in order to inform clinicians and professionals working in prevention and treatment programs (Compton and Volkow 2006). We have approached the epidemiology of drug abuse and dependence from the viewpoint of an integrated model. In examining drug abuse and dependence, we have proceeded from a proximal to a distal perspective that includes the following features: 1) genetic considerations, 2) individual characteristics, 3) family and peer influences, 4) adult factors, and 5) societal dimensions. It is important to examine the risk and protective factors for SUDs inherent in the larger social units in which individuals function. For example, it is necessary to evaluate the interplay between psychosocial risk factors (e.g., a history of family drug use, personality vulnerabilities) and contextual risk factors. Broader risks present in society include residence in impoverished and stressful neighborhoods, a drug-salient milieu, neighborhood social disorganization, and racial and ethnicity-based discrimination. Although a considerable amount of work in this area has been accomplished, additional information is required for a more complete understanding of the mechanisms through which these interactions occur. In the past decade, there have been numerous advances in behavioral genetics research. As noted earlier, genetic factors related to drug abuse and dependence are very complex. Following Rutter et al. (2006), we have specified three types of gene–environment interplays. The first type of interplay refers to gene–environment interactions. The second type of interplay is referred to as epigenetic and involves environmental cues that influence genetic expression. The third type of gene–environment interplay pertains to how the individual's genes influence the environment to which he or she is exposed. As noted by Frederick and Iacono (2006), identifying the genes that underlie the vulnerability to drug abuse and dependence in the context of environmental factors is critical for effective diagnosis, prevention, and treatment. Therefore, it is necessary to further explore the processes related to each of these kinds of gene–environment interplays. There are several implications for methodology. In future investigations, researchers should incorporate a variety of measures, such as laboratory assessments, naturalistic observations, and structured observations, in addition to the further development of interviews and questionnaires. It will also be important to develop instruments to assess drug abuse and dependence that are appropriate for individuals of different ethnic backgrounds. In order to develop more comprehensive assessments and further the construct validity of the various instruments, assessments across sources, situations, and time would benefit the field greatly. Laboratory and clinical research findings may not receive enough attention from investigators working on large-scale epidemiologic studies. Conversely, laboratory and clinical researchers may not pay sufficient attention to the results that emerge from large-scale

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epidemiological studies. As noted by Compton et al. (2005b), "epidemiological studies offer unique, powerful, and efficient opportunities for addressing this concern by embedding ('nesting') hypothesized measures of causal mechanisms into existing studies and sub-studies" (p. 1499). Exploration of the causal mechanisms should facilitate the translation of findings from basic research to clinical applications and policy-appropriate interventions. Continued advances in the development of statistical techniques would go a long way toward testing the complex models that attempt to explain the epidemiology and etiology of substance abuse and dependence. Recent developments include growth-mixture modeling (Roeder et al. 1999; White et al. 2002), which attempts to study the trajectories of drug abuse and dependence. Advances in structural equation modeling have also enabled us to more clearly delineate the mechanisms involved in the development of drug abuse and dependence. Finally, to quote Compton et al. (2005b), large-scale survey research "such as the National Survey on Drug Use and Health, the Monitoring the Future Study. . .and the National Epidemiologic Survey on Alcohol and Related Conditions might be augmented with or compared to community-level research to examine relatively rare drug use (e.g., heroin), regional variations, pockets of drug use, emerging trends in drug use, and certain high-risk groups not living in permanent households" (p. 1499). This chapter has approached the epidemiological study of substance abuse and dependence from numerous viewpoints, proceeding outward from genetic considerations, to individual characteristics, to family and peer influences, to adult factors, to contextual influences. As noted in several chapters of this book, there are other important areas to be considered. At present, there is considerable interest in the study of the epidemiology and etiology of drug abuse and dependence. Such attention is likely to broaden inquiry and yield a sounder base of evidence, both of which augur well for future investigations and additional comprehension of the epidemiology and etiology of substance use, abuse, and dependence.

KEY POINTS Drug abuse and dependence are multidetermined by genetic predispositions, personality attributes, and social-environmental influences. Anyone involved in the treatment of substance use disorders must take into consideration this complex matrix of influences. Despite the differences in prevalence rates of drug abuse and dependence among ethnic groups, the risk factors for drug abuse and dependence are quite similar among various ethnic groups. Many individuals have comorbid psychiatric disorders (e.g., substance dependence and major depressive disorder). Further research into the comorbidity of psychiatric disorders may illuminate some of the etiological pathways for each disorder. From a treatment perspective, it is necessary to treat the drug dependence as well as the comorbid disorders. There seem to be genetic influences on the overall vulnerability to substance abuse and dependence. Future research into the interplay of genetic and environmental factors related to drug dependence is clearly warranted. In trying to understand the development of substance use disorders, it is of crucial importance to use a life-course approach. New statistical methods, such as growth-mixture modeling, have enabled us to identify prototypical trajectories of drug use behavior over time. Future research will continue to reveal the antecedents, co-occurring developmental processes, and consequences of these distinct substance use patterns.

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SUGGESTED READING American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Brook JS, Brook DW, Pahl K: The developmental context for adolescent substance abuse intervention, in Adolescent Substance Abuse: Research and Clinical Advantages. Edited by Liddle HA, Rowe CA. New York, Cambridge University Press, 2006, pp 25–51 Brook JS, Pahl K, Ning Y: Peer and parent influences on longitudinal trajectories of smoking among African-Americans and Puerto Ricans. Nicotine Tob Res 8:639–651, 2006 Compton WM, Thomas YF, Conway KP, et al: Developments in the epidemiology of drug use and drug use disorders. Am J Psychiatry 162:1494–1502, 2005 Johnston LD, O'Malley PM, Bachman JG, et al: Monitoring the Future National Survey Results on Drug Use, 1975–2005, Vol 2: College Students and Adults Ages 19–45 (NIH Pub No 06-5884). Bethesda, MD, National Institute on Drug Abuse, 2006 Sloboda Z (ed): Epidemiology of Drug Abuse. New York, Springer, 2005

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Chapter 4. Cross-Cultural Aspects of Addiction

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Nady el-Guebaly: Chapter 4. Cross-Cultural Aspects of Addiction, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.345154. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Cross-Cultural Aspects of Addiction Nady el-Guebaly, M.D., D.Psych., D.P.H.

CROSS-CULTURAL ASPECTS OF ADDICTION: INTRODUCTION In our ever-shrinking global village, the need for cross-cultural sensitivity and clinical competence increases as the pace of our contact with people from other cultures accelerates, either through travel or permanent resettlement. Clinical cultural competence is a lifelong journey. This chapter focuses on identifying the clinically relevant variables of culture and their implications for assessment and management. Most of the recent scientific literature in English addresses culture in the context of our modern multiethnic societies in the United States, Great Britain, Canada, and Australia.

CONCEPTS AND DEFINITIONS In multiethnic societies, the following definitions represent current attempts to explain cross-cultural terminology: Culture is the sum total of a group's life ways, including its shared material environment, worldview, social organization, symbols, status, child-raising style, language, technology, and citizenship. Ethnicity applies to people from diverse cultural backgrounds who share a common national culture. Background refers to identity with a national and/or shared language of origin, religious practice, dress, diet, holidays or ceremonial events, traditional family rituals, use of disposable income, and leisure activities (Keyes 1976). Subculture refers to distinct groupings, resulting, for example in the context of addiction, from substance use, abuse, or dependence, and can be applied to groupings resulting from other addictions, such as affiliations with cocktail lounges, gambling outlets, shooting galleries, or crack houses. Acculturation is the accumulative social learning process in which people assimilate the values of the host culture while retaining the values of the original culture. Cross-cultural refers to the comparison of characteristics across culture groups or, in the case of addiction, treatment strategies addressing both clinician and patient differences in cultures. Operationally, in census gatherings or clinical surveys in the United States, categorization of major ethnic groups may represent an oversimplification. Hispanic or Latino ethnic groups have diverse roots traced to more than 20 countries with various phenotypic admixtures, divergent historical origins, ad diverse social and educational levels and patterns of use of services. The same can be said of African American, Asian, Native American, and other ethnic groupings that are traditionally recorded at the introduction of any medical history or clinical presentation. The identification of ethno-cultural groups also depends on national political priorities. In Canada, the study of cultures based on English and French languages have been prioritized; in the United Kingdom, particular attention has been paid to religious Muslim groups.

HISTORICAL CONTEXT A testimony to the creativity of man across civilizations is that different alcoholic beverages came to prominence in various times and places, first to address the need for a more palatable and safer alternative to brackish water, then to be used in religious rites, and also as a means of celebration and social bonding. The farming of cereal grains in the plains of the Near East some 10,000 years ago

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resulted in the appearance of a rudimentary form of beer. The early grain farming civilizations of Mesopotamia and Egypt instituted a wage system largely consisting of bread and beer (el-Guebaly and el-Guebaly 1981). Ancient Greece popularized wine at drinking parties or symposia where diluted wine was provided in a shared bowl. Originally from grapes grown in mountainous areas, wine became the basis of a vast Mediterranean seaborne trade. The Roman Empire embraced Greek wine drinking and adapted it to its elaborate hierarchical society. The quality of the wine became a symbol of social differentiation. In the post-Renaissance era, from the fifteenth century onward, during the age of global exploration, distillation refined by Arab scholars provided alcohol in a more concentrated form resulting in the creation of brandy, rum, and whiskey. These beverages became currencies with which people could buy slaves to develop newly discovered colonies in North America and other parts of the world. During the eighteenth century, in the Age of Reason, coffee was introduced to Europe from the Middle East and tea was imported from China. In the late eighteenth century, carbonated beverages originated in Europe but came to prominence in America a century later when coca leaves and caffeine-based kola nuts were added to soda water. In fact, Coca-Cola was first marketed as stimulant medicine (Standage 2006). Other psychoactive drugs were also identified from vegetation around the world, originally for medical purposes and, eventually, for elaborate religious rites. Neolithic archeological discoveries from around 6,000

BC

included opium pellets at burial sites, marijuana seeds, hallucinogens such as black hembane

(hyoscyamus niger) in prehistoric Britain, and ergot (claviceps) and hallucinogenic fungi (psilocybin) in ancient Greece. The Mesopotamic civilization documented the use of opium (papaver somniferum) as far back as 3,000

BC

(Rudgley 1995).

Nowadays, human migration is often associated with the exportation of favorite drugs from their countries of origin. Khat (Catha edulis), for example, a mild stimulant derived from a flowering bush native to the Horn of Africa, is now used by migrant populations from the area (Griffiths et al. 1997). The North American indigenous contributions to psychoactive drugs include, among others, peyote buttons once used mainly by Native Americans. In the last few decades, the arrival of designer drugs (drugs concocted in laboratories) has played an increasing role in the pursuit of intoxication. Throughout the ages, substance use has served as a mechanism of social integration and, when used in excess, as an instrument of social disorganization.

RISK AND PROTECTIVE FACTORS MODERATING THE IMPACT OF ETHNICITY Given the multiplicity of ethnic groups, a listing of recorded differences is beyond the scope of this chapter. Assimilation of the related empirical literature is a complex undertaking, and, to avoid stereotyping, one must exercise caution when interpreting results. Confounding variables, such as those outlined in the following sections, are commonly noted to affect prevalence estimates comparing the impact of addiction on ethnic groups. Most studies to date, however, do not account for many of the confounding effects referred to below; more prospective studies are required to tease out the relative impact of these variables.

Disentangling Sociodemographic Variables From Culture It is crucial to control sociodemographic variables so that results can be reliably and effectively interpreted. Differences in age distribution must be taken into account. For example, the higher proportion of youth, a high-risk group for substance use among Native Americans, influences the prevalence of substance abuse in that ethnic group. In another example, like the societal norms of many ethnic groups, Mexican societal attitudes are more negative toward women's alcohol consumption than men's. Therefore, this societal norm is likely to have a protective effect on the prevalence estimates of women's alcohol consumption. Differences in family stability and the occurrence of domestic violence in a given ethnic group may also be a cause and/or consequence of the prevalence of

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substance use in that group. The same can be said about differences in socioeconomic status and work history.

Extent of Acculturation The extent of recent migration in an ethnic group is viewed as both a risk and protective factor. For example, first- and second-generation acculturation may create socioeconomic stressors, which increase the vulnerability to addiction. Yet, a New York survey also shows that the stronger the ties are to Hispanic culture among persons born outside the United States who speak mostly Spanish, the less likely that group is to use drugs, compared with Hispanics born in the United States who speak mostly English (Frank et al. 1988). Hawaiian residents of Chinese and Japanese ancestry also have lower levels of alcohol use if born in Asia than if born in Hawaii (Johnson et al. 1987).

Impact of Sampling and Other Survey Designs The method of population selection is of critical importance in estimating the prevalence of substance abuse in an ethnic group. For example, school survey results must account for potential ethnic differences in rates of school retention. The ethnicities of school dropouts are not reflected in school surveys. Furthermore, a group's urban-rural distribution may also confound estimates. For example, Native Americans live mostly in rural settings under basic sanitary conditions and limited access to treatment. Language barriers also represent a variable that must be accounted for in research design. Numerous challenges must be met to establish validity and reliability in research methodology that controls for variables such as language barriers for non-English-speaking groups and cultural biases for groups such as African Americans, immigrants, and Native Americans. The timing of the survey is also relevant. Is the group experiencing an epidemic superimposed on traditional consumption? For example, from the sixteenth century onward, the gin epidemic in the United Kingdom and the opium epidemic across Asia heralded the onset of episodic epidemics of substance abuse. More recently, the methamphetamine epidemic may temporarily affect the prevalence figures of designated ethnic groups. The selection of a particular addictive substance or behavior surveyed will also affect ethnic differences. Certain Asian groups, for example, may report a lower prevalence of alcohol use but a higher prevalence of gambling behaviors.

Legal Frameworks of Home and Host Countries The traditional use of coca leaves in the Andes and marijuana and hashish in India and the Middle East adds to the cultural disconnect felt by migrants from these countries who arrive in a new community where their drug is illegal, but other substances are socially promoted. Indeed, in North America, the criminalization of some drugs over others has been associated with the need to protect the majority from the habits of recently migrated minorities. In the nineteenth century, temperance and abstinence movements may have originated as a reaction to the new Irish and German-Catholic immigrants' "wet" cultures, which presented a conflict for the original abstemious Protestant groups. Anti-opium legislation in Canada and the United States was enacted to protect the majority from newly migrant Chinese railroad workers' opium dens. In the early twentieth century, the cocaine laws were spurred by the fear of use among African Americans. In the 1930s, the marijuana laws reflected similar concerns about its use by Mexican migrant workers. Currently, there is a differential propensity for arrests and imprisonment for alcohol-related offenses among aboriginal groups in various countries (Adrian 2002; Kamien 1986).

Biological Factors and Physical Comorbidities Studies on the impact of genetic factors on the predisposition toward substance use by and pharmacological treatment of ethnic groups are only just beginning to be conducted. An example of an

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early finding is that approximately 50% of Northeast Asians (Chinese, Japanese, Koreans) have a deficiency in the liver aldehyde dehydrogenase (ALDH2), which leads to slower oxidation of acetyldehyde and a resulting "flushing reaction" following ingestion of alcohol. This is considered to be a protective factor against alcohol abuse by Asians (Li 2000). Coping with the reaction, however, can be learned in order to accommodate a Western lifestyle. An inactive cytochrome P450 2A6 (CYP2A6) enzyme may also account for a reduced rate in smoking among certain groups, but this finding requires further replication (Pianezza et al. 1998). Socioeconomic disadvantage also leads to differential health outcomes, including fatal and nonfatal overdoses, hepatitis B and C infection, AIDS, increased risk of pregnancy, and perinatal complications.

Psychological Factors Cultures fostering shame and guilt as means of social control have been reported to facilitate alcohol abuse. Low self-esteem, self-confidence, assertiveness, and a "loss of face" have all been related to the use of substances among adolescents in general and in migrant groups in particular (Bhattacharya 1998). The higher rate of suicide among Native American youth following substance use is the ultimate resulting tragedy (Resnick and Dizmang 1971). The general protective effect of norms and values in Asian cultures has also been investigated, including traditional values such as responsibility to others, interdependence, restraint, and group achievement (Sue 1987).

CLINICAL CULTURAL FORMULATION Through a cultural assessment, the clinician can gather a better understanding of the patient's subjective view of the world, the meaning of the illness to him or her, and his or her expected recovery process. The DSM-IV-TR outlines the following assessment categories (American Psychiatric Association 2000): Identification of the cultural identity. The overarching ethnic group must be complemented by further descriptors, such as where the patients were raised and by whom, parents' and grandparents' ethnicity, and involvement with both culture of origin and host culture. Explanation for the current illness. The predominant idioms of distress must be articulated, in addition to the meaning and perceived severity of the symptoms in relation to cultural norms. Traditionally, diagnostic evocation of culture has been associated with rare culture-bound syndromes rather than the much more common clinical presentations found in daily practice, which include the following factors: Norm conflict. When standards held desirable by a culture conflict with the person's behavior. Normative versus deviant behavior. Any substance use in an abstinence-based group would be considered deviant, but not necessarily pathological from a health perspective. Socially prescribed use. As when use in religious rites is replaced by secular use, often involving new routes of administration (e.g., from eating to smoking opium) and/or new forms of the substance (e.g., opium to heroin). Cultural change. Achieved through migration and exposure to new norms. Cultural environment and function. Patient's interpretations of social stressors and available social supports are elicited, including religion and levels of functioning and disability. Cultural aspects of the clinician–patient relationship. Similarities and differences between the clinician and patient's language, social context, as well as beliefs and behaviors of relevance to the clinical onset, course, and treatment create a set of dynamics that should be part of the cultural formulation (Figure 4–1). Transference and countertransference issues can be understood once underlying mechanisms, such as projection or stereotyping, become visible (Moffic et al. 1988; Westermeyer et al. 2006). FIGURE 4–1. Cultural dynamics in clinical assessment.

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Realistic clinical challenges arise when the largely open-ended socioanthropological conversation that is required to assess culture collides with the need for a clinical interview focused on making a diagnosis and establishing a treatment plan. An adequate cultural assessment may require several interviews to get to know the person behind the illness. Often, belief systems may differ with regard to the nature of the behavior or diagnosis versus treatment compliance, adding to the complexity of clinical care (Bhui and Bhugra 2002). Attempts at bridging qualitative or quantitative gaps to improve cross-cultural research methodology have included the design of instruments, such as the somewhat elaborate Explanatory Model Interview Catalogue (Weiss 1997) or the briefer Short Explanatory Model Interview, using vignettes (Lloyd et al. 1998).

CULTURAL INFLUENCES ON DSM AND ICD NOSOLOGICAL CLASSIFICATIONS Do our current diagnoses, such as substance use dependence and its criteria, have universal applicability or are cultural influences strong enough to require reframing our diagnoses and criteria (Room 2006)? So far, the answer to the question is mixed. Kraepelin (1902) was perhaps the first to use a universalistic approach to psychopathology. Jellinek (1960), in his conceptualization of alcoholism as a disease, recognized different types whereby the "Gamma" species derived from the Anglo-Saxon drinking pattern, the "Delta" species from the French drinking pattern, and the "Epsilon" from the Finnish pattern. Analyses of the applicability of the World Health Organization's Alcohol Use Disorders Identification Test (AUDIT) in six diverse cultures elicited considerable cross-cultural generalizability (Hall et al. 1993). Site-specific, cross-cultural analysis of the validity of DSM and ICD classifications showed that the constructs of alcohol dependence items were more familiar to respondents in Sydney, Australia, than to respondents in Bengalore, India, thereby resulting in lower reliability (Chatterji et al. 1997). The attribution of causality varies across cultures. A World Health Organization survey of key informants on the cross-cultural applicability of diagnostic criteria found differences as to when item threshold was considered positive. For example, in Athens, Greece, and Santander, Spain, where regular drinking is normalized, problem thresholds were set much higher. The value, moral judgment, and stigma associated with use of other psychoactive substances also differ from society to society (Schmidt et al.

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1999). Stigmatization also influences the terminology used to describe substance abuse. The term addiction, defined as compulsive drug-seeking behavior, was cast away in 1987 by the DSM-III-R committee in favor of the term dependence, which was perceived as more neutral by a single majority vote (American Psychiatric Association 1987). Currently, dependence is perceived to be too closely associated with physical dependence and its consequent withdrawal symptoms. A lobbying effort to revert to addiction and its connotation of loss of control over intense urges despite negative consequences is underway for the planned DSM-V. Pain patients, for example, in need of opiate medication may forgo their treatment due to the fear of dependence (O'Brien et al. 2006). ICD-10's harmful use shuns, in principle, negative social consequences or reaction of others to drug use as criteria, whereas DSM-IV-TR's abuse incorporates them (American Psychiatric Association 2000; World Health Organization 1992). British psychiatry takes the view that social reactions and consequences do not belong in the definitions of diseases and disorders (Room 2006). Both categories of harmful use and abuse do not perform very well in test-retest studies. In the United States, half of the cases diagnosed as alcohol abuse are related to the criterion of hazardous use, as in, "driving under the influence," raising the question of whether a culturally reprehensible and unwise behavior in isolation warrants a psychiatric diagnosis (Hasin et al. 1999). Differences in health care systems, from a national insurance to a more entrepreneurial fee-for-service, may also influence the nosology, depending on a more or less assertive determination of the limits of practice through recognized diagnoses.

MANAGEMENT IMPLICATIONS Empowering a community to manage its own risks for addiction is a complex but promising task. The process involves culturally sensitive public and private leadership and coordinated health, education, law enforcement, and social programming. The goals vary depending on community needs and values, from responsible drinking or gambling to a focus on reducing intoxication to the establishment of "dry" communities. A multigenerational healing process may be required, as has been successfully initiated in a number of Native American communities. An often-repeated research finding is that treatment resources in Western countries are underused by minority ethnic groups. Legal prospective immigrants to these countries are subject to health screening in their home countries. In Canada, the discovery of a person's undeclared, preexisting, chronic illness prior to obtaining citizenship may be grounds for deportation, providing a disincentive for immigrants to use the health care system. Encounters with the health care system and/or the social welfare system and the intimacy involved in dealing with health care issues are fraught with wide ranging cross-cultural challenges. Language appreciation (i.e., proficiency, fluency), the individual right for confidentiality versus the family expectation for information, the fear of rights being taken away, the ease of disclosure in a therapeutic group involving both sexes, as well as the use of condoms or needle exchange are all examples of barriers to using the health care system.

Alternate Models of Care The increasing multiethnicity of Western English-speaking countries has sparked a debate about optimal models of culturally sensitive delivery of care. In this section, we examine some possible models.

Separate services for ethnic minority groups In the United States, separate public and voluntary sector services for African Americans, Hispanic Americans, and Native Americans are commonplace. Religious denominations sponsor certain hospitals and social services for members of their religion. Lending credibility to the argument for allowing creation of separate services are consistent research findings that show that members of ethnic minorities may experience increased coercive treatment and social encounters that promote their distrust in secular hospitals. These experiences are often based on a mutual lack of knowledge of

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cherished cultural, spiritual, and religious beliefs, as well as a perceived slow pace of change. Against the idea of separate services are the fears of promoting "ghettoization" and further marginalization of many people who are already marginalized (Bhui and Sashidharan 2003).

Cultural consultation model How should major urban centers in which over a hundred languages are spoken respond to health care needs? In Montreal, Canada, a specialized multidisciplinary team brings together clinical experience with cultural knowledge and linguistic skills. The team provides consultations to other clinicians, rather than taking on patients, for continuing care over two to three interviews, which includes the family as well. Team members are involved in the training of interpreters and other culture-link workers (Kirmayer et al. 2003).

A melting pot approach for the cultural mosaic In the melting pot approach, institutional factors promoting ethnic inequalities are addressed. Culturally influenced or capable services are important to the mainstream delivery of services and not only to minority ethnic groups. In this approach, culture is not perceived as a problem or disability for minority groups that require specialized interventions. Mainstream services are commonly enriched by responding to the needs of all cultural groups, guaranteeing equality of access, and ensuring rights for all individuals (Bhui and Sashidharan 2003).

A hedge-your-bets approach Advocates of a hedge-your-bets strategy acknowledge, for example, that following both prescribed medication and ethnic spiritual therapy may be the best hope for securing adherence. This model also encourages a more honest discussion of the other therapies being tried and their interaction from the reading of sacred texts to the possible infliction of physical harm. Two potent instruments of change are commonly recognized in the cross-cultural treatment literature. The significance of the family as the conduit of cultural norms and values is recognized in most ethnically sensitive programs. Supporting the family foundation and home stability are cherished goals in communities originating from cultures with a strong extended-family network and threatened by the reduced family mosaic in our societies. A sensitive family assessment will encompass the individual roles of all members and respect their potential utilization toward a positive outcome (Delgado 1995). Religious affiliation and religious beliefs also play a major positive role in the development of prevention networks for recovery and treatment compliance in many ethnic groups (Galanter 2006). The adaptation of 12-step programs to many cultures in various parts of the world is an example of a common value placed on spiritual growth as an ingredient of recovery. Cultural recovery may involve regaining a viable ethnic identity and developing a healthy affiliation with an individual's ethnic group, as well as reacquiring a functional social network, a religious or spiritual commitment, a rebuilt social status in the recovering as well as the cultural community, and reestablished vocational and recreational activities. Cultural recovery starts after physical and psychological recovery begins and often takes years (Westermeyer et al. 2006). Unreasonable cultural expectations, as well as cultural cues to resume the addictive behavior, may delay recovery, whereas cultural abstinence-based programs may facilitate recovery.

CONCLUSION The goal of this chapter is to advance knowledge of how to provide optimal clinical care to individuals from cultures different than our own. The impact of ethnicity is moderated by a number of risk and protective factors. Sometimes everything is attributed to ethnicity or culture, whereas at other times the existence of cultural impact is completely denied. Concentration on cultural differences may lead to missed important diagnostic signs. Cultural sensitivity is not a fixation on culture and it should not be a ready explanation for the unexplained. Currently, the methodological differences used in various studies lead us to caution about the validity and reliability of the results. Many conclusions range from the

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subjective to the speculative. A better understanding of the patient can be gained through systematic cultural formulation, which includes the cultural aspects of the clinician–patient relationship. Minority groups underutilize our treatment and social services. Making these services more user friendly should be a first-order concern in our multicultural societies when the subject of alternate models of care is addressed.

KEY POINTS Culturally sensitive clinical care is required for individuals from different cultures. The impact of ethnicity is moderated by both risk and protective factors. A cultural assessment provides a better understanding of the patient's subjective views. Nosological classifications are influenced by culture. Culturally sensitive care can be delivered either through separated services, a consultation model, or a sensitized melting pot approach.

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Hasin D, Paykin A, Endicott J, et al: The validity of DSM-IV alcohol abuse: drunk drivers versus all others. J Stud Alcohol 60:746–755, 1999 [PubMed] Jellinek EM: The disease concept of alcoholism. New Brunswick, NJ, Hillhouse Press, 1960 Johnson RC, Nagoshi CT, Ahern FM, et al: Cultural factors as explanations for ethnic group differences in alcohol use in Hawaii. J Psychoactive Drugs 19:67–75, 1987 [PubMed] Kamien M: Alcohol and drug problems in minority groups. Australian Drug and Alcohol Review 5:59–61, 1986 Keyes CF: Towards a new formulation of the concept of ethnic groups. Ethnicity 3:202–212, 1976 Kirmayer LJ, Groleau D, Guzder J, et al: Cultural consultation: a model of mental health service for multicultural societies. Can J Psychiatry 48:145–153, 2003 [PubMed] Kraeplin E: Clinical Psychiatry. Adapted by Defendor AR. New York, The Macmillan Company, 1902 Li TK: Pharmacogenetics of responses to alcohol and genes that influence alcohol drinking. J Stud Alcohol 61:5–12, 2000 [PubMed] Lloyd KR, Jacob KS, Patel V, et al: The development of the Short Explanatory Model Interview (SEMI) and its use among primary care attenders with common mental disorders. Psychol Med 28:1231–1237, 1998 [PubMed] Moffic MS, Kendrick EP, Reid K. Cultural psychiatry education during psychiatric residency. J Psychiatr Educat 12:90–101, 1988 O'Brien CP, Volkow N, Li T-K: What's in a word? Addiction versus dependence in DSM–V. Am J Psychiatry 163:764–765, 2006 [Full Text] [PubMed] Pianezza LM, Sellers EM, Tyndale RF. Nicotine metabolism defect reduces smoking (letter). Nature 393:750, 1998. Resnick KH, Dizmang LH: Observations on suicidal behavior among American Indians. Am J Psychiatry 127:882–887, 1971 Room R: Taking account of cultural and societal influences on substance use diagnoses and criteria. Addiction 101 (suppl 1):31–39, 2006 Rudgley R: The archaic use of hallucinogens in Europe: an archeology of altered states. Addiction 90:163–164, 1995 [PubMed] Schmidt L, Room R, et al: Cross-cultural applicability in international classifications research on alcohol dependence. J Stud Alcohol 60:448–462, 1999 [PubMed] Standage T: A History of the World in 6 Glasses. Toronto, Canada, Random House, 2006, p 311 Sue D: Use and abuse of alcohol by Asian Americans. J Psychoactive Drugs 19:57–66, 1987 [PubMed] Weiss M: Explanatory Model Interview Catalogue (EMIC): framework for comparative study of illness. Transcult Psychiatry 34:235–263, 1997 Westermeyer J, Mellman L, Alarcon R: Cultural competence in addiction psychiatry. Addictive Disorders and Their Treatment 5:107–119, 2006 World Health Organization: International Statistical Classification of Diseases and Related Health Problems, 10th Revision. Geneva, World Health Organization, 1992 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 5. Assessment of the Patient

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Shelly F. Greenfield, Grace Hennessy: Chapter 5. Assessment of the Patient, in The A merican Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.34 9209. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Assessment of the Patient Shelly F. Greenfield, M.D., M.P.H. Grace Hennessy, M.D.

ASSESSMENT OF THE PATIENT: INTRODUCTION Clinicians encounter patients with substance use disorders in all clinical settings. In 1995, health care spending in the United States associated with alcohol, tobacco, and drug abuse was estimated to be more than $114 billion (Horgan et al. 2001). It has been estimated that there were nearly 2 million drug-related emergency room admissions in 2004, and that out of those, approximately 1.3 million were associated with drug use or misuse (SAMHSA 2006). As much as 40% of medical inpatient admissions are related to the complications of alcohol dependence (Horgan 1993), and on any given day more than 900,000 individuals receive alcohol or drug treatment in specialized treatment programs, with most of these receiving treatment as outpatients (Horgan et al. 2001). There were nearly 1.7 million admissions to publicly funded substance abuse treatment programs in 2003 (SAMHSA 2006). However, despite the prevalence of these disorders in both general and treatment-seeking populations, substance use disorders are often undetected and undiagnosed in a variety of clinical settings (Cummings and Cummings 2000; Deitz et al. 1994) and fewer than one-third of physicians in the United States carefully screen for addiction (National Center on Addiction and Substance Abuse 2000). A thorough and accurate substance use history should therefore be a part of any medical or psychiatric interview. A number of factors influence the accurate identification, assessment, and diagnosis of substance use disorders among patients presenting for treatment. These include the clinical setting; the style of interviewing; the attitude of the clinician; and patient characteristics such as the patient's motivation and stage of readiness to change, the presence of another co-occurring medical or psychiatric disorder, and the stage of use or abuse of the substance (e.g., current intoxication, current withdrawal, early abstinence, sustained abstinence, or recent relapse). Successful treatment of substance use disorders depends on a careful, accurate assessment and diagnosis. The goals of assessment of patients with substance use disorders are 1) identifying the presence of substance abuse or dependence, as well as identifying signs and symptoms of harmful or hazardous substance use, so that prevention and early intervention might take place; 2) making an accurate diagnosis and relating this to any other co-occurring medical or psychiatric disorder; 3) formulating and helping to initiate appropriate interventions and treatment; and 4) enhancing the patient's motivation for change. In this chapter, we review principles of eliciting the history of substance abuse, key elements of the patient history, formulation of an accurate diagnosis, the use of biological tests and interviews with significant others, the use of screening instruments and structured interviews, and the enhancement of motivation through the interview. Work for this chapter was supported in part by grant K24DA019855 from the National Institute on Drug Abuse (Greenfield). The authors gratefully acknowledge assistance preparing the manuscript from Rebecca Popuch, B.A.

ELICITING THE SUBSTANCE ABUSE HISTORY The interview and elicitation of the substance abuse history are essential to making an accurate diagnosis. The setting of the interview, the clinician's style of interviewing, and patient factors can

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influence the accuracy of the history.

Setting Accurate assessment is facilitated by interview settings that provide privacy and patient confidentiality and permit adequate time to ask key questions, follow up on positive patient responses, and give feedback to the patient. It is important to address patients' concerns about confidentiality (Senay 1997). Patients may worry about whether their history will be transmitted to parents, spouses, employers, licensing boards, the courts, or other parties. The laws governing patient confidentiality—especially with respect to substance abuse by minors—may vary according to state or federal jurisdiction or with respect to the class of drug involved (e.g., narcotic treatment supported by federal funds has strict safeguards for confidentiality). It is important for the clinician to be aware of these particular laws and to communicate them to the patient (Senay 1997). In particular, the U.S. Department of Health and Human Services issued the Standards for Privacy of Individually Identifiable Health Information as part of the provisions of the Health Insurance Portability and Accountability Act. This privacy rule requires that programs notify patients that federal law and regulations protect the confidentiality of alcohol and drug abuse patient records and give them a written summary of the regulations' requirements (SAMHSA 2004). A statement that gives the patient accurate information regarding confidentiality can be critical in the patient's willingness to provide a valid self-report. Similarly, privacy in the interview setting can also allow the patient to feel comfortable providing an accurate history. Research studies have shown that patients give valid self-reports when honest self-reporting is encouraged (Weiss et al. 1998) and when they perceive few negative consequences. The time allotted should be sufficient to accomplish the essential tasks of the interview. For example, it is helpful to give the patient several minutes to freely describe his or her problem. The clinician can then move toward a more active style of gathering the history through specific questions. After completion of the history taking, there must be sufficient time for the clinician to provide the patient with a summary of what he or she has heard from the patient, to provide feedback about possible diagnoses and treatment options or recommendations, and to address the patient's specific questions.

Interviewing Style The clinician's attitude and style of history taking can also facilitate a thorough and accurate assessment. One key to the accurate assessment of individuals with substance use disorders is to be mindful of the great heterogeneity of these patients. Patients with substance use disorders may be of any ethnic background, socioeconomic circumstance, age, gender, marital or partner status, and level of employment. The epidemiology of substance use disorders reveals that there is no "typical" person with substance abuse or dependence (Robins and Regier 1991). The first possible mistake to be made in an assessment is not asking the appropriate questions to elicit the substance use history because the patient does not fit a particular profile that the clinician has in mind. A substance use history should therefore be obtained from all patients presenting for treatment. Patients with substance use disorders often report that they do not discuss their substance use openly with physicians because of their feelings of shame, discomfort, fear, distrust, and hopelessness (Center for Substance Abuse Treatment 2004; Weiss et al. 2000b). They often exhibit certain typical defenses, including denial, minimization, rationalization, projection, and externalization (Schottenfeld and Pantalon 1999). It is important to recognize these defenses and note that they can present obstacles to obtaining an accurate history. A number of interview strategies and approaches can help to circumvent these obstacles. It is often useful to begin the interview by asking an open-ended question such as "How can I help you?" or "What brought you here to see me today?" Allowing the patient to begin this way can help the clinician understand how the patient defines the problem, and this can set the direction for the rest of the interview. At the start of the interview, the clinician can permit the patient to take several minutes to further elaborate his or her understanding of the nature of the problem before

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moving into a more active and detailed mode of history taking. This also allows the clinician to get to know the patient more fully before obtaining a detailed substance abuse history. For example, it is helpful to ask the patient about other areas of his or her life history that might be less threatening, including work, family, or relationships. This helps develop rapport with the patient and can help the patient feel more at ease. Patients with substance use disorders may vary in their insight into the nature of the problem, their readiness to change, their feelings of shame, or their own explanations for what has caused their problem. For this reason, as in most psychiatric interviewing, asking questions in a simple and straightforward manner and maintaining a nonjudgmental stance is most helpful. This may be demonstrated by the phrasing of specific questions. For example, the clinician can ask, "How has cocaine caused you problems?" rather than "How has your use of cocaine been a problem?" Instead of asking "Why did you drink alcohol then?" the clinician might ask "How were you feeling before you drank?" or "Do you think there were any specific circumstances or triggers to drinking at that time?" Another approach to diminishing shame can be to phrase questions in a manner such as "Some people with alcohol problems experience blackouts (or other negative consequence or behavior). I am wondering if you have ever had that experience." This technique can be used to convey to the patient a range of experiences that others with similar problems have had and can show that the clinician is knowledgeable about these experiences and is able to hear what the patient might have to say, thereby serving to reduce shame. Clinicians can avoid using labels; instead, they can ask patients to describe their pattern of use without labeling it. For example, if the patient says, "I just drink socially but I am not an alcoholic," the clinician can explain, "It would be most helpful for me to be able to understand the pattern of your drinking, so if we look at this past week/month/etc., tell me about your drinking." As in all clinical interactions, asking questions in an honest, respectful, and matter-of-fact manner is likely to be most effective (Center for Substance Abuse Treatment 2004). Attributes of clinicians that have been shown to be effective in establishing a therapeutic alliance with patients presenting with addiction problems include respect, nonpossessive warmth, friendliness, genuineness, empathy, a supportive style, reflective listening, and a patient-centered approach (Center for Substance Abuse Treatment 2004; Miller and Rollnick 2002). Finally, it is also important that the clinician's interviewing style reflect cultural sensitivity, knowledge, and empathy (Westermeyer et al. 2004a). In practically all settings, clinicians will provide care for patients with diverse backgrounds, and such culturally competent assessment is necessary when interviewing patients to assess their substance use history. Clinicians' attitudes toward their own substance use or non-use, as well as toward their own cultural identity, can affect their attitudes toward patients' substance use, as well as toward patients' cultural and ethnic identity (Westermeyer et al. 2004a).

Patient Characteristics The interview can also be influenced by a number of patient characteristics that can affect the clinical presentation of a substance use disorder. Bearing in mind this matrix of patient characteristics can help the clinician adjust the interview to most effectively facilitate an accurate history. These patient characteristics include Age, gender, partner or marital status, legal and employment status, as well as culture and ethnicity Degree of insight into and explanation for the nature of his or her problem Medical or psychiatric comorbidity Stage in the course of the illness (e.g., recovery, recent relapse, first treatment) Current phase of use (e.g., intoxicated, withdrawing, interepisode) Stage of readiness for change and motivation A number of patient characteristics can influence the approach to the interview. For example, an interview with an adolescent who is dependent on marijuana is likely to require a different interview style than an interview with an elderly widow who has developed a drinking problem in the several

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years following her husband's death. Women may be more likely than men to explain their presenting problem as mood or anxiety related and may see their drinking or substance use as a consequence of these difficulties and not as the primary problem (Greenfield and O'Leary 2002; Greenfield et al. 2007). Cultural norms may differ regarding the quantity or frequency of use of a substance and may affect the social acceptability and the patient's description of his or her use (Westermeyer 1997). A growing literature emphasizes an ethnoculturally competent substance abuse assessment that takes into account the patient's views of how his or her ethnicity or cultural background may affect the substance abuse history or treatment (Straussner 2001). Lack of knowledge about the ways of life of others' cultures (e.g., social roles, life-cycle rituals, family and social organization, literature, art) or ethnic bias (e.g., bias toward a distinctive subgroup that exists within a culture) can lead to inappropriate diagnosis and treatment (Westermeyer et al. 2006). Clinically relevant areas of inquiry for cultural influences on substance use include normative versus deviant substance use, ceremonial versus secular substance use, and assessment of the patient's social network (Westermeyer et al. 2006). A patient's marital or partner status and employment status may also influence his or her presentation; individuals may present themselves for evaluation because of the urging or demand of significant others or because of work or legal complications resulting from their substance use. The clinical presentation may also vary depending on whether the patient presents for treatment early in the course of the illness or at a more advanced phase. For example, a patient who has intermittent binge alcohol use may present for treatment after a recent legal charge of driving while intoxicated. The patient's alcohol use may not yet qualify for a diagnosis of an alcohol use disorder. However, this interview may allow for identification of an alcohol problem early in its evolution and may provide an opportunity for early intervention. This interview will likely differ in scope and focus, for example, from that with a patient who has a 15-year history of alcohol dependence presenting for a second admission for detoxification. The current phase of drug use will also influence the clinical presentation and interview. Patients may present in different clinical settings in a state of intoxication, withdrawal, remission, slip, relapse, or maintenance. The clinician is unlikely to elicit a valid history from a patient who is acutely intoxicated (Babor et al. 1987). If possible, during intoxication the interview may be confined to the ascertainment of acute medical conditions in need of intervention (e.g., respiratory depression, pancreatitis, gastrointestinal bleeding). The complete history is best deferred to a time when the patient is no longer intoxicated. Clinicians may interview substance-using patients when they are requesting detoxification or exhibiting signs and symptoms of acute withdrawal (American Psychiatric Association 2006). In this circumstance, ascertainment of the medical need for detoxification and the prevention of withdrawal complications are the most important goals of the assessment. Because untreated alcohol withdrawal or sedative-hypnotic (e.g., benzodiazepines and barbiturates) withdrawal can result in seizures, delirium tremens, and death, the clinician must first assess the patient for signs and symptoms of withdrawal. The presence of such signs and symptoms, such as tachycardia, diaphoresis, increased hand tremors, anxiety, psychomotor agitation, nausea or vomiting, and transient perceptual disturbances (American Psychiatric Association 2000), indicates a need for inpatient detoxification. Signs and symptoms of opioid withdrawal include dysphoric mood, muscle aches, nausea or vomiting, lacrimation or rhinorrhea, yawning, fever, insomnia, as well as pupillary dilation, piloerection (gooseflesh) or diaphoresis (American Psychiatric Association 2000, 2006; Center for Substance Abuse Treatment 2004). Although opioid withdrawal is not associated with severe medical complications, inpatient detoxification may be necessary to ameliorate withdrawal symptoms that, if left untreated, could result in ongoing opioid use. With the passing of the Drug Addiction Treatment Act of 2000, outpatient detoxification and treatment with buprenorphine or buprenorphine-naloxone may also be an option, and this can be assessed in the interview as well (Center for Substance Abuse Treatment 2004). The clinician can assess if the patient is interested in buprenorphine treatment and the patient's appropriateness for such treatment by inquiring about the patient's understanding of the risks and benefits, ability to adhere to the treatment plan and follow

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safety procedures, and medical and psychiatric conditions, including pregnancy, among other factors (Center for Substance Abuse Treatment 2004). Generally, withdrawal syndromes associated with the use of marijuana and stimulants such as cocaine do not require inpatient detoxification (American Psychiatric Association 2006). Nicotine withdrawal is also managed on an outpatient basis (American Psychiatric Association 2006). A patient may also present in full, sustained remission from a substance use disorder but may report symptoms of another medical or psychiatric illness or a new onset of urges and cravings. It is important in this instance to find out the supports the patient has used to maintain abstinence and recovery, to examine how any other illness, whether it is chronic or of new onset, may be affecting the patient's ongoing recovery, and to ascertain what types of treatments or interventions may help support the patient's ongoing recovery. Similarly, the interview with a patient who presents with a recent slip or relapse to substance use may be directed toward understanding the triggers to the recent drug use, as well as an effort to identify strategies that will help circumscribe the relapse and help the patient get back on the recovery track. The patient's current stage of motivation for change will also affect the interview (Prochaska et al. 1992). The interview with a patient who is precontemplative will usually require more probing to elicit the history. Interview strategies that focus on establishing a pattern of use and that then elicit advantages and disadvantages of such use may be helpful. To establish a pattern of use, the clinician might say to the patient, "It would be helpful for me to understand the pattern of your alcohol/cocaine /marijuana/etc. use. As you know, people's use of alcohol/cocaine/marijuana/etc. varies greatly, and it would help me to understand the usual pattern for you." The clinician might then proceed to use a calendar method of ascertaining days of use in the past week, month, 3 months, 6 months, and year (Sobell et al. 1992). For the more recent time periods, the clinician can ask for patterns of use (type of substance, quantity, frequency, time of day, etc.) for each day of the past week or month. For the more distant time periods, it is helpful to anchor the questions in seasonal events or events important to the patient. So, for example, the clinician might ask whether the patient's use was the same during the previous winter holidays as it is currently. Alternatively, the clinician might ask the patient to compare the past week's or month's use of a substance to previous 6-month time intervals, such as "Would you say the current pattern of use that you just described is the same pattern you have had for the last 6 months? What about the previous 6 months? Was there ever a period when you were using more heavily? When was that?" A similar style of interviewing can be used to obtain the lifetime substance abuse history, with the clinician asking for patterns of use during successive developmental periods, such as, "Tell me about your first use. Your use in high school? College? Your twenties? After you were married?" until the clinician is satisfied that he or she has understood the course of use throughout the lifespan. After identifying these use patterns, the patient might be encouraged to identify any ways in which he or she perceives that the alcohol/cocaine/marijuana/etc. has caused negative consequences for him or her. This interview will likely differ from interviews with patients who have had a brief recent relapse after a sustained period of recovery. Elicitation of such patients' earlier history is likely to be more straightforward and to require less probing. Such patients are likely to provide an overview of their previous substance problem and of what helped them in their recovery. These interviews may be more likely to focus on the nature of the recent relapse, the particular triggers to substance use, any consequences of the relapse, and plans to help the patient return to abstinence and recovery. As in all psychiatric interviews, the empathic stance is helpful. An empathic capacity to feel the patient's experience but at the same time to maintain objectivity is critical (Frances and Franklin 1989). Patients often feel great relief when they are asked questions about their condition, because these questions reveal that the clinician is knowledgeable about the condition, can understand what the experience of the condition might be like, and may be able to offer the patient relief through some form of treatment. It is therefore also important to reserve time at the end of the interview to summarize for the patient

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what the clinician has heard about the patient's history, the way in which the clinician formulates this, any diagnostic implications that the clinician is considering, and any possible treatment options and recommendations. The clinician may begin this part of the interview by saying, "I would like to save some time to give you feedback about what we have discussed and to let you know some of my thoughts. Before I do this, is there anything else that is important that we have not had a chance to discuss or that you think I haven't asked you?" After the patient has had a chance to add any further information, the clinician can then present what he or she has heard. It is often useful to first let the patient know of any particular risk factors or vulnerabilities that he or she may have. For example, the clinician might say, "It sounds to me as if you have had a number of risk factors. You have told me that both of your parents had alcohol problems, and we know that this is likely to have made you more vulnerable to the substance. Second, you have told me that you have struggled with a mood disorder, and we know that often patients with other psychiatric disorders such as mood disorders are more vulnerable to developing problems with drugs and alcohol." The clinician might then proceed to summarize the history the patient has given and to relate the key elements of the history to specific diagnostic criteria. This should then lead to a formulation of the diagnosis and the treatment implications. To elicit key elements of the history that allow the clinician to formulate the diagnosis and to relate these elements back to the patient in a straightforward manner, it is important for the clinician to have in mind the diagnostic criteria and to use the interview to elicit history that will help establish a differential diagnosis and exclude or include the likely diagnosis for the particular patient.

DIAGNOSING SUBSTANCE USE DISORDERS Psychiatric disorders attributable to substances of abuse can generally be divided into disorders produced by the substance's pharmacological effects—such as intoxication, withdrawal, and substanceinduced disorders—and disorders related to the pattern or negative consequences of such use (Woody and Cacciola 1997). In DSM-IV and DSM-IV-TR (American Psychiatric Association 1994, 2000), both categories of these disorders are covered in the section entitled Substance-Related Disorders, which consists of two subsections, Substance Use Disorders and Substance-Induced Disorders. The substance use disorders include both substance dependence and substance abuse.

Substance Use Disorders According to DSM-IV-TR, a diagnosis of substance dependence is made when there has been a maladaptive pattern of substance use leading to clinically significant impairment or distress, as manifested by at least three of seven symptoms or behaviors that have occurred within the same 12-month period. The DSM-IV-TR criteria for substance dependence are listed in Table 5–1. In DSM-IV-TR, it is specified that the substance dependence diagnosis can be further characterized as being "with physiological dependence" if the substance dependence diagnosis is accompanied by evidence of tolerance or withdrawal or as being "without physiological dependence" when there is no evidence of either tolerance or withdrawal. A diagnosis of substance abuse is made when the individual has never before met criteria for dependence and exhibits a maladaptive pattern of substance use leading to significant impairment or distress as manifested by any one or more behaviors that have occurred within a 12-month period. The DSM-IV-TR criteria for substance abuse are listed in Table 5–2. Importantly, the criteria for substance abuse or dependence are the same, regardless of the actual substance of abuse. The presence of the behaviors and symptoms listed in Table 5–2 within the 12 months before the interview constitutes a current diagnosis, and their presence in any 12-month period earlier in the individual's life is consistent with a past diagnosis. DSM-IV-TR also provides for a number of course specifiers. Early full remission is specified if for at least 1 month but for less than 12 months no criteria for dependence or abuse have been met. Early partial remission is specified if for at least 1 month but less than 12 months one or more criteria for dependence or abuse (but less than the full criteria for dependence) have been met intermittently or

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continuously. Sustained full remission is specified when none of the criteria have been present for 12 months or longer. Sustained partial remission is used when the full criteria for dependence have not been met for a period of 12 months or longer but one or more criteria for dependence or abuse have been present. The specifier on agonist therapy is used if the individual is taking a prescribed agonist, partial agonist, or agonist/antagonist medication and no criteria for dependence or abuse have been met for that class of medication for at least 1 month. The specifier in a controlled environment is similarly used when there is full remission for a month or more and the individual is in an environment where there is restricted access to substances. Such an environment could be a locked hospital unit, a supervised residential setting, or a substance-free prison.

Harmful or Hazardous Substance Use In addition to individuals who meet criteria for substance abuse or dependence, a significant number of individuals use substances in a way that is harmful or hazardous even though their use does not meet criteria for abuse or dependence or for another substance-related disorder. With respect to alcohol, the World Health Organization defines hazardous drinkers as those whose pattern of drinking poses a high risk of future damage to physical or mental health (Babor et al. 2001; Bohn et al. 1995). It defines harmful drinking as a pattern of alcohol use that is already resulting in problems (Babor et al. 2001; Bohn et al. 1995). In addition to application of these definitions of harmful and hazardous alcohol use, in the 10th Revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10), harmful substance use is defined as "clear evidence that the substance use was responsible for (or substantially contributed to) physical or psychological harm, including impaired judgment or dysfunctional behavior" (World Health Organization 1992). This category of harmful use is the closest that ICD-10 comes to the DSM-IV-TR diagnosis of substance abuse. However, the DSM-IV-TR diagnosis of substance abuse focuses on social consequences of behavior, whereas the ICD-10 definition of harmful use focuses on psychological or physical harm. Importantly, the ICD-10 category of harmful use has greater utility cross-culturally, because the social acceptability of substance use may vary greatly from country to country (Woody et al. 1997). Although the DSM-IV-TR diagnoses of substance use disorders are in wide use in the United States, the concepts of hazardous or harmful substance use defined by the World Health Organization are especially useful to consider when the patient describes the overuse or misuse of substances and the pattern of use does not meet criteria for a DSM-IV-TR definition of a substance use disorder, but the patient's use of substances nevertheless increases vulnerability to developing a substance use disorder or is currently creating some difficulties. Such an ascertainment allows the clinician the opportunity to provide education and recommendations that may constitute early intervention for an individual when problem use already exists or that may constitute prevention in the case of someone whose use places him or her at risk. Certainly, an assessment of a patient's risk factors for developing a substance use disorder (e.g., family history of substance use disorder, personal history of problems with the substance, the presence of another psychiatric disorder) may lead the clinician to advise reduction or cessation of a particular substance even if abuse or dependence is not yet present. In the case of patients with new-onset psychiatric illness, such as bipolar disorder or schizophrenia, the risk of developing a substance use disorder is great. Moreover, intervention that leads to cessation of any substance use is a good example of prevention (Brems et al. 2002; Greenfield and Shore 1995).

Substance-Induced Disorders Disorders produced by the direct pharmacological effects of the substance are referred to as substanceinduced disorders. These include the intoxication and withdrawal syndromes, as well as syndromes such as substance-induced dementia and amnestic, psychotic, mood, anxiety, sleep, and sexual dysfunction disorders. Although all categories of substances produce an intoxication syndrome, the symptoms, signs, and durations of the syndromes vary by substance category. On the other hand, according to DSM-IV-TR, not all categories of substances produce a withdrawal syndrome or all of the other substance-induced disorders. Knowledge of the syndromes characteristic of each category of substances

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is important in eliciting an accurate history and clinical status.

CONTENT OF THE INTERVIEW History of the Substance Use Disorder An understanding of the major categories of the different substances of abuse provides the interviewer with knowledge about their characteristic intoxication and withdrawal syndromes. With this knowledge, the interviewer is better able not only to assess the patient but also to make appropriate treatment recommendations. It is important to ask patients about all categories of substances and not just the patient's primary substance of abuse. The major categories of substances of abuse are Central nervous system depressants such as alcohol and sedative-hypnotics, such as barbiturates and benzodiazepines Stimulants, such as amphetamines, cocaine, and phencyclidine (PCP) Cannabis (marijuana and hashish) Opiates, including heroin, morphine, codeine, oxycodone, methadone, buprenorphine, and fentanyl Hallucinogens, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin (mushrooms) Nicotine in the form of cigarettes, chewing tobacco or dip, and snuff Inhalants, such as paint thinner, gasoline, glue, and cleaning fluids Designer drugs, including 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy"), ketamine, and -hydroxybutyrate (GHB) A systematic and organized way of collecting information about the patient's history of substance use is to address the following areas: Age at first substance use Frequency of substance use Amount of the substance taken during an episode of use Route of administration for the substance Consequences associated with substance use Treatment history Periods of abstinence Relapses The information obtained by asking about the age at first substance-use episode serves as the framework for the history and guides the interviewer's subsequent questions. In addition, the patient's age when he or she began using substances has diagnostic and prognostic implications. Studies have shown that early onset (before age 15 years) of substance use is associated with the subsequent development of substance abuse and dependence (Chen et al. 2005; Hingson et al. 2006; Robins and Przybeck 1985; Wills et al. 1996). The early onset of substance use disorders has also been associated with childhood psychopathology that preceded the development of the substance use disorder (Hahesy et al. 2002; Ostacher et al. 2006). The age at first use of nicotine is also an important component of the history of the substance use disorder. Studies have shown that nicotine use often precedes experimentation with illicit drugs (Adler and Kandel 1981; Warren et al. 1997; Yamaguchi and Kandel 1984a, 1984b) and is more prevalent in individuals with other substance use disorders (Breslau et al. 1991; Budney et al. 1993; DiFranza and Guerrera 1990). Although it is incorrect to assume that all nicotine users have also used illicit drugs or have another substance use disorder, the age at first use of nicotine in a patient who uses other substances helps the interviewer have a more complete picture of the patient's history of substance use. Once the age at first substance use is established, inquiries about the frequency of substance use as well as the amount of the substance used and the route of administration (oral, inhaled, insufflated or snorted, intravenous, subcutaneous) help the interviewer understand the progression or regression of

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substance use over time. For example, a patient who says she started snorting (route of administration) one bag (amount) of heroin once a week for 1 year (frequency) and then began using three bags of heroin per day by the intravenous route is reporting her progression of heroin use in all three areas. In addition, the frequency of use, the amount of the substance used, and the route of administration may be related to the development of medical disorders associated with a particular substance and will be relevant when discussing the patient's medical history. General questions about the consequences of substance use focus on changes in academic performance, occupational functioning, and interpersonal relationships, as well as medical and legal problems associated with substance abuse. The history of substance abuse treatment includes questions about hospital admissions for detoxification, as well as admissions to other controlled living situations to support ongoing abstinence. Such programs include residential programs, halfway houses, sober houses, and therapeutic communities. Outpatient programs such as partial hospital programs, as well as group, individual, and pharmacological therapies (e.g., disulfiram, naltrexone, nicotine delivery systems) may also be a part of the patient's prior treatment. Understanding which earlier treatments did or did not help the patient achieve and maintain abstinence can serve as a guide for treatment recommendations. Finally, the interviewer should ask about involvement in self-help groups such as Alcoholics Anonymous, Narcotics Anonymous, Cocaine Anonymous, Self-Management and Recovery Training, Rational Recovery, and Women for Sobriety. Some patients may express positive or negative feelings about a particular type of self-help group. The interviewer should not support or discredit the patient's feelings about self-help groups but should try to understand the patient's reasons for such reactions, both to educate the patient about self-help groups and to formulate a treatment plan that will be most beneficial to the patient. Other components of the history of substance use are the patient's periods of abstinence and the circumstances surrounding relapses. The information about abstinent periods and relapses indicates the progression or regression of substance use, the severity of the substance use disorder, and the external factors—such as relationship difficulties, psychiatric symptoms, legal or medical problems, and treatment termination—that may have influenced the return to substance use. Finally, the interviewer should review other substances of abuse with the patient to ensure that no other substances are being used currently or have been used in the past. A patient may say he only has a problem with cocaine; however, by asking about other substances of abuse, the interviewer may find that the patient has used marijuana daily for the past 10 years but did not mention the marijuana use because he does not consider it to be problematic. Although daily marijuana use may not be significant to the patient, this pattern of use could represent marijuana abuse or dependence that should be addressed with the patient.

Psychiatric History Research studies have demonstrated an increased prevalence of substance use disorders among patients diagnosed with psychiatric disorders. For example, patients diagnosed with bipolar disorder are six times more likely than the general population to have a co-occurring substance use disorder (Regier et al. 1990). Other psychiatric disorders (Biederman et al. 2006; Hesselbrock et al. 1985; Kessler et al. 1997; Krausz et al. 1998; Regier et al. 1990; Rodriguez-Llera et al. 2006; Rounsaville et al. 1991) and personality disorders (Helzer and Pryzbeck 1988; Rodriguez-Llera et al. 2006; Rounsaville et al. 1991; Weiss et al. 1993) have also been associated with substance use disorders. Conversely, patients diagnosed with substance use disorders are more likely to have a co-occurring psychiatric disorder (Brady et al. 1991; Currie et al. 2005; Drake and Wallach 1989; Miller et al. 1989; Mueser et al. 1992, 2000). Studies have shown that the co-occurrence of substance use disorders and psychiatric disorders can worsen the prognosis for both disorders (Greenfield et al. 1998; Hides et al. 2006; Sonne et al. 1994; Weiss et al. 1988). By diagnosing coexisting substance use and psychiatric disorders, however, patients can be referred to integrated treatment for both disorders. There is increasing evidence that integrated treatment improves and enhances outcomes for both disorders (Bennett et al. 2001; Mueser

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et al. 1992; Najavits et al. 1998, 2005; Weiss et al. 2000c). It is therefore important to assess substance use disorders in patients presenting for the treatment of their psychiatric disorder and equally important to assess psychiatric disorders among patients presenting for treatment of their substance use disorder. If the patient reports symptoms consistent with a psychiatric disorder, the interviewer should inquire about the relationship between substance use and the emergence, exacerbation, or regression of psychiatric symptoms. Substance-induced psychiatric disorders occur when the symptoms of the disorder represent a change in affective or cognitive states that arises from the direct physiological effects of a substance. These symptoms are generally seen when the patient is intoxicated or is experiencing withdrawal symptoms. Examples of substance-induced psychiatric disorders include a patient who has exhibited symptoms of mania only when intoxicated with cocaine and a patient who has had panic attacks only during benzodiazepine withdrawal. In contrast, a psychiatric disorder is independent of a substance use disorder when the patient reports a history of psychiatric symptoms that predates substance use or that does not resolve after the substance use has been stopped. A useful way to determine whether psychiatric disorders predate or continue after abstinence from substances is to inquire about the presence or absence of psychiatric symptoms before the patient began using substances and during periods of abstinence. For example, a patient who was diagnosed with major depression 10 years ago and reports having used alcohol daily for the past 6 years in an attempt to ameliorate his untreated depressive symptoms had developed psychiatric symptoms before the initiation of substance use. Similarly, a patient who says that he or she continues to have auditory hallucinations 6 months after his or her last use of marijuana demonstrates psychiatric symptoms that persist during a period of abstinence. Reviewing the patient's history of psychiatric symptoms before the onset of substance use, during episodes of intoxication with or withdrawal from substances, and after cessation of substance use can help the interviewer distinguish between substance-induced psychiatric disorders (which exist because of a substance use disorder) and co-occurring psychiatric and substance use disorders.

Medical History Evaluating clinicians need to elicit a complete medical history—including current and past medical problems, surgical procedures, and medication allergies—from patients presenting for assessment of a substance use disorder. Regardless of their relationship to substance use, medical problems require treatment, and the interviewer would be remiss if he or she did not make inquiries about medical conditions and recommend treatment or make referrals for further evaluation for any conditions mentioned. In addition, patients with substance use disorders have often neglected their health and routine medical care. The clinician can ask when was the last time the patient had a complete physical examination and follow-up for any medical problems past or current. As the patient describes symptoms of a medical disorder, the interviewer will want to determine if the symptoms are related to or independent of substance use. Questions about a reported medical problem should include inquiries about the temporal relationship between the development of the medical condition and substance use. For example, a patient reports that her asthma, which was diagnosed at age 12 years, worsened about 2 years after she began smoking cigarettes at age 18. Other questions for this patient would include the continuation or resolution of symptoms after periods of abstinence. This same patient may report that when she stopped smoking for 2 weeks she had fewer asthma attacks. The role of pharmacological interventions in the treatment of medical disorders is another way to determine the effect of substance use on a medical disorder. For example, this patient may also report the failure of her previously effective steroid inhalers to treat asthma attacks in the past year. In this case, the patient's cigarette use exacerbated her asthmatic symptoms to the point that steroid inhalers were of limited therapeutic value. It is also important to ask about current and past medical problems that are specific to use of a particular substance. A description of all the medical problems associated with each category of substances is beyond the scope of this chapter; the major medical problems and disorders associated

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with the more commonly abused substances are listed below (see also Table 5–3): Alcohol: blackouts, hangovers, withdrawal tremors, withdrawal seizures and delirium tremens, aspiration pneumonia, cardiomyopathy, cerebellar degeneration, gastritis, gastroesophageal reflux disease, hepatitis, pancreatitis, Wernicke-Korsakoff syndrome. Cocaine: transient ischemic attacks, cerebral vascular events, ischemia of the gastrointestinal tract, chest pain, and myocardial infarctions. Ischemic necrosis of the nasal septum is associated with insufflating or snorting powder cocaine, whereas smoking crack cocaine may lead to dyspnea, pneumothorax, pneumomediastinum, and pulmonary infarction. Intravenous cocaine use may cause cellulitis or endocarditis. Marijuana: the evidence for medical disorders associated with marijuana use is sparse and inconclusive. Long-term marijuana use may be associated with the earlier development of respiratory carcinomas in subjects who also use tobacco or alcohol (Taylor 1988), as well as an increased risk of prostate and cervical cancer (Sidney et al. 1997). Opiates: intravenous opiate use may result in the same medical disorders as intravenous cocaine use. Other medical problems resulting from opiate use include constipation and, in overdose, respiratory depression, coma, and death. Nicotine: chronic obstructive pulmonary disease, emphysema, cardiovascular disease, peripheral vascular disease, and lung and oral carcinomas. Sedative-hypnotics: in overdose, respiratory depression, coma, and death; withdrawal tremors and seizures, as well as a major abstinence syndrome. Patients who abuse substances are at risk of contracting infectious diseases. Intravenous substance use (most commonly heroin and cocaine) with contaminated needles can result in infection with the human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. Individuals under the influence of substances may engage in risky sexual behaviors, resulting in exposure to HIV, hepatitis B, hepatitis C, and the organisms that cause gonorrhea, chlamydia, syphilis, herpes, genital warts, and human papillomavirus infection. Additionally, elevated rates of substance use have been reported among individuals with tuberculosis (Centers for Disease Control and Prevention 2007). In 2005, among approximately 13,000 tuberculosis cases in which information about substance use was available, 2.2% were injection drug users, 7.8% were noninjection drug users, and 13.9% were excessive alcohol drinkers (Centers for Disease Control and Prevention 2007). Because identification and treatment of infectious diseases has important implications for the individual and society, the medical history should include questions about risk factors for infectious diseases, as well as prior testing and treatment. In the evaluation of women with substance use disorders, it is important to ask about reproductive health history. Relevant history among women of childbearing age includes a menstrual history and ascertaining whether the patient is or may be pregnant. Women who know they are pregnant may wish to obtain additional information on risk to the fetus of the patient's most recent or ongoing substance use. If a pregnancy is in question, the patient can be offered a pregnancy test as well. A pregnancy can serve as a powerful motivator for cessation of substance use and pregnant women may wish to seek substance abuse treatment that has specialized services (Brady and Ashley 2005). Recent research emphasizes sex differences in all phases of the addiction process including patterns and levels of use, as well as the progression of the addiction process and relapse (Lynch 2006). Women can experience changes in craving and substance use during different phases of the menstrual cycle (Allen et al. 1999; Evans et al. 2002; Franklin et al. 2004; Snively et al. 2000) as well as differences in likelihood of success in stopping their use of substances such as nicotine by phase of menstrual cycle (Franklin et al. 2004; Perkins 2001). For women experiencing perimenopause or for those who are postmenopausal, changes in sleep or symptoms such as hot flashes may be relevant factors in use of substances. Lastly, understanding the relationship between the development and exacerbation of medical disorders and substance use provides the interviewer with information that may motivate the patient to change addictive behavior. The medical history will also provide the information necessary to refer the patient to appropriate medical care regardless of the origin of the medical disorder.

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Family History The family history of substance use disorders may reveal a genetic vulnerability to the patient's own development of these disorders. In one study of 1,030 female twin pairs, it was estimated that the heritability of alcohol dependence liability ranged from 51% to 59%, with the balance being attributable to environmental factors (Kendler et al. 1992, 1994). These results are similar to the estimate reported in studies of male alcohol-dependent twins (McGue 1994; National Institute on Alcohol Abuse and Alcoholism 1997). Family (Bierut et al. 1998; Kendler et al. 1997; Merikangas et al. 1998; Mirin et al. 1991; Prasant et al. 2006), twin (Kendler et al. 2006; Kendler and Prescott 1998), and adoption (Cadoret et al. 1980, 1995) studies provide compelling evidence for the relationship between genetic determinants and the development of substance use disorders. The environment created by families who have substance use disorders may also have an impact on the development of substance use disorders in their children. For example, parental modeling of drinking behavior, ethnic differences in drinking customs, parental as well as familial psychopathology, socioeconomic status, family aggression and violence, and parental cognitive impairment are risk factors that have been shown to affect the development of both alcohol dependence and other mental health problems in the children of alcoholic parents (Ellis et al. 1997). Interviewers can educate patients about genetic vulnerability to substance use disorder and risk factors in the family environment associated with the development of substance use disorder, which can provide patients with an understanding of their current problems with substances as well as compelling reasons why they should refrain from substance use.

Social and Developmental History Patient social and developmental histories provide information about factors that may have influenced the development and perpetuation of substance use disorders. An important psychosocial factor to explore is the patient's relationships with others (i.e., family, friends, peers, significant others, authority figures). During adolescence, peer relationships are a powerful influence on both the initiation and continued use of substances (van den Bree and Pickworth 2005). The interviewer will also want to know if the patient had any positive influences during adolescence such as emotionally supportive parents, membership in school organizations, or a focus on academic achievement; such factors are associated with a lower risk for substance use (Brounstein et al. 2007; Kumpfer et al. 2007; Lochman et al. 2007). Some patients may report both initial and continued use of substances because of the effects of abusive relationships. Several studies have shown an association between self-reported histories of physical and sexual abuse and the development of substance use disorders (Brown and Anderson 1991; Greenfield et al. 2002; Nelson et al. 2006; Rice et al. 2001; Wilsnack et al. 1997; Windle et al. 1995). A history of abuse may also be associated with poorer drinking outcomes in alcohol-dependent subjects after treatment (Greenfield et al. 2002; Haver 1987). A study of individuals who received intensive substance abuse treatment found that those with a lifetime history of physical and/or sexual abuse had a worse psychiatric status, more psychiatric hospitalizations, and more outpatient treatment at 1-year follow-up than those without an abuse history (Pirard et al. 2005). Conversely, the ability to have meaningful interpersonal relationships can help the patient build a social support network that might support recovery and help the patient remain abstinent (Havassy et al. 1991). Patients with substance use disorders may report the effects of substance use on their educational attainment and subsequent employment. Studies have shown that substance use may lead to school absenteeism, poor school performance, and dropout (Bray et al. 2000; Lynskey and Hall 2000; Lynskey et al. 2003). In turn, lower educational attainment has been associated with the development of alcohol abuse and dependence in adulthood (Crum et al. 1992, 1993, 2006) and may have effects on abstinence in alcohol-dependent individuals (Curran and Booth 1999; Greenfield et al. 2003). By affecting educational attainment, alcoholism has been associated with lower income and occupational status (Crum et al. 1998; Mullahy and Sindelar 1989). Finally, the interviewer should inquire about the patient's marital or partner status, because studies

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have shown that the presence or absence of a spouse or partner can be an important influence on the development and perpetuation of a substance use disorder and may also affect treatment outcomes. For example, women seeking treatment for substance use disorders are more likely than men to be single (Griffin et al. 1989; Weiss et al. 1997), to be involved with an addicted partner (Gossop et al. 1994; Griffin et al. 1989; Hser et al. 1987), or to cite interpersonal factors such as substance use by spouse, partner, or friend as reasons for their own continued substance use (Greenfield 1996; Kandel and Logan 1984). The presence of a supportive partner (Anglin et al. 1987; Eldred and Washington 1976) and the absence of an addicted partner (Nurco et al. 1982) have been shown to be the most consistent factors associated with better treatment outcomes for opiate-dependent women but not for opiate-dependent men. The social history, therefore, helps both patient and interviewer comprehend which interpersonal relationships, negative experiences, and positive achievements shaped the development and progression of the patient's substance use disorder. These same factors may also affect the outcome of the patient's treatment for substance use disorders.

PHYSICAL AND MENTAL STATUS EXAMINATIONS Physical and mental status examinations of patients presenting for an assessment of a substance use disorder are a critical part of the evaluation because (as discussed earlier) both medical and psychiatric disorders are commonly found in this population. Although a mental status examination can and must be performed regardless of the treatment setting, the interviewer may be unable to perform the physical examination. Lack of appropriate space, equipment, and training can interfere with the interviewer's ability to perform the physical examination. Patient factors such as refusal to undergo an examination or inability to cooperate with the examination due to substance intoxication or withdrawal may also be reasons to defer the physical examination at the time of evaluation. Under such circumstances, the interviewer should refer the patient to the appropriate person (e.g., primary care physician) or facility (e.g., emergency room) for a complete physical examination. Specific signs of substance use present during the physical or mental status examination will depend on the type of substance used and the presence of intoxication with or withdrawal from substances (Washburn 2002). According to DSM-IV-TR, patients who are intoxicated with amphetamines or cocaine may exhibit psychomotor agitation or retardation, diaphoresis, evidence of weight loss, and confusion. Alcohol and sedative-hypnotics can cause slurred speech, incoordination, unsteady gait, memory impairment, stupor, or coma in an intoxicated patient. Similarly, opioid intoxication is characterized by slurred speech, drowsiness, and memory impairment. One distinguishing characteristic of opioid intoxication is the appearance of pupillary constriction; severe overdose of opiates can result in pupillary dilation secondary to anoxia in the central nervous system. Cannabis intoxication can cause motor incoordination, euphoria or anxiety, sense of slowed time, and impaired judgment. An often obvious sign of cannabis intoxication is conjunctival injection. A patient who is intoxicated with hallucinogens may be anxious, depressed, or paranoid after use. Hallucinations, illusions, perceptual distortions, incoordination, diaphoresis, and tremors can also be present. Signs of PCP intoxication include psychomotor agitation, impaired judgment, dysarthria, sensitivity to sounds, ataxia, seizures, or coma. Inhalant use may cause euphoria and impaired judgment, as well as a number of observable physical signs, including incoordination, slurred speech, lethargy, ataxia, psychomotor retardation, stupor, or coma. Also described in DSM-IV-TR are withdrawal symptoms for the different substances of abuse. Patients withdrawing from either amphetamines or cocaine may present with dysphoria, psychomotor agitation or retardation, and signs of fatigue; they may complain of increased appetite, vivid and unpleasant dreams, insomnia, or hypersomnia. The withdrawal symptoms of alcohol and sedative-hypnotics may include diaphoresis, tremulousness, psychomotor agitation, responsiveness to internal stimuli, and seizures. Patients in withdrawal from central nervous system depressants may also report anxiety, insomnia, nausea, and vomiting. Lacrimation, rhinorrhea, pupillary dilation, piloerection, and yawning

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are the observable signs of opioid withdrawal; symptoms that may be reported by patients undergoing opioid withdrawal are dysphoria, fever, nausea, vomiting, muscle aches, and diarrhea. Cannabis, hallucinogens, PCP, and inhalants do not have defined withdrawal syndromes. Although many physical signs of substance use are easily observed when the interviewer performs the mental status examination, other signs of substance use are best detected by performing a thorough physical examination. For example, small circular lesions representing the point of injection of a drug into both large and small veins, also known as tracks, may be found when examining a patient who uses drugs intravenously. If infected, these injection sites may be erythematous, purulent, and warm to the touch. Similarly, a patient with hepatic damage secondary to chronic alcohol use or with hepatitis infection as a result of intravenous drug use may present with scleral icterus or a slightly enlarged liver or, in more advanced cases of hepatic damage, jaundice, abdominal distention secondary to ascites, gynecomastia, spider angiomas, palmar erythema, and caput medusa. A complete description of all the physical findings associated with substance use is beyond the scope of this chapter; these two examples are presented to illustrate the importance of a thorough physical examination to detect other signs of substance-related medical disorders that require immediate treatment. The physical and mental status examinations of a patient presenting for an evaluation of a substance use disorder can be dramatically affected by states of intoxication or withdrawal. Alterations in mood, affect, psychiatric symptoms, thought processes, thought content, speech, memory, orientation, cognition, insight, and judgment are commonly seen when patients are intoxicated with or are withdrawing from a particular substance. Similarly, substance intoxication or withdrawal can lead to significant changes in the patient's physiological state, causing abnormalities in blood pressure, body temperature, and level of consciousness, and disrupting the stability and functioning of major organ systems such as the neurological and gastrointestinal systems. In addition, the mental status examination provides important information for the diagnosis of other psychiatric disorders and for the evaluation of the current remission, recurrence, or stability of any other concurrent psychiatric disorder. A comparison of the patient's physical and mental status examinations during different stages of substance abuse treatment is one way to evaluate changes in substance use and in any concurrent medical and psychiatric disorders.

Biological Markers Biological markers can help detect the degree and regularity of the patient's substance use (Kolodziej et al. 2002). These biological markers are most frequently tested and analyzed by sampling breath, urine, blood, hair, and saliva. The highly sensitive and specific breath alcohol testing provides immediate results at low cost and minimal discomfort to the patient. The drawbacks of breath analysis include its narrow window of assessment, which varies from minutes to hours after drinking, depending on the amount of alcohol consumed and on individual differences in alcohol metabolism. Metabolites of many substances of abuse are excreted in the urine and may be detected by urine toxicology screens. The major disadvantage of urine testing is the variations in detection time for the metabolites of different substances. For example, because cocaine metabolites remain in the urine for approximately 3 days, a urine screening test performed 5 days after the last cocaine use would not detect recent use. Conversely, cannabis metabolites may remain in the urine for a month, resulting in positive urine toxicology screens after several weeks of abstinence. In turn, the detection duration may be affected by dose, frequency of use, cutoff concentration level that results in a positive urine screen, and the patient's rate of metabolism (Cone 1997). Although quantitative urine screening may overcome some of the limitations of urine toxicology screens and reduces the numbers of false positive and false negative urine screens, the cost of this test may be prohibitive, and the technology involved in qualitative urine screening requires further evaluation. In addition, adulterants and urine substitutes designed to defeat urine toxicology tests are widely available and can be easily researched and purchased over the internet, thus increasing the possibility of false negative results for patients who may use these techniques (Jaffee et al. 2007).

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Recent heavy substance use can be detected by serum testing. Alcohol exerts a direct toxic effect on hepatocytes, leading to increased levels of glycoprotein carbohydrate-deficient transferrin (Javors and Johnson 2003), glutamyltranspeptidase (Conigrave et al. 2003), serum glutamic oxaloacetic transaminase (also known as aspartate aminotransferase or AST) and serum glutamic pyruvic transaminase (also known as alanine aminotransferase or ALT). The mean corpuscular volume of red blood cells may also be increased with heavy alcohol use, demonstrating hepatic damage as well as hematological problems, such as deficiencies in vitamin B12 and folate. These blood markers can help clinicians monitor changes in the patient's physical health and may be used as a motivator to help the patient decrease or abstain from the use of alcohol. These markers, however, are not specific for alcohol-related medical problems and may be present with other disease states. In addition, blood markers may differ due to individual factors such as age, body mass index, gender, smoking, caffeine consumption, and the use of certain medications (Aubin et al. 1998; Daeppen et al. 1998). A new method for evaluating biological markers of substance use is hair testing (Klein et al. 2000). Although it is not fully understood how drugs enter the hair, hair testing may provide a longer time to detect substance use because of the greater stability of the drug in hair samples compared with samples of bodily fluids. The disadvantages of hair testing include the possibility of false positive results due to passive contact with a substance, the possible effect of individual hair characteristics (such as hair length) on the test results, and racial bias in hair testing. In addition, hair testing is a new technology that cannot provide information about the amount of the substance used or the temporal relationship between the presence of the substance in the hair and the use of the substance. Saliva testing is primarily used to detect very recent substance use and is used to identify substance use in accident victims, automobile operators, and employees before their involvement in activities in which safety is paramount. The detection time for saliva testing is relatively brief, and the technology requires further evaluation to demonstrate its validity (Kaufman and Lamster 2002). Sweat testing may detect past substance use and may act as a cumulative measure of substance use and may extend drug detection times by one week or longer compared with urine testing, but it may be less sensitive than urine testing (Huestis et al. 2000). This test is not commonly used because of individual variations in sweat production, possible environmental contamination, and difficulties in collecting and storing sweat samples. Testing for biological markers can serve an important function in the detection of substance use. The evaluating clinician should consider the substance used, the duration for substance detection, the invasiveness of the technique, and the expense of the test to determine which test is most appropriate for individual patients.

Screening Instruments and Standardized Interviews Standardized instruments exist for screening, diagnostic assessment, and evaluation of severity (see Table 5–4). A number of short self-report instruments have been developed as screens for the presence of a drug or alcohol use disorder (Allen and Columbus 1995; Kolodziej et al. 2002; Rounsaville and Poling 2000). Such tests do not provide a formal diagnosis but rather provide an indication of the likely presence of substance abuse or dependence. The CAGE Questionnaire (named for its four questions) (Kitchens 1994; Mayfield et al. 1974) asks "Have you ever: 1) felt you should Cut down on your drinking? 2) felt Annoyed by criticism of your drinking? 3) felt bad or Guilty about your drinking? 4) taken a drink first thing in the morning (Eye-opener) to steady your nerves or get rid of a hangover?" The CAGE is useful because of its brevity and ease of scoring. One positively answered question has a 90% rate of detecting an alcohol-related disorder. The Alcohol Use Disorders Identification Test (AUDIT) (Allen et al. 1997; Babor et al. 1992; Donovan et al. 2006) was designed to screen hazardous or harmful alcohol consumption as defined by the World Health Organization in a range of clinical and nonclinical settings. This 10-item questionnaire uses a 0–5 score for each question and takes less than 2 minutes to administer and 2 minutes to score (Connors

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and Volk 2004). A score of 8 or more has reasonably good sensitivity in detecting an alcohol use disorder (Conigrave et al. 1995). A three-item version (AUDIT-C) is also available (Gordon et al. 2001; Piccinelli et al. 1997). The Michigan Alcohol Screening Test (MAST) is useful in assessing the extent of lifetime alcohol-related consequences (Allen et al. 1995; Westermeyer et al. 2004b). Commonly used are a 25-item self-test version (Selzer 1971), a 13-item short MAST (SMAST; Shields and Caruso 2003, 2004; Shields et al. 2007), and other shortened forms have also been developed (Connors et al. 2004). The Drug Abuse Screening Test (DAST) (McCabe et al. 2006; Skinner 1982; Staley and el-Guebaly 1990) is a 20-item self-test designed to detect abuse of or dependence on a wide range of substances other than alcohol. The TWEAK test (the name is derived from its five items) was originally designed to screen for high-risk drinking during pregnancy (Bush et al. 2003; Dawson et al. 2001). The T-ACE (Sokol et al. 1989) is a four-item test designed to identify pregnant women at risk for drinking alcohol in quantities that might be dangerous to the fetus (Chang 2001). Neither the TWEAK nor the T-ACE has gender-based items, and the TWEAK has been validated in both male and female populations (Chan et al. 1993). The six-question CRAFFT is designed for an adolescent population and covers both alcohol and drugs (Knight et al. 2002). Questions focus on whether the adolescent has driven in a car with someone who was using substances, uses drugs and alcohol to relax, uses them alone, forgets things while using, has gotten into trouble while using substances, or has family or friends who have asked for him or her to cut back. The CRAFFT is advantageous in adolescent and young adult populations because of its brevity, ease of administration, and inclusion of items relevant to this population. It is scored 0–6: a score of 1 provides a high sensitivity and a score of 2 has reasonably good sensitivity and specificity (Knight et al. 2003). The Risk Behavior Survey (RBS) is a brief questionnaire that assesses frequency of various HIV sexual and needle-use risk behaviors and has established construct validity (Deren 1996) and demonstrated test-retest reliability (Needle et al. 1995; Weatherby et al. 1994). Several structured interviews that are used in research settings (Kolodziej et al. 2002) may also be helpful in some clinical settings. The Timeline Follow-Back (TLFB; Sobell et al. 1992) uses a calendar method that asks patients to reconstruct the type, quantity, and frequency of substance use during a specific time period. The Addiction Severity Index (ASI; McLellan et al. 1992) was developed as a structured interview to assess problem severity in seven areas frequently affected by substance use disorders. There are several other questionnaires that measure other aspects of severity. These include the Drinker Inventory of Consequences (Miller et al. 1995), which assesses the adverse consequences of alcohol dependence, and the eight-item Clinical Institute Withdrawal Assessment for Alcohol, Revised (CIWA-Ar; Sullivan et al. 1989), which provides a clinical quantification of the severity of alcohol withdrawal syndrome. The Fagerström Test for Nicotine Dependence (Heatherton et al. 1991; Sledjeski et al. 2007) was designed to provide an ordinal measure of nicotine dependence related to cigarette smoking. The Clinical Opiate Withdrawal Scale (COWS) is an 11-item screening tool with a possible score range between 0 and 48; it provides ratings for four levels of withdrawal severity of opiate withdrawal (Center for Substance Abuse Treatment 2004; Wesson and Ling 2003). Structured interviews are also reliable ways to assess diagnostic information. The Structured Clinical Interview for DSM-IV (SCID; Spitzer et al. 1992) is a clinically-based interview that aids in diagnosis of DSM-IV-TR substance-related disorders and other psychiatric disorders. The Psychiatric Research Interview for Substance and Mental Disorders (PRISM) facilitates diagnosis of DSM-IV-TR psychiatric disorders and demonstrates good reliability for establishing psychiatric diagnoses among patients with drug and alcohol use disorders (Hasin et al. 1996).

INVOLVEMENT OF SIGNIFICANT OTHERS People who seek assessment for substance use disorders often do so at the prompting of significant

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others such as family members, friends, coworkers, or treating clinicians who are concerned about the person's well-being. Several studies have shown that significant others, serving as collateral informants, can both corroborate and provide additional information about the patient's reported substance use history (Carroll 1995; Maisto et al. 1979; Sobell et al. 1997). Speaking to the patient's significant others also allows for their early involvement in treatment planning. As noted in the section "Social and Developmental History," establishing social networks may support the patient's recovery and help him or her remain abstinent (Havassy et al. 1991). Contact with collateral informants should occur only with written permission from the patient. If the request for contact with significant others is denied, it is appropriate to explore the patient's reasons for refusal. In some cases, the patient cannot provide the name of a collateral informant because he or she is socially isolated and has no significant supports in his or her life (Weiss et al. 2000a). The patient may be ambivalent about changing his or her addictive behaviors and therefore does not want significant others involved in his or her treatment. Other reasons that a patient might refuse to authorize communication with certain individuals could include involvement of a significant other in substance use; involvement of a significant other in physical, emotional, or sexual abuse of the patient; and ability of a significant other to cause social consequences such as unemployment or loss of significant relationships. The involvement of significant others as both collateral informants and social supports can have either a positive or a negative effect on the patient's initiation of and retention in substance abuse treatment. Because significant others may be a powerful influence in the patient's life, it is recommended that the interviewer contact only those who will support, rather than hinder, the recovery process.

STAGES OF CHANGE AND MOTIVATIONAL INTERVIEWING Before discussing treatment options with a patient who has a substance use disorder, the interviewer will want to assess the patient's willingness to stop using substances of abuse. Prochaska et al. (1992) described the five stages of change that patients proceed through before giving up their addictive behavior. Patients are said to be in precontemplation, the first stage, if they do not want to change their addictive behavior. These patients may resist change because they do not believe they have a problem or fail to see the seriousness of their problem with substances. The second stage, contemplation, occurs when patients are aware of and are thinking about changing their addictive behavior but have not yet committed to change. Patients may remain in this stage for an extended period of time as they weigh both the positive and negative aspects of continued substance use. When patients are in the preparation stage, they have decided to change their behavior and will do so in the near future. Patients may prepare by reducing the amount of the substance they are using or seeking a substance abuse treatment facility where they may receive help for their problem. The fourth stage, action, occurs when patients are modifying their addictive behavior, such as cessation of substance use. Finally, patients are in the maintenance stage when they sustain their changed behaviors and continuously work on relapse prevention. An example of maintenance would be a patient who has achieved 6 months of sobriety and continues to attend self-help groups to receive support for his abstinence and to educate himself about relapse prevention. The standard questionnaire, the University of Rhode Island Change Assessment (URICA), is a 32-item instrument that can be used to formally assess a patient's readiness to change (McConnaughy et al. 1983). Understanding the patient's stage of change is important for treatment recommendations. For example, a patient seeks a voluntary evaluation of marijuana use and says she is ready to stop using marijuana. Recognizing that the patient is in the preparation stage, the interviewer may refer this patient to an appropriate outpatient treatment such as psychotherapy, group therapy, or self-help groups. Giving this patient a follow-up appointment in 1 month to reevaluate her marijuana use without any other treatment recommendations would be inappropriate because she wants and is ready to change her addictive behaviors. The patient may rethink her decision to abstain from all marijuana use during that month and may choose to not seek treatment at all. For ambivalent patients in the contemplative stage, the interviewer can use motivational interviewing

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(Miller and Rollnick 2002). Motivational interviewing primarily describes a therapeutic style in which a therapist adopts a nonjudgmental and supportive stance to explore a patient's ambivalence about changing addictive behaviors. This emphasis on therapeutic style (also referred to as adherence to the "spirit" of motivational interviewing) has recently found strong empirical support that lends increased credence to the importance of the therapist's interpersonal approach to the client, as opposed to specified motivational interviewing techniques (Miller et al. 2005). The desired outcome of motivational interviewing is the resolution of the patient's ambivalence and the facilitation of an increased readiness to consider actual behavior change. This method of interviewing avoids confrontational questions and employs a communicative style that educes the patient's rationale for and the benefits of change. By using motivational interviewing, the interviewer circumvents a patient's defensiveness about substance use and creates an environment where the patient may speak more freely about the advantages and disadvantages of change. Support for the efficacy of motivational interviewing is mounting and a variety of meta-analytic integrations yield significant reductions in substance use among clients receiving motivational interviewing or adapted motivational interviewing interventions (e.g., Burke et al. 2003).

CONCLUSION In this chapter we have discussed the importance of assessing use and abuse of substances in all patients seen in the clinical setting. We have outlined the content areas of inquiry of the interview as well as the adjunctive use of the physical examination, mental status examination, biological markers, reports of significant others, and screening instruments. We have also provided suggestions for the style of interviewing that will enhance accurate assessment and motivation to change. A careful and accurate assessment of the patient will provide the necessary information for intervention and treatment planning and will increase motivation by beginning to engage the patient in the process of change.

KEY POINTS Successful treatment of substance use disorders depends on a careful, accurate assessment and diagnosis. Accurate assessment is facilitated by interview settings that provide privacy and patient confidentiality and that permit adequate time to ask key questions, to follow up on positive patient responses, and to give feedback to the patient. A substance use history should be obtained from all patients presenting for treatment. Patient assessment can be influenced by a number of patient characteristics including the patient's age, gender, ethnicity, legal, marital, and employment status; degree of insight into the nature of the problem; medical or psychiatric comorbidity; stage in the course of illness (e.g., recovery, recent relapse, first treatment); current phase of use (e.g., intoxication, withdrawing, interepisode); and stage of readiness for change and motivation. In addition to diagnosing a substance-related disorder (e.g., a substance use disorder or a substanceinduced disorder), it is important to assess individuals for harmful or hazardous use of substances. A complete substance use assessment will include eliciting history use for all the major categories of substances addressing age of first use, frequency and amount used, consequences of use, and substance abuse treatment history, as well as complete psychiatric, medical, family, and social and developmental histories. Biological markers that might be helpful in assessment include sampling of breath, urine, blood, hair, and saliva. The most commonly used biological markers are breath alcohol testing, urine toxicology screens, and serum testing of liver transaminases and carbohydrate-deficient transferrin. Assessment can be enhanced by routine use of standardized screening instruments such as the Alcohol Use Disorders Identification Test (AUDIT), the Drug Abuse Screening Test (DAST), the TWEAK or T-ACE, the Addiction Severity Index (ASI), and the Risk Behavior Survey (RBS).

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Significant others can both corroborate and provide additional information about the patient's reported substance use history, and their early involvement can be helpful in treatment planning. For ambivalent patients who are contemplating their readiness to change, the interviewer can use motivational interviewing techniques that include a nonjudgmental and supportive stance to explore the patient's ambivalence about changing addictive behaviors.

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SUGGESTED READING American Psychiatric Association: Practice Guideline for the Treatment of Patients with Substance Use Disorders, 2nd Edition. Washington, DC, American Psychiatric Publishing, 2006 Cummings NA, Cummings JL: The First Session with Substance Abusers: A Step-by-Step Guide. San Francisco, CA, Jossey-Bass, 2000 Johnson SL: Therapist's Guide to Substance Abuse Intervention, San Diego, CA, Academic Press, 2003 Miller WR, Rollnick S: Motivational Interviewing: Preparing People for Change, 2nd Edition. New York, Guilford Press, 2002 National Institute on Alcohol Abuse and Alcoholism: The Clinician's Guide, Revised, 2005 Edition. Bethesda, MD, National Institutes of Health, 2005 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 6. Patient Placement Criteria

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David Mee-Lee, David R. Gastfriend: Chapter 6. Patient Placement Criteria, in The Am erican Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.34 5322. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Patient Placement Criteria David Mee-Lee, M.D. David R. Gastfriend, M.D.

PATIENT PLACEMENT CRITERIA: INTRODUCTION Patient placement criteria are decision rules that guide care providers and care managers in assigning patients to the optimal clinical and cost-effective level of care. Extensive reviews of the treatment outcome literature demonstrate that treatment for addictive disorders is effective, but that no single treatment model or level of care is appropriate for all individuals (Berglund et al. 2003; Institute of Medicine 1990; Miller et al. 2002; National Institute on Drug Abuse 1999). However, most programs still deliver services with one predominant ideological model, whether that model is abstinence-mandated, 12-step recovery; the Minnesota Model; harm reduction, opioid maintenance treatment; social model therapeutic communities; behavior therapy models; or psychiatric and mental health approaches. In addition, most treatment and funding systems still provide for only a limited continuum of care. This treatment and funding deficiency continues to occur despite the availability of detailed criteria for a broad array of service levels that has existed for over two decades. Even without investigators whose research findings compel them to call for broad treatment options and levels of care, the multidimensional nature of addiction alone speaks to the need for implementing patient placement criteria. Substance use disorders are heterogeneous in etiology and expression and cause diverse biopsychosocial problems that vary by population. No single treatment orientation and level of care could effectively and efficiently meet the needs of all patients. Yet, in the minds of the general public and health care providers, the perception of drug rehabilitation is a fixed level of care for all patients (usually residential) for a fixed program length of stay (usually 28 days). The diagnosis drives the placement decision, not the assessed needs of the patient. Individuals are fit into fixed length-of-stay programs designed more around program specifications, which are often influenced by the available funding or benefit structure. Beginning in the latter half of the 1980s, cost containment and managed care brought pressure on providers to justify treatment referrals for each patient. After a few years of respite from health care inflation, the resurgence of costs at double and triple the general rate of inflation has once again revived the pressure for providers to manage care and costs. On a broader scale, effective use of resources is of interest not only in the context of the managed care process in the United States but also internationally, particularly in countries with national health care systems. It is in this larger context that patient placement criteria are increasingly being implemented.

RATIONALE FOR PATIENT PLACEMENT CRITERIA To understand PPC, one must be aware of the distinction between placement matching and modality matching. Placement matching refers to patient assignments made to a treatment setting with certain resource intensity. Modality matching refers to patient assignments made according to the optimal theoretical model or clinical approach that corresponds to a patient's problems (Gastfriend et al. 2000). Placement matching applies to a setting, such as intensive outpatient or residential care, whereas modality matching is focused on, for example, the suitability in a particular instance of motivational enhancement therapies or 12-step facilitation. Treatment planning involves combining modality matching with placement matching for all pertinent problems and priorities identified in the assessment

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, which identifies the least intensive level of care that can safely and effectively provide the needed resources to meet the patient's needs (Mee-Lee 1998; Mee-Lee and Shulman 2003). Level-of-care matching is the basis for cost-effective patient placement criteria. Care providers and care managers have their best opportunity for clinical and cost optimization when level-of-care matching rules are valid and a range of settings is available. In contrast to treatment modalities, levels of care are placement options or settings that offer varying treatment intensities, and degrees of 0- to 24-hour structure and medical or nursing management. Levels of care have important cost implications. For example, the following settings represent decreasing levels of expense: hospital treatment, residential treatment, day treatment, and outpatient treatment. In addition to cost implications, levels of care also have treatment effectiveness implications. For example, detoxification in a hospital level of care is far more expensive and brief compared with utilization of a continuum of five levels of detoxification, which allows a much longer length of monitored withdrawal management for the same or probably lower cost. Theoretically, certain levels of care might be expected to yield better cost savings than others; however, outcome studies have not shown conclusive benefits for inpatient versus outpatient rehabilitation or detoxification (Annis 1988; Berglund et al. 2003; Hayashida et al. 1989; Litt et al. 1989; Miller and Hester 1986). In fact, studies have consistently failed to prove that more intensive treatment settings offer better outcomes than less intensive ones. Managed care entities have used this pattern to justify eliminating higher levels of care, such as hospital-based detoxification and rehabilitation. A critical point, however, is that investigators in these studies did not attempt to distinguish which patients experience the best outcomes from which level of care. The patient placement criteria model is designed to match patients to treatment by incorporating multidimensional assessment: problem and priority identification within the context of severity of illness and the client's level of function; treatment matching of needs to services and an intensity of service within a broad continuum of care; and, finally, ongoing assessment of progress and treatment response. This system of continuous quality improvement employs a cycle of assessment, treatment matching, level-of-care placement, and progress evaluation. The approach provides a broad nomenclature and comprehensive guidelines to expand and promote flexible use of a wide continuum of services. The enhanced use of limited resources helps maintain the patient in ongoing treatment, which can improve outcome and prevents dropout and relapse. Standardized assessment should increase treatment effectiveness by helping to individualize treatment.

ORIGINS AND ORGANIZATION OF THE AMERICAN SOCIETY OF ADDICTION MEDICINE PATIENT PLACEMENT CRITERIA The most widely used and researched patient placement criteria for addiction treatment are the Patient Placement Criteria (PPC) for the Treatment of Substance-Related Disorders of the American Society of Addiction Medicine (ASAM). The most recent edition includes criteria for people with co-occurring mental and substance use disorders (Mee-Lee et al. 2001). A review of the origins and organization of the ASAM PPC is instructive for understanding PPC in general. Managed care cost pressures during the 1980s prompted the development of 40–50 sets of treatmentmatching protocols for addictions, many of which were proprietary and conflicting. The result was a haphazard, confusing system that frustrated providers who sought admission for their patients. Early in these efforts to define PPC, two sets of criteria were developed by nonprofit professional provider organizations. The Cleveland Criteria was funded by the Northern Ohio Chemical Dependency Treatment Directors Association, and the National Association of Addiction Treatment Providers (NAATP) developed their criteria. These guidelines defined rules for matching patients with addictive disorders to a variety of levels of care, within a continuum of care, based on multidimensional severity or level of function (Hoffmann et al. 1987; Weedman 1987). Despite the poor predictive validity of the Cleveland Criteria, these guidelines nonetheless became recognized as a significant contribution to the pursuit of treatment matching. Work groups of experts from internal medicine, adult and child psychiatry, pediatrics, psychology, social work, and addiction

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counseling subsequently critiqued the Cleveland Criteria and NAATP criteria and revised these into a single, new system. The result of these consensus reviews was the 1991 publication of the first edition of the ASAM PPC (Hoffmann et al. 1991). This volume describes four levels of care for adult and adolescent treatment. Levels of care are distinguished by the degree to which they provide medical management, structure, security, and treatment intensity. Several important principles guided development of the ASAM PPC. Table 6–1 outlines the principles and implications of the ASAM PPC (Mee-Lee et al. 2001, pp 15–16). The ASAM criteria specify rules for treatment matching at three time points: admission, continued-stay review, and discharge. To place a patient, the evaluator is required to screen and diagnose the patient, then assess patient characteristics in six dimensions encompassing all pertinent biopsychosocial aspects of addiction that determine the severity of the patient's illness and level of function, as described in Table 6–2. These problem areas (dimensions) have been identified as essential in the formulation of an individual patient's treatment plan and, subsequently, in making patient placement decisions. A comprehensive evaluation of a patient's immediate and longer-term needs informs the treatment and service plan regarding the variety and intensity of interventions necessary and the modalities and strategies needed (Figure 6–1). The dose and intensity of these services determine the level-of-care placement decision. For example, on Dimension 3— emotional, behavioral, or cognitive conditions and complications—if the patient is depressed, but not suicidal and impulsive, then the mental health services would not have to be intense and can be delivered at a "dose" that can safely and efficiently be provided in an outpatient clinic or a therapist's office. On the other hand, if the patient is depressed, but also impulsively suicidal, with a suicide plan and no mitigating factors, then the mental health services should be intensive, with close monitoring, and delivered at a "dose" that could safely be provided only in a closed psychiatric facility. FIGURE 6–1. Matching assessment and treatment/placement.

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Therefore, in clinical practice, the placement decision is the last step in a multidimensional assessment that guides the variety and intensity of services needed in an individualized treatment plan. Where the patient is placed should ideally be determined by the patient's unique treatment plan, not by reimbursement limitations, program ideology, or utilization reviewers. In the ASAM criteria, one prevention level and four basic treatment levels of care exist within which later editions of the criteria indicate additional sublevels and modalities: Level 0.5: early intervention. Early intervention services are designed to explore and address problems or risk factors that appear to be related to substance use, and to help the individual

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recognize the harmful consequences of inappropriate substance use. Level I: outpatient services. Level I services are provided in regularly scheduled sessions and are designed to help the individual achieve permanent changes in his or her alcohol- and drug-using behavior and mental functioning. The services address major lifestyle, attitudinal, and behavioral issues that have the potential to undermine the goals of treatment or inhibit the individual's ability to cope with major life tasks without the nonmedical use of alcohol or other drugs. Level II: intensive outpatient/partial hospitalization. Level II is an organized outpatient service that delivers treatment services during the day, before or after work or school, in the evening, or on a weekend. For appropriately selected patients, such programs provide essential education and treatment components while allowing patients to apply their newly acquired skills in real-world environments. These programs offer to arrange medical and psychiatric consultation, psychopharmacological consultation, medication management, and 24-hour crisis services. Level III: residential/inpatient services. Level III encompasses organized services in a 24-hour, live-in setting. Services are provided to individuals who need 24-hour structure and services in order to prevent imminent danger of negative consequences and to develop sufficient recovery skills to be safely transitioned to less intense levels. Level IV: medically managed intensive inpatient services. Staffed by designated physicians with credentials in treating addiction, including psychiatrists and other mental health clinicians, Level IV programs provide 24-hour, medically directed evaluation, care, and treatment of mental and substance use–related disorders in an acute care inpatient setting. Patients' mental health and substance use–related problems are sufficiently severe to require primary biomedical, psychiatric, and nursing care services. Treatment is specific to mental and substance use–related disorders. However, the skills of the interdisciplinary team and the availability of support services allow the conjoint treatment of any co-occurring biomedical conditions that must be addressed. Practitioners and others involved in running treatment programs who seek more rigorous and comprehensive multidimensional methods of assessment, especially in research settings, can most effectively evaluate the dimensions through the use of structured interviews (Gastfriend et al. 1994). Such instruments include the Addiction Severity Index (ASI; McLellan et al. 1992), the Recovery Attitude and Treatment Evaluator (RAATE; Gastfriend et al. 1995; Mee-Lee 1988; Mee-Lee et al. 1992; Najavits et al. 1997), the Clinical Institute Withdrawal Assessment (CIWA; Sullivan et al. 1989), and the Clinical Institute Narcotics Assessment (CINA; Fudala et al. 1991). The CIWA and CINA are standardized scales that can be used to evaluate the first assessment dimension: acute intoxication or withdrawal. The ASI and the RAATE can be used to evaluate patients on several dimensions. The ASI is a widely utilized, structured interview tool designed to assess substance abuse patients on seven dimensions: medical status, employment/support status, drug use, alcohol use, legal status, family/social relationships, and psychiatric status. The RAATE was initially developed by Mee-Lee (1988) and later modified and adapted for use in research on the ASAM PPC. Typical items from the RAATE include the following questions: Does the patient demonstrate a commitment to seeking help or treatment? Does the patient realize that recovery is an ongoing process requiring personal responsibility? Does the patient have a chronic physical condition or disability which interferes with treatment or recovery efforts? Is the patient able to focus on addictions treatment even if he/she has psychiatric/psychological symptoms? and Is the work/school system accommodating or supportive of the treatment/recovery program? The instruments listed above are the main feeders of an automated decision tree created to facilitate the use of the first edition of the ASAM PPC (Turner et al. 1999).

RESEARCH FINDINGS AND AUTOMATION Publication of these nonproprietary matching criteria raised considerable interest, which ranged from creation of continuing education courses on the criteria instruments across the United States to adoption of the assessment tools by managed care entities and state agencies in more than 20 states in the United States. A shortcoming existed, however, because no process of field trial testing preceded the

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publication of the criteria. This led scientists to subject the PPC to the crucial process of research testing. The literature, in general, strongly supports the need for PPC based on multidimensional assessment in treatment planning (Gastfriend et al. 2000; Hser et al. 1999; McLellan et al. 1997). Numerous studies have shown the predictive validity and cost-effectiveness of models such as the dimensions and levels of care of the ASAM PPC (Alterman et al. 1994; Annis 1988; Gastfriend and McLellan 1997; Hayashida et al. 1989; Mechanic et al. 1995). More specifically, a considerable body of work exists on the ASAM PPC itself, including at least nine evaluations involving a total of 3,641 subjects. Federal agencies—including the National Institute on Drug Abuse, the National Institute on Alcohol Abuse and Alcoholism, and the Center for Substance Abuse Treatment—have invested more than $7 million in research on the various assessment tools and placement guidelines of the PPC (Gastfriend 2001). In the earliest evaluation of the ASAM PPC, the Boston Target Cities Project used a one-page version of the ASAM criteria in a large, urban, public population. Compared with direct self-referred admission to treatment programs, patients who were referred via centralized intake centers using standardized assessment with a coarse implementation of the ASAM criteria were 38% more likely to make the transition to longitudinal treatment within 30 days and were significantly less likely to return for detoxification within 90 days (Plough et al. 1996). These findings suggested that feasibility would be within reach, because even this shortened version of the ASAM criteria was associated with improved retention. An incomplete implementation of the original ASAM criteria by McKay et al. (1997) was used to retrospectively test its psychosocial dimensions. This study suggested some areas of validity but highlighted a need for further revision. A prospective, naturalistic study examined the validity and impact of the PPC, comparing the placement of 287 adults in Washington state with 240 adults in Oregon, where a statewide PPC training model was fully implemented. Results showed that the use of standardized criteria such as the PPC led to better length-of-stay differentiation and improved utilization of the intensive outpatient level of care (Deck et al. 2003). To help deal with the complexity of the multidimensional branching logic of the PPC, researchers at the Massachusetts General Hospital Addiction Research Program implemented the ASAM criteria as a comprehensive computerized interview (Turner et al. 1999). This real-time, computerized method yielded good inter-rater reliability for the level-of-care assignment (intraclass correlation coefficient = 0.77; P <0.01) (Baker and Gastfriend 2003), comparing favorably with the literature on diagnosis and severity rating (Endicott et al. 1976; Hall 1995; Regier et al. 1994). To date, three prospective studies have tested this method in three different samples (public system Medicaid and uninsured patients, insured patients, and veterans) using three different outcomes (acute no-show to treatment, 90-day drinking rates, and long-term hospital utilization), but all three trials used the same computerized algorithm to implement the ASAM PPC in a standardized fashion (Turner et al. 1999). The first prospective study, a multisite trial in Massachusetts, is the only randomized, controlled trial of placement criteria to be conducted to date. In this project, 700 subjects were randomly selected to receive Level II or Level III treatment, either matched or mismatched, according to the recommendation of the ASAM PPC algorithm. Results showed good concurrent validity (Turner et al. 1999) and evidence for predictive validity, because higher acute no-show rates occurred in patients who were mismatched to a lower level of care than was recommended, both overall (Gastfriend 2001), in subsamples with high-frequency cocaine use (Kang et al. 2002), and in the subset of patients with comorbid symptomatology, which also had higher no-show rates when mismatched to higher level of care than recommended (Angarita et al. 2007). In the second trial, a naturalistic study of 248 newly admitted, primarily alcohol-dependent subjects in New York City, Magura et al. (2003) showed that outpatients who had received a lower level of care than that recommended by the ASAM PPC (e.g., Level I, or outpatient care was received, whereas Level II, intensive outpatient care was recommended) had significantly and substantially poorer alcohol-use outcomes 90 days later. Also of note is that this study revealed that overtreatment, according to the ASAM PPC, did not improve outcome.

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In the third trial, a naturalistic study of 95 Department of Veterans Affairs patients near Boston, Massachusetts, initial ASAM PPC matching was associated with reductions in subsequent hospital utilization. Patients whom the algorithm judged as needing Level IV (i.e., hospital) care but who were undermatched to Level III care (residential rehabilitation) utilized significantly and substantially more hospital bed days over the next 12 months than patients who were judged to be appropriately matched (Sharon et al. 2003). These results support the predictive validity and cost-effectiveness of the use of PPC. The ultimate goal of this ongoing research work is revision of the PPC that will emerge not simply from the current expert consensus process but also through the findings of multiple national and international research studies.

REVISION OF THE ASAM PPC The way that services were grouped or "bundled" in the original ASAM criteria did not allow for ample flexibility to meet individual patient needs. Between 1994 and 1995 the Coalition for National Clinical Criteria, an informal collection of stakeholders, invested in developing national criteria and formed workgroups to revise the ASAM criteria. In particular, they addressed criticism that included the limitations of featuring only four levels of care, the absence of criteria for methadone treatment, and the required association of detoxification with inpatient care (Book et al. 1995). Most critical was the need for a method of unbundling the levels of care into their component services. The second edition of the ASAM PPC (American Society of Addiction Medicine 1996) addressed many of these needs. This revision, ASAM PPC-2R, unbundled pharmacotherapies such as detoxification, and created five levels of detoxification that encompassed two levels of ambulatory detoxification, social detoxification, and medically monitored and managed detoxification. Opioid maintenance therapy (e.g., methadone) was included, and the treatment continuum was expanded to describe multilevel criteria for both outpatient and inpatient settings. For Level II (intensive outpatient) care, new criteria were described to distinguish between evening care or day treatment programs (Level II.1) and partial hospitalization (Level II.5); for Level III (residential inpatient) care, criteria were added to distinguish between clinically managed, low-intensity residential treatment (e.g., Level III.1, supervised domiciliary or working halfway house); clinically managed, medium-intensity residential treatment (e.g., Level III.3, modified, individualized treatment for cognitively impaired patients); clinically managed, high-intensity residential treatment (e.g., Level III.5, therapeutic community or residential treatment center); and medically monitored, intensive, inpatient treatment (e.g., Level III.7, residential rehabilitation with onsite nursing supervision). Criteria were added for a new level of care: Level 0.5, early intervention, which was defined as professional services for individuals who are at risk of developing substance use–related problems, but who may not yet qualify for a diagnosis. The following example illustrates the distinctions that are made in the ASAM PPC-2R (Mee-Lee et al. 2001). An alcoholic patient with a history of withdrawal seizures but only mild medical conditions would be matched to Level III.7 (medically monitored inpatient detoxification). After 2–3 days without complications, the patient would be "stepped down" to Level III.5 (therapeutic community) to deal with problems such as poor adherence; difficulty postponing gratification, with imminent relapse risk; continued support for lingering withdrawal discomfort; and lack of a safe place to live. In contrast, if the patient had a supportive family and living environment and was more committed to recovery, even though he or she was experiencing cravings to use, he or she could be safely treated in a partial hospital or even in an intensive outpatient setting. Self-/mutual-help groups would supplement professional care and provide more extensive daily recovery support. Such flexible use of levels of care would employ the least intensive and least costly settings that could be expected to address the patient's needs in both phases of treatment. The PPC-2R addressed the needs of patients with dual diagnoses (co-occurring mental disorder and substance use–related disorder), along a continuum of mental health and substance-use service sublevels. In addition, the criteria for adolescents were completely revised.

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The following features highlight specific changes made in the second edition and the ways in which the revisions have helped practitioners and programs retool services: Adolescent criteria were fully revised to broaden the continuum of care to eight levels of care. They expanded the assessment of emotional, behavioral, and cognitive conditions and complications by adding criteria for five subdomains (dangerousness/lethality, interference with addiction recovery efforts, social functioning, capacity for self-care, course of illness). These changes reflect the needs of adolescents who have co-occurring mental health and addiction problems. Level I outpatient treatment criteria were expanded to promote greater access to care for dual-diagnosis patients, unmotivated patients mandated into treatment, and others who previously had access to care only if they agreed to periods of intensive primary treatment. Knowledge and application of cognitive behavioral therapies such as motivational interviewing, motivational enhancement, solution-focused therapy, and stages-of-change work greatly increased between the PPC editions. The PPC-2R increased options for patients who previously would have been turned away as not ready for treatment or as "in denial," requiring coerced intensive treatment levels. These improvements were designed to increase access to care and hopefully engage clients earlier, utilize resources more efficiently, and improve effectiveness of recovery efforts. Expansion of criteria in Dimension 3 to "emotional, behavioral or cognitive conditions and complications." Also, with the addition of the new subdomains of assessment that address co-occurring mental and substance use–related disorders, multiple needs, not just the addiction, can now be met. Dimension 4 was changed from "treatment acceptance/resistance" to "readiness to change." This expanded the field's understanding of Dimension 4 to include assessment of the patient's readiness to change. The change also helped to make treatment more readily available to all, not just those ready to embrace abstinence and recovery. Dimension 5 was expanded to "relapse, continued use, or continued problem potential" to encompass mental health clinical presentations. Also, Dimension 5 was enhanced with an expanded "sequence of factors" that are known to contribute to relapse potential. The sequence involves the historical pattern of relapse, the acute pharmacologic response to substance(s), second-order behavioral responsivity that may mediate the preceding factors, and third-order personality or learned responses that may modify the preceding factors. "Continued-service and discharge/transfer criteria" were reduced and simplified. General continued-service and transfer/discharge criteria guidelines applicable to all levels of care were developed to replace separate continued-service and discharge criteria for each separate level of care. These changes facilitated reassessment and modification of the individual's treatment and services plan, allowing clinicians to focus more on the individual treatment plan, rather than on the patient's achievement of preset program goals. New criteria and descriptions of services were provided for the management of the patient with co-occurring mental and substance use disorders. Dual diagnosis capable (DDC) services typically can meet a patient's needs so long as the patient's psychiatric disorders are sufficiently stabilized and the individual is capable of independent functioning to such a degree that his or her mental disorders do not significantly interfere with participation in addiction treatment. Dual diagnosis enhanced (DDE) services encompass the ability to screen for and address a wide variety of mental health levels of function that co-occur with the patient's addiction-treatment needs. DDE programs are specifically designed and enhanced to meet those needs onsite for patients with significant and unstable or disabling dual-diagnosis needs. With addiction-only services, the policies and procedures for admission criteria and ongoing services and program content do not accommodate co occurring mental disorder. For example, individuals taking psychotropic medications are not generally accepted, coordination or collaboration with mental health services is not routinely present, and mental health issues are not usually addressed in

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treatment planning.

Significance As the ASAM criteria have evolved, support has broadened and resulted in adoption by payers, single-state agencies, and state Medicaid programs. In 1997, the ASAM criteria were adopted for worldwide use by the U.S. Department of Defense and by the U.S. Department of Veterans Affairs for its 171 hospitals nationwide. International collaboration has been initiated to implement the use of the criteria in European, Asian, and South American countries. A survey of 450 private substance abuse treatment agencies conducted by the National Treatment Center revealed that adoption of the first-edition ASAM PPC was associated with program survival. Specifically, programs that had not survived 24 months after an earlier survey were less likely to be ASAM adopters, and those that closed within 6 months of the initial survey had even lower adoption rates. The association between adoption of the criteria and program survival is intriguing. The National Treatment Center study group will propose more detailed, longitudinal follow-up, which will include a study of the impact of ASAM PPC on treatment quality and outcomes (Clinical Trials Network Bulletin 2004). Yet, despite the support shown for the ASAM PPC-2R, a desirable continuum of care is still only in the planning stages in many regions. Many areas lack options such as methadone treatment access for halfway house residents or office-based detoxification programs. Benefit plans and public funding often remain restricted to a limited continuum of care, even though a broader range of options could provide longer lengths of care and monitoring using the same or even fewer resources; for example, a flexible use of five levels of detoxification would likely be less expensive and allow longer withdrawal management than a few days of high-cost, hospital level of care detoxification. Nevertheless, these criteria are useful guides for improving the quality and reducing the cost of patient care, particularly for capitated systems. Hypotheses about matching services to particular patient characteristics or needs should also serve as strategic guidelines for health care networks in program development and acquisition. There is, however, the need for further methodological work and field trials to determine the efficacy of the criteria employed (Longabaugh et al. 1994).

ALTERNATIVES TO PATIENT PLACEMENT CRITERIA There is an increasing requirement for evidence-based treatment in substance abuse programs and closer scrutiny for accountability in health care delivery and quality improvement (Miller et al. 2005). More than 10 years of research in the ASAM Criteria Validity Study and several controlled studies indicated that use of the ASAM criteria is associated with less morbidity, better client functioning, and more efficient service utilization than mismatched treatment (Gastfriend and Mee-Lee 2003). As such, the ASAM criteria, if implemented faithfully, can assist the addiction treatment system in meeting these pressing requirements. However, the ASAM criteria orient treatment-matching according to fixed levels of care; and level of care is a coarse distinction that lumps together heterogeneous groups of patients with a range of needs. Instead, it may be more advantageous to orient placement criteria in the opposite direction—meeting patient needs rather than fitting program requirements (Longabaugh et al. 1995; McLellan et al. 1997). This approach of needs-to-services matching is clinically useful whether performed formally in a research design or informally in the clinic. The key operations are a multidimensional consideration of the patient's range of needs and the provision of services to address those needs. Results from several studies have shown that matching clinical services to patient needs generally yields the best outcomes in that distinct problem area, validating needs-to-services matching (Ball and Ross 1991; Institute of Medicine 1990–1992; Joe et al. 1991; McLellan et al. 1983a, 1983b, 1993a, 1993b, 1994; Moos and Finney 1995). Although needs-to-services treatment matching is a logical starting point for a new model of care planning, it is still necessary to consider the setting or level of care within which services can best be

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provided. A highly flexible, individualized approach to level-of-care assignment seems essential to clinical quality and cost efficiency. To achieve this integration with flexibility, Gastfriend (1994) proposed to the National Consortium on Patient Placement Criteria an approach termed the Cumulative Block Increment (CBI) model. Based on a building-block concept of small service units (e.g., hour-by-hour of care), this approach recommended a high-resolution assessment of individual clinical needs, followed by grouping these needs to determine the best setting for the constellation of services necessary for the patient. With the CBI model, services could be designed to taper more incrementally in an individualized fashion and would integrate level-of-care consideration with needs-to-services matching. Although the CBI model appears to offer face validity, as did earlier PPC models, empirical validation is necessary. To further advance exploration of alternatives to traditional fixed levels of care, the ASAM PPC-2R (Mee-Lee et al. 2001) proposed an experimental matrix format that matches the patient's needs to specific treatment services, rather than to broader levels of care (Table 6–3). The matrix format is multidimensional and is formatted in three columns. For each assessment dimension (which corresponds to Dimensions 1 to 6 of the traditional PPC), the "risk rating and description" (first column) suggests the severity of the patient's problem in that dimension. The treatment priorities represented by the "types of services and modalities needed" (second column) suggest the specific types of treatment services/modalities the patient requires, as well as the intensity with which those services should be delivered to appropriately address the patient's multidimensional service needs. The corresponding rating in the "intensity of service/level of care/setting" (third column) suggests the intensity of the level of care and setting that appropriately allow the treatment and service plan to be effectively delivered. Each dimension is considered separately (unbundled) from the other dimensions to allow independent assessment of all areas of potential concern, followed by an assessment of dimensional interaction.

CONCLUSION Psychiatrists, physicians, and other providers can address patients' substance use problems on a rational basis with the help of published patient-placement criteria. Adoption of formal rules such as the ASAM PPC-2R is under way in numerous states, managed care entities, professional provider societies, and provider groups, and interest in the criteria has increased internationally. Initially, such criteria relied more heavily on consensus recommendations than on empirical matching data, but outcome research data drive their continuous revision. The technology for conducting psychosocial treatment matching studies has been rapidly increasing in sophistication, and has been demonstrated to yield adequate reliability and concurrent validity. Although its predictive validity continues to be studied, the national research portfolio on placement criteria is expanding. Given the push for evidence-based practices and recent dramatic cost pressures, there is an essential public health need for further research in this area if addiction services are to continue to grow in quality and availability.

KEY POINTS Treatment outcome research demonstrates that treatment for addictive disorders is effective, but that no single model or level of care is appropriate for all individuals. The services themselves and where they are delivered should therefore be individualized to each patient's assessed needs. The patient placement criteria incorporate multidimensional assessments of severity-of-illness and level-of-function; problem and priority identification; treatment matching of needs-to-services; and level-of-care placement within a broad continuum of care. Ongoing assessment of progress and treatment response determines movement to less or more intensive levels of care. The most widely used and researched patient placement criteria tool for addiction treatment is the Patient Placement Criteria (PPC) for the Treatment of Substance-Related Disorders of the American Society of Addiction Medicine (ASAM). The most recent edition, published in 2001, includes criteria for people with co-occurring mental and substance use disorders. The ASAM PPC describe a broad range of levels of care. Yet benefit plans, public funding, and provider programs are frequently restricted to a limited continuum of care, even though a broader

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range of options could provide longer lengths of care and monitoring using the same or even fewer resources. More than a decade of research on the ASAM PPC supports the predictive validity and cost-effectiveness of the use of PPC. Based on this research, a variety of computer-assisted assessment and placement tools are in development.

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Gastfriend DR, Filstead WJ, Reif S, et al: Validity of assessing treatment readiness in patients with substance use disorders. Am J Addict 4:254–260, 1995 Gastfriend DR, Lu SH, Sharon E: Placement matching: challenges and technical progress. Subst Use Misuse 35:2191–2213, 2000 [PubMed] Hall R: Global assessment of functioning: a modified scale. Psychosomatics 36:267–275, 1995 [Full Text] [PubMed] Hayashida M, Alterman AI, McLellan AT, et al: Comparative effectiveness and costs of inpatient and outpatient detoxification of patients with mild-to-moderate alcohol withdrawal syndrome. N Engl J Med 320:358–365, 1989 [PubMed] Hoffmann NG, Halikas J, Mee-Lee D: The Cleveland Admission, Discharge and Transfer Criteria: Model for Chemical Dependency Treatment Programs. Cleveland, OH, Northern Ohio Chemical Dependency Treatment Consortium, 1987 Hoffmann NG, Halikas J, Mee-Lee D, et al: American Society of Addiction Medicine Patient Placement Criteria for the Treatment of Psychoactive Substance Use Disorders. Washington, DC, American Society of Addiction Medicine, 1991 Hser YI, Polinsky ML, Maglione M, et al: Matching clients' needs with drug treatment services. J Subst Abuse Treat 16:299–305, 1999 [PubMed] Institute of Medicine: Broadening the Base of Treatment for Alcohol Problems: A Report of a Study by a Committee of the Institute of Medicine, Division of Mental Health and Behavioral Medicine. Washington, DC, National Academy Press, 1990 Institute of Medicine, Committee for Substance Abuse Coverage Study: Treating Drug Problems. Edited by Gerstein DR, Harwood HJ. Washington, DC, National Academy Press, 1990–1992 Joe GW, Simpson DD, Hubbard RL, et al: Treatment predictors of tenure in methadone maintenance. J Subst Abuse 3:73–84, 1991 [PubMed] Kang SK, Sharon S, Pirard S, et al: Predictors for residential rehabilitation and treatment no-show in high frequency cocaine users: validation of the American Society of Addiction Medicine (ASAM) Criteria. Las Vegas, NV, American Academy of Addiction Psychiatrists, 2002 Litt M, Boca F, Cooney N: Matching Alcoholics to Aftercare Treatment by Empirical Clustering. Farmington, CT, University of Connecticut Health Center, 1989 Longabaugh R, Wirtz PW, DiClemente CC, et al: Issues in the development of client-treatment matching hypotheses. J Stud Alcohol Suppl 12:46–59, 1994 [PubMed] Longabaugh R, Wirtz PW, Beattie MC, et al: Matching treatment focus to patient social investment and support: 18-month follow-up results. J Consult Clin Psychol 63:296–307, 1995 [PubMed] Magura S, Staines GL, Kosanke N, et al: Predictive validity of the ASAM Patient Placement Criteria for naturalistically matched vs. mismatched alcohol-dependent patients. Am J Addict 12:386–397, 2003 [PubMed] McKay JR, Cacciola JS, McLellan AT, et al: An initial evaluation of the psychosocial dimensions of the American Society of Addiction Medicine criteria for inpatient vs. intensive outpatient substance abuse rehabilitation. J Stud Alcohol 58:239–252, 1997 [PubMed] McLellan AT, Woody GE, Luborsky L, et al: Increased effectiveness of substance abuse treatment: a prospective study of patient-treatment "matching". J Nerv Ment Dis 171:597–605, 1983a McLellan AT, Woody GE, Luborsky L, et al: Predicting response to alcohol and drug abuse treatments. Arch Gen Psychiatry 40:620–625, 1983b

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McLellan AT, Kushner H, Metzger DS, et al: The fifth edition of the Addiction Severity Index. J Subst Abuse Treat 9:199–213, 1992 [PubMed] McLellan AT, Arndt IO, Metzger DS, et al: The effects of psychosocial services in substance abuse treatment. JAMA 269:1953–1959, 1993a McLellan AT, Grissom GR, Brill P, et al: Private substance abuse treatments: are some programs more effective than others? J Subst Abuse Treat 10:243–254, 1993b McLellan AT, Alterman A, Metzger DS, et al: Similarity of outcome predictors across opiate, cocaine and alcohol treatments: role of treatment services. J Clin Consult Psychol 62:1141–1158, 1994 [PubMed] McLellan AT, Grissom GR, Zanis D, et al: Problem-service "matching" in addiction treatment: a prospective study in 4 programs. Arch Gen Psychiatry 54:730–735, 1997 [PubMed] Mechanic D, Schlesinger M, McAlpine DD, et al: Management of mental health and substance abuse services: state of the art and early results. Milbank Q 73:19–55, 1995 [PubMed] Mee-Lee D: An instrument for treatment progress and matching: the Recovery Attitude and Treatment Evaluator (RAATE). J Subst Abuse Treat 5:183–186, 1988 [PubMed] Mee-Lee D: Use of patient placement criteria in the selection of treatment: overview of addiction treatment, in Principles of Addiction Medicine, 2nd Edition. Chevy Chase, MD, American Society of Addiction Medicine, 1998, pp 363–370 Mee-Lee D, Shulman GD: The ASAM Patient Placement Criteria and matching patients to treatment: overview of addiction treatment, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 453–465 Mee-Lee D, Hoffmann NG, Smith M: Recovery Attitude and Treatment Evaluator (RAATE) Manual. St Paul, MN, CATOR/New Standards, 1992 Mee-Lee D, Shulman GD, Fishman M, et al: ASAM Patient Placement Criteria for the Treatment of Substance-Related Disorders, 2nd Edition, Revised (ASAM PPC-2R). Chevy Chase, MD, American Society of Addiction Medicine, 2001 Miller WR, Hester RK: The effectiveness of alcoholism treatment: what research reveals, in Treating Addictive Behaviors: Processes of Change. Edited by Miller WR, Heather N. New York, Plenum, 1986, pp 121–174 Miller WR, Wilbourne PL, Hettema JE: What works? A summary of alcohol treatment outcome research, in Handbook of Alcoholism Treatment Approaches: Effective Alternatives. Edited by Hester RK, Miller WR. New York, Allyn and Bacon, 2002, pp 13–63 Miller WR, Zweben J, Johnson WR: Evidence-based treatment: why, what, where, when, and how? J Subst Abuse Treat 29:267–276, 2005 [PubMed] Moos RH, Finney JW: Substance abuse treatment programs and processes: linkages to patients' needs and outcomes. J Subst Abuse 7:1–8, 1995 [PubMed] Najavits LM, Gastfriend DR, Nakayama EY, et al: A measure of readiness for substance abuse treatment: psychometric properties of the RAATE research interview. Am J Addict 6:74–82, 1997 [PubMed] National Institute on Drug Abuse: Principles of drug addiction treatment: a research-based guide (NIH Publ No 00–4180). Rockville, MD: National Institute on Drug Abuse, 1999 Plough AL, Shirley L, Zaremba N, et al: CSAT Target Cities Demonstration Final Evaluation Report, Boston Office for Treatment Improvement. Boston, MA, Massachusetts Bureau of Substance Abuse Services, 1996

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Regier DA, Kaebler CT, Roper MT, et al: The ICD-10 clinical field trial for mental and behavioral disorders: results in Canada and the United States. Am J Psychiatry 151:1340–1350, 1994 [Full Text] [PubMed] Sharon E, Krebs C, Turner W, et al: Predictive validity of the ASAM Patient Placement Criteria for hospital utilization. J Addict Dis 22 (suppl 1):79–93, 2003 Sullivan JT, Sykora K, Schneiderman J, et al: Assessment of alcohol withdrawal: the revised Clinical Institute Withdrawal Assessment for Alcohol Scale. Br J Addict 84:1353–1357, 1989 [PubMed] Turner WM, Turner KH, Reif S, et al: Feasibility of multidimensional substance abuse treatment matching: automating the ASAM Patient Placement Criteria. Drug Alcohol Depend 55:35–43, 1999 [PubMed] Weedman RD: Admission, Continued Stay and Discharge Criteria for Adult Alcoholism and Drug Dependence Treatment Services. Irvine, CA, National Association of Addiction Treatment Providers, 1987

SUGGESTED READING Gastfriend DR (ed): Addiction Treatment Matching—Research Foundations of the American Society of Addiction Medicine (ASAM) Criteria. Binghamton, NY, Haworth Medical Press, 2004 Mee-Lee D: ASAM patient placement criteria: implications for assessment and treatment of patients with co-occurring disorders. Counselor Magazine 5:28–33, 2005 Mee-Lee D: ASAM's placement criteria: what's new. Behavioral Health Management 3:32–34, 2005 Mee-Lee D, Shulman GD: The ASAM Patient Placement Criteria and matching patients to treatment: overview of addiction treatment, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 453–465 Mee-Lee D, Shulman GD, Fishman M, et al: ASAM Patient Placement Criteria for the Treatment of Substance-Related Disorders, 2nd Edition, Revised (ASAM PPC-2R). Chevy Chase, MD, American Society of Addiction Medicine, 2001 Miller SD, Mee-Lee D, Plum B, et al: Making treatment count: client-directed, outcome informed clinical work with problem drinkers, in Handbook of Clinical Family Therapy. Edited by Lebow J. New York, Wiley, 2005, pp 281–308 TIPS and TOPICS: Free monthly newsletter that provides clinical knowledge and skills tips on personcentered services and application of PPC principles. Sign up on www.DMLMD.com Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 7. Evolution in Addiction Treatment Concepts and M...

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A. Thomas McLellan: Chapter 7. Evolution in Addiction Treatment Concepts and Methods, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.345610. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Evolution in Addiction Treatment Concepts and Methods A. Thomas McLellan, Ph.D.

FORCES LEADING TO A CHANGED APPROACH TO ADDICTION TREATMENT There has always been broad recognition that alcohol and drug abuse are partly or fully responsible for such serious public health and public safety problems as traffic accidents, street crime, transmission of infectious diseases, child abuse and neglect, and excessive use of medical services. During the 1970s, addiction treatments gained prominence as a social response to these addiction-related problems. This was because addiction treatments were less expensive than the available alternatives (e.g., jail or hospitalization) and because there was social compassion for the many addicted veterans of the Vietnam War whose substance use problems were seen as a result of that war. Because of concern for patients as well as concern over the pressing public health and safety problems associated with addiction, treatments were predominantly hospital based or residential (Musto 1973), focused upon bringing total abstinence from all substances, and designed to develop a sense of "right living" (De Leon 2000) among those affected and bringing an end to the "addiction lifestyle." Concurrent with the increase in public willingness to treat addiction, not just punish it, came substantial increases in federal funding for research on addiction within the National Institutes of Health (White 1998, 2004). Although cure for addiction was virtually never discussed as a treatment goal, the treatment system was structured, delivered, insured, and evaluated under this tacit expectation (McLellan et al. 2005; White 1998). Specifically, almost all treatments were time limited; proximal goals for providers were to bring patients to graduation or completion of care; and evaluations were conducted 6 or 12 months after treatment completion, with "1-year abstinence rates" being the implicit standard of evaluation within the field (see McLellan 2002). However, by the last decade of the twentieth century, there was broad dissatisfaction with the country's response to drug abuse problems. Increased surveillance, interdiction, and criminal penalties had not reduced drug availability appreciably (see SAMHSA 2002). In addition, a series of new drug epidemics, including crack cocaine starting in the 1980s and methamphetamine and pharmaceutical opioids starting in the 1990s, brought new public demands for an effective approach to the "drug problem." The country's response to drug abuse problems also revealed a general dissatisfaction with the effectiveness of treatments for addiction ("Editorial Commentary" 1997). The addiction treatment field had not met either public expectations for reduction of addiction-related problems or its own intentions to produce lasting abstinence among those treated. Indeed, a majority of patients, including courtordered patients, were leaving care prematurely, and relapse rates, even for those who completed care, were generally more than 50% by 6 months (for reviews see McLellan and Meyers 2004; Prendergast et al. 1998). Moreover, the costs of health care in general and addiction care specifically were seen as catastrophic by employers, prompting them to engage various managed care intermediaries to reduce the "runaway increases" in care utilization and costs (Institute of Medicine 1997, 1998). By the end of the century, the cost-containment effects of managed care had eliminated or drastically reduced most residential care to less than 10% of all care provided by 2000 (Institute of Medicine 1997, 1998, 2006; McKusick et al. 1998). The author of this chapter is supported by ongoing National Institute on Drug Abuse Health Services

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Research grants and by an unrestricted grant from the Robert Wood Johnson Foundation.

RESEARCH LEADING TO A NEW MODEL OF ADDICTION TREATMENT At this writing, the addiction problems facing the United States are somewhat different but no less significant than at other points over the past 50 years. The public is still demanding action to address substance abuse and the related problems, and the experience garnered in recent decades has offered some hard-learned lessons as well as four promising new research findings, discussed in the text that follows, that have set the stage for a new model of care for addiction.

A Continuing Care Perspective The research of Drs. M. Douglas Anglin, Yih-Ing Hser, Christine E. Grella, and their University of California, Los Angeles, colleagues was among the first to examine the lifetime trajectory of those with addiction problems, putting perspective on the effects of any single treatment episode. Their findings indicated that most addicted individuals had "addiction careers" of 20 years or more in which relatively brief episodes of treatment and incarceration gradually led to increasingly long periods of abstinence (Anglin et al. 1997; Hser et al. 1997, 2003). This work showed the chronic and complex nature of addiction; showed that problems of crime, unemployment, mental illness, and infectious disease were not all etiologically linked to the addiction; and helped to reset expectations about the nature and extent of benefits that might be expected from any single treatment episode. Abstinence by itself was not likely to result in substantial reductions in the associated public health and safety problems, and without a reduction in those problems, abstinence was not likely to be sustained.

A Staged Model of Treatment Since 1985, Simpson et al. (1999) followed and researched a very large sample of publicly treated patients during and after an index treatment episode. These researchers measured the nature and amount of treatment elements and services actually delivered during standard care. With these measures and state-of-the-art statistical modeling, they ultimately arrived at a multistage model of care that provided a new perspective on the way treatments might be expected to provide benefits. Rather than consider treatment as a single box containing a fixed set of ingredients, they identified a staged care model in which each stage of the treatment episode had definable behavioral goals for the patient that would prepare him or her to do well in the subsequent stage of care (Simpson 2004). This model of care suggests the benefits of extending treatment over a greater period of time and offers an evidence-based method of evaluating a patient's (and a treatment program's) progress in attaining those goals.

Parallels With Other Chronic Illnesses In a contemporaneous set of studies at the Treatment Research Institute and at the University of Pennsylvania School of Medicine, my colleagues and I examined parallels between addiction and chronic medical illnesses such as hypertension, diabetes, and asthma (see McLellan 2002; McLellan et al. 2000; O'Brien and McLellan 1996). This research showed that although there were differences among these illnesses, there were significant similarities in terms of the behavioral factors associated with the onset of all the illnesses, the genetic influences associated with vulnerability to these illnesses, and remarkably, the rates of treatment compliance (30%–50%) and relapse (30%–70%). The similarity of findings were striking to the point that they led to broad efforts to reconsider the manner in which addiction treatments were conceptualized, delivered, and evaluated.

Monitoring to Extend Treatment Benefits A final set of research findings combines with the others to suggest a different approach to addiction treatment. Researchers such as Stout et al. (1999), Dennis et al. (2003), and McKay (McKay 2001, 2005; McKay et al. 1999) have shown that traditional addiction treatments can be significantly improved and sustained by simple efforts to re-contact patients for brief monitoring and support sessions after their discharge from formal care. Stout et al. (1999) were the first to show that brief monitoring phone

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calls, done as part of the research and evaluation efforts, had the unexpected effects of increasing and sustaining the abstinence rates of those contacted. This finding was examined very thoroughly by McKay (2005) in both alcohol- and cocaine-dependent samples following intensive outpatient treatments. Again, they found that simple telephone monitoring contacts at 1-month intervals after treatment discharge were as effective or more effective than more sophisticated (and more costly) therapy sessions. A more intensive clinical procedure designed to achieve the same effects has been initiated by Dennis et al. (2003). In this recovery check-up procedure, periodic, postdischarge home visits to patients are designed for the dual purpose of evaluating the status of the patients and, when appropriate, reengaging them into care as a means of forestalling significant drug-related problems and a severe and costly relapse. Evaluations of the intervention have shown it is effective and cost-efficient at prolonging quality of life, reducing costs, and sustaining recovery.

A NEW APPROACH TO ADDICTION TREATMENT The work just described has combined to influence contemporary thought about and approaches to addiction and addiction treatment. There is now increasing acceptance that many (but not all) of those with serious addiction problems develop a chronic form of the disorder, one that is best served by a long-term clinical approach, with staged behavioral goals as suggested by Simpson (2004) and using components of care that have been shown to address the expensive addiction-related problems that are so significant to the public and so related to readdiction in the patient. Substantial research has shown that brain changes associated with addiction may persist for years following cessation of use (Volkow et al. 1992). In addition, drug cravings and high-risk situations (drug-using friends, emotional problems, stressful life events) may be lifelong issues for those in recovery to deal with. Thus, treatment of addiction, like the treatment of so many other illnesses, is now seen as a key part of a longer-term effort to help patients develop effective and rewarding self-management strategies over the long term (see Wagner et al. 1996). Treatment efforts are now more likely to supplement traditional abstinenceoriented counseling with specific efforts to equip patients with effective self-management strategies and to support those strategies through linkage to mutual help organizations such as Alcoholics Anonymous (AA) and through periodic contacts from the treatment organization in the manner suggested by the research of McKay, Dennis, and their colleagues. As addiction care has begun to take on the elements of "disease management" (Bodenheimer et al. 2002; Wagner et al. 1996) and as research has provided new clinical options such as medications, therapies, and support services, new clinical information systems have been developed to assist care delivery (Carise et al. 2005) and to simultaneously evaluate client progress, modifying the nature of care as needed to ensure continued progress (see McLellan et al. 2005). This is referred to as adaptive care in other areas of health care, and it is likely to become more prevalent in the future of addiction care (McKay 2005). It must be said that at this writing this "new approach" is still in the formative stage, and most care continues to be provided in traditional ways, predominantly in outpatient settings by specialty care providers (Institute of Medicine 2006; SAMHSA 2002). At the same time, there has been pressure from regulators (e.g., Joint Commission on Accreditation of Healthcare Organizations, state licensing) to incorporate evidence-based components of care into these programs that will promote a continuing care approach and improve the engagement and retention of patients for at least 1 year. Within the staged care model proposed by Simpson (2004), programs are encouraged to use components of care that have been developed and studied in an empirical manner—the so-called evidence-based components of care. Thus, the remainder of this chapter considers three categories of these components—medications, therapies, and services—as part of a broader approach to addiction treatment. The review is restricted to those components that have shown evidence of effectiveness in at least two randomized, controlled experiments (compared with placebo or standard care). This standard of evidence has been used by the

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U.S. Food and Drug Administration (FDA) as a key determinant for decision making. Thanks to unprecedented research support, there are now many medications, therapies, and support services that have met this standard of evidence. The number of these makes it difficult to fully account for all within the page limitations of this chapter. Thus, this chapter concentrates upon those that have shown both experimental evidence of effectiveness and evidence of applicability in real-world trials.

Three Stages of Addiction Treatment Prior to a review of research evidence on the effective components of treatment, it is important to differentiate the three phases of treatment (detoxification/stabilization, rehabilitation, and continuing care) because they have distinctly different goals and may apply different methods. These have been adapted from the Simpson model (Simpson 2004) but are somewhat truncated for ease of description.

Detoxification/Stabilization The detoxification and/or stabilization phase of treatment is designed for people who experience frank withdrawal symptoms or significant physiological or emotional instability after a period of prolonged abuse of drugs. The most significant withdrawal occurs in alcohol, opioid, or sedative/tranquilizer dependence; a characteristic rebound physiological withdrawal syndrome is experienced usually about 8–30 hours after the last dose of the drug (depending on the drug, dosage, and period of use). Users of amphetamine, marijuana, and cocaine often also experience substantial emotional and physiological symptoms and often require a period of stabilizing treatment. The purpose of this phase of treatment is not to produce lasting sobriety, but rather to prepare an unstable patient to do well in the subsequent rehabilitation phase of treatment. The major components of this phase of care include medications to relieve physiological and emotional symptoms and to reduce craving for the abused substance(s). These medications are typically accompanied by rest and motivational forms of therapy—usually in the context of a residential or hospital setting. On its own, detoxification is unlikely to be effective in helping patients achieve lasting recovery; this phase is better seen as a preparation for continued rehabilitation.

Rehabilitation The rehabilitation stage of treatment is appropriate for patients who no longer experience the acute physiological or emotional effects of recent substance abuse. In turn, the goals of this phase of treatment are to prevent a return to active substance use, to assist the patient in developing control over urges to abuse drugs, and to help the patient gain improved personal health and social functioning. Professional opinions vary widely regarding the underlying reasons for the loss of control over alcohol and/or drug use typically seen in treated patients. In turn, there is an equally wide range of treatment strategies and treatment components designed to correct or ameliorate the hypothesized underlying problems. Strategies have included such diverse elements as medications for psychiatric disorders; medications to relieve drug craving; group and individual counseling and therapy sessions to provide insight, guidance, and support for behavioral changes; and participation in peer-led, mutual-support groups (e.g., AA, Narcotics Anonymous) to provide continued support for abstinence (for reviews, see Moos 2003; Simpson 2004). Short-term residential rehabilitation programs are typically delivered over 30–90 days; residential therapeutic community programs usually range from 3 months to 1 year; outpatient, abstinenceoriented counseling programs run from 30 to 120 days; and methadone maintenance programs can have an indefinite time period. Many of the more intensive forms of outpatient treatment (e.g., intensive outpatient and day hospital) begin with full- or half-day sessions five or more times per week for approximately 1 month. As the rehabilitation progresses, the intensity of the treatment reduces to shorter sessions of 1–2 hours delivered twice per week and then tapering to once per week. Regardless of the specific setting, modality, philosophy, or methods of rehabilitation, all forms of rehabilitation-oriented treatments for addiction have the following four goals: 1) to maintain

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physiological and emotional improvements initiated during detoxification/stabilization; 2) to enhance and sustain reductions in alcohol and drug use (most rehabilitation programs suggest a goal of complete abstinence); 3) to teach, model, and support behaviors that lead to improved personal health, improved social function, and reduced threats to public health and public safety; and 4) to teach and motivate behavioral and lifestyle changes that are incompatible with substance abuse.

Continuing care The continuing care stage of treatment is the final stage of the substance abuse treatment process and is appropriate for patients who have achieved the major goals of rehabilitation. It is designed to provide continuing support for the behavioral changes achieved during detoxification and rehabilitation as well as monitoring to detect early threats to relapse. All aftercare is delivered in outpatient settings or by telephone, typically in tapering doses of group or individual counseling sessions (weekly to monthly) over a period of approximately 1 year, typically in association with parallel activities in self-help groups. Continuing care is less formalized than earlier stages and has only recently received research attention. Most of the medications, therapies, and services that have been applied and studied in the rehabilitation phase of treatment are also appropriate in the aftercare phase of treatment, but telephone and Internet forms of continuing care and monitoring are also under investigation.

Review of Effective Treatment Components Here I focus on the research findings from studies of rehabilitation—and to a lesser extent, continuing care—rather than detoxification. Studies of detoxification methods, adolescent treatments, or smoking cessation treatments were not included. As indicated previously, the components of care presented here derive from that larger body of research in which at least two randomized, controlled trials showed effectiveness of the focal component and there had been at least one large study in an important, real-world setting and population in which the component appeared to improve the outcome of care. The review began with all research studies published in English since 1986 that studied a medication, therapy, or other adjunctive service as part of the rehabilitation or continuing care stages and in which the component of care was expected to promote or extend the cessation of substance use (this last factor is quite important). Of course individuals who present for addiction treatment typically have a range of medical, employment, family, legal, and psychiatric problems—the so-called addiction-related problems. Many medications have shown significant effects in reducing some of the important general medical conditions (e.g., pain, diabetes, hypertension, infectious diseases) and the specific psychiatric disorders (e.g., depression, anxiety, attention-deficit/hyperactivity disorder, posttraumatic stress disorder) that are so prevalent among addicted patients. Because of space considerations, only medications and therapies that focus upon the goals of initiating and sustaining abstinence from substance use are considered here.

Medications There are now many medications that have shown effectiveness in reducing craving for and relapse to alcohol and other drugs. A review of the now more than 200 randomly controlled trials of various types of addiction treatments is beyond the scope of this paper (for a review see O'Brien and McKay 2002). What follows here is a brief overview of those medications that have the best-developed evidence base at this writing and are most widely used. In this regard, although there are an increasing number of effective new medications available, their use is still infrequent in part because of the lack of studies documenting their long-term effects and particularly due to state regulatory restrictions and poor insurance coverage (Institute of Medicine 2006). Thus, the appropriate use of medications in the treatment of substance dependence disorders is among the most important topics for future research in the treatment field (for a review see Finkelstein and Ramos 2002).

Medications for opioid addiction Methadone

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Methadone has been used effectively as a maintenance medication because of its oral administration, slow onset of action, and long half-life. Thirty years of studies on the effectiveness of methadone reliably report major reductions in opiate use, crime, and the spread of infectious diseases associated with heroin dependence (O'Brien and McKay 2002). The medication is also very cost effective (Zarkin et al. 2005). Despite the overwhelming research evidence, both the medication and the methadone maintenance modality continue to have a poor public image.

Buprenorphine Buprenorphine, a partial agonist, was approved in 2002 by the FDA for treatment of opioid dependence in general practice settings. Buprenorphine is administered sublingually and is also effective in reducing opiate craving for 24–36 hours. The partial agonist action of buprenorphine has some advantages over methadone, such as few or no withdrawal symptoms upon discontinuation and lower risk of overdose even if combined with other opiates (see O'Brien and McKay 2002). The fears of diversion that accompanied the release of the medication for office-based practice have not been borne out, likely because of the three policy efforts that were put into place to minimize these risks: First, only certified physicians who complete an instructional course and agree to be listed on a national registry of providers are able to prescribe the medication. Second, physician caseloads were restricted to 30 patients until late 2006, when demand for the medication—combined with the safety record to that point—led to a change to a 100-patient caseload. Finally, the manufacturer of the medication agreed to develop a combined formulation (Suboxone) that included naloxone with the buprenorphine to prevent injection use of the medication. At this writing the use of this medication has increased steadily in response to its acceptance by patients, its efficacy in reducing withdrawal symptoms and preventing new opioid use, and the low level of individual and community side effects.

Naltrexone Naltrexone (Trexan) is an orally administered opioid antagonist that blocks opioid effects through competitive binding for 48–72 hours. Naltrexone was designed for use as a maintenance medication, but compliance has been generally poor, with most field studies showing retention rates of less than 20%. Because of this, the medication has been primarily used in two populations of opioid- addicted individuals—professional groups and criminal justice patients—wherein the threat of significant personal loss appears to sustain motivation to take the medication. For example, naltrexone has been used effectively in the monitored treatment of physicians, lawyers, nurses, and other professionals for whom maintaining a license to practice is contingent upon maintaining abstinence (DuPont et al., in press). Similarly, the medication has been used effectively with opioid-dependent probationers and parolees, again under close monitoring, for whom re-incarceration will result upon a return to opioid use (Cornish et al. 1998). It remains to be seen whether these findings affect the willingness of the criminal justice system to request or even require the medication.

Medications for alcohol dependence Disulfiram Disulfiram (Antabuse) has been used in the treatment of alcohol dependence for three decades. It produces vomiting, facial flushing, and headaches following a drink of alcohol through interference with the metabolism of acetaldehyde, which is an intermediate byproduct of alcohol metabolism. Because of the unpleasantness of these effects, there has been very poor compliance with the medication among patients (O'Brien 2005; Wesson 2006) and reluctance on the part of physicians to prescribe it because of fear of a serious cross-reaction if alcohol is ingested. Nonetheless, field studies and substantial clinical experience suggest that the medication can be effective in blocking alcohol drinking for selected individuals over extended periods of time (Bien et al. 1993; Brewer 1992).

Naltrexone Naltrexone (Revia) was approved by the FDA in 1994 for reducing drinking among alcohol-dependent

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patients, without producing unpleasant physiological effects were alcohol to be consumed. It blocks alcohol-mediated stimulation of endogenous opioids, thus blunting some of alcohol's pleasurable effects. At this writing, there have been more than 20 field studies of the medication in a variety of clinical samples (O'Brien 2005). Overall, these studies have shown a statistically significant—and modestly clinically significant—response compared with placebo or with standard outpatient treatment involving no medication. O'Malley et al. (1996) found that the best candidates for the medication include those with high levels of alcohol dependence, a familial history of alcohol dependence, significant cravings for alcohol, and lower educational levels. Because of problems with compliance with the oral form of the medication, there have been efforts to develop depot or sustained-release formulations of the medication, culminating in the FDA approval of an injectable product (Vivitrol) in early 2006 that provides clinically effective blood levels of the medication for at least 30 days. Early findings with this formulation indicated that more than 85% of those given the initial injection returned for five additional monthly injections; that side effects were modest and not long lasting; and that the effectiveness was substantially greater than placebo injections (Garbutt et al. 2005). At this writing, this form of the medication has only recently been made available, and time will tell whether it is more desirable or effective in practice than the oral form of the medication.

Acamprosate In 2004, a new alcohol-blocking agent called acamprosate (Campral) was approved by the FDA to block craving and return to alcohol abuse. Although acamprosate acts on different receptors than naltrexone, the clinical results have been remarkably similar—but also somewhat less potent—in most trials. The most recent trial of naltrexone and acamprosate provided alone or in combination showed only modest effects for acamprosate versus placebo (Anton et al. 2006); only naltrexone (orally administered) showed significant enhancement of abstinence rates.

Medications for stimulant dependence During the 1980s and 1990s many medications have been tried in the treatment of cocaine dependence. At this writing, there are no medications that have been approved for the treatment of cocaine dependence or any other stimulant dependence. However, there are many trials in process, and one medication, disulfiram, has shown replicated positive effects in randomized trials with cocainedependent patients (O'Brien 2005; Vocci and Elkashef 2005). Disulfiram, a medication traditionally used in the treatment of alcohol dependence, has been found to be effective in promoting cocaine abstinence (Carroll et al. 1998, 2004). Originally, it was thought that because alcohol use is often a trigger for cocaine craving, disulfiram's ability to prevent alcohol ingestion also prevented triggering situations that led to cocaine use (Carroll et al. 1998). However, basic pharmacological studies showed a direct effect of disulfiram on the metabolism of cocaine—reducing one of the active metabolites and thereby reducing the reinforcing properties of the drug (Carroll et al. 2004). No medication has shown positive effects in controlled trials with methamphetamine-dependent patients.

THERAPIES Great progress has been made in the development and evaluation of new therapies in the treatment of alcohol addiction and other drug addictions (Woody et al. 1990). As in the case of medication development, this area of research has followed a three-stage process (Rounsaville et al. 2001), including pre-testing of the underlying concept and procedures as well as manual development; randomized trials in controlled settings; and finally, field trials, usually in multiple sites. A complete review of all therapy trials is beyond the scope of this chapter (for complete reviews see Carroll and Onken 2005; Woody 2003). Reviewed here are four therapies that have been developed and tested in the previously described manner with significant benefits over treatment as usual.

Brief Therapies The past decade has seen the development and testing of several brief therapies typically consisting of

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more than one session but fewer than six sessions. One-session interventions are considered advice (see Bien et al. 1993 for a review). Brief therapies are designed to promote problem recognition among reluctant or unaware substance abusers, to foster a sense of willingness and ability to address the problem, and often to promote engagement in treatment. These brief therapies have been tested extensively in more than 100 trials with alcohol- and other drug-dependent individuals, usually as a strategy for encouraging non-treatment-seeking individuals to enter into formal treatment but also as a treatment intervention (see Bien et al. 1993; Moyer et al. 2002 for reviews). Studies of non-treatmentseeking individuals typically show small to medium effect sizes compared with no intervention at all, with the best effects seen for individuals with less severe forms of addiction (Moyer et al. 2002). Studies of brief interventions have been particularly interesting because they typically have shown posttreatment outcomes that are not different from those seen among individuals with more extensive treatments (Moyer et al. 2002; Project MATCH Research Group 1997; Saitz et al. 2005). Because of their brevity and low reliance on treatment compliance, brief interventions have been particularly attractive to primary care physicians dealing with alcohol-dependent individuals in family medicine or emergency medical settings (Saitz et al. 2005).

Structured Therapies Cognitive-behavioral therapy Cognitive-behavioral therapy (CBT) in the treatment of addictions emphasizes the role of thinking in determining both craving for drugs and the ensuing drug seeking and use. Put simply, the therapy is based on the findings that thoughts as well as people and situations cause the feelings and behaviors associated with relapse, and in turn, it is possible with therapy to change thoughts about and reactions to relapse-provoking situations. There are several approaches to, or variations on, CBT, including rational emotive behavior therapy, rational behavior therapy, rational living therapy, cognitive therapy, and dialectical behavior therapy. In the addiction field, most of the versions studied have been adapted from Marlatt and Gordon's (1985) relapse prevention treatment for problem drinking. As studied in most research trials, the therapy is usually individual (but also group), delivered in 8–16 weekly sessions. Change in thinking about and reactions to relapse-provoking situations requires practice and time. Thus, one of the hallmarks of CBT is homework assignments to provide practice in the cognitive techniques learned during the formal sessions. CBT may be the most studied of all the therapies in addiction, perhaps because of the very carefully developed manuals whose purposes are to train and guide the provision of the therapy (Kadden et al. 1997; National Institute on Drug Abuse 1998). Studies of CBT with cocaine-dependent patients have shown general acceptance by patients (attendance at more than 50% of planned sessions) and better posttreatment rates of abstinence than for patients given no therapy or group counseling alone (see Carroll and Onken 2005; Carroll et al. 1994; Morgenstern et al. 2001a for review). Similarly, CBT has also been associated with generally good engagement and posttreatment outcomes among alcoholdependent patients (Balldin et al. 2003). Although the evidence for the effectiveness of this therapy is quite consistent across trials and field studies, the effects have been generally modest in clinical impact (Crits-Christoph et al. 1999; Leichsenring and Leibing 2003; Morgenstern and Longabough 2000; Ouimette et al. 1997).

Marital, family, and couples therapies Since the early 1990s there have been more than 60 studies in which marital, family, or couples therapies have been provided to reduce substance abuse or substance abuse–related problems, such as violence. In a recent review of controlled studies of this type in alcohol-dependent patients, marital and family therapy and particularly behavioral couples therapy was significantly more effective than individual treatments at inducing and sustaining abstinence, improving relationship functioning, and reducing domestic violence and emotional problems of children (O'Farrell and Fals-Stewart 2003). Similar reductions in substance use and partner violence have also been seen in controlled trials of

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marital, family, or couples therapy with opiate- and cocaine-dependent patients (Fals-Stewart et al. 2001, 2002; Higgins et al. 1994b).

Behavioral couples therapy Behavioral couples therapy treats the substance-abusing patient with his or her spouse to arrange a daily "sobriety contract" in which the patient states his or her intent not to drink or use drugs, and the spouse expresses support for the patient's efforts to stay abstinent. Behavioral couples therapy also teaches communication and non-substance-associated positive activities for couples. Findings show that this approach produces greater abstinence and better relationship functioning than typical individual-based treatment and also reduces social costs and domestic violence (McCrady et al. 1999; O'Farrell and Fals-Stewart 2002, 2003; Winters et al. 2002).

Community reinforcement and family training Community reinforcement and family training (CRAFT) is based on a combination of standard functional analysis of behavior and principles of reinforcement. The therapy was developed to teach and promote the practice of these principles by members of a household. Specifically, families who learn the CRAFT intervention are taught skills for modifying a loved one's alcohol- or drug-using behavior and for enhancing treatment engagement (Smith et al. 2001). The intervention has been generally well accepted by families, and several studies have shown that CRAFT produces greater likelihood of entry and engagement of substance-abusing family members and greater likelihood of posttreatment abstinence than standard treatments (Kirby et al. 1999; Meyers et al. 2002). In addition, families of the substance abusers in these studies show significantly less depression, anxiety, anger, and physical abuse than families of patients who received standard treatment (Meyers et al. 2002; Smith et al. 2001).

Twelve-step facilitation therapy Twelve-step facilitation therapy (TSF) was originally developed as a practical control condition to be implemented by counselors and to be compared with theoretically derived therapies implemented by trained therapists in a controlled trial with alcohol-dependent patients (i.e., Project MATCH). It is a structured therapy designed to engage reluctant patients to consider the effects of their substance use on their lives and the lives of their loved ones and to ultimately begin to take steps to deal with the problems through the 12 steps and 12 traditions of AA (Nowinski et al. 1994). TSF is typically delivered as a time-limited (12- to 15-session) intervention, either as an individual treatment or as group treatment (Maude-Griffin et al. 1998). In either format, TSF is a highly structured intervention; sessions begin with a review of the patient's recovery week, including any 12-step meetings attended, episodes of substance use, and urges to drink or use drugs. Each session concludes with assignments to recoveryoriented tasks such as readings from the AA literature and attending AA meetings, which the patient agrees to undertake between sessions. One aspect of TSF that clearly separates it from other therapies is its active promotion of spirituality as a key to lasting recovery. In this context spirituality is considered a force that provides direction and meaning to one's life. The evidence for effectiveness of TSF was first shown in the large, multisite National Institute on Alcohol Abuse and Alcoholism's Project MATCH study of alcohol-dependent patients (Project MATCH Research Group 1997). There were no overall differences among the three therapies tested in that study over the 3-year period, but as designed, the TSF group was more successful in getting patients involved with AA and was in turn more effective in getting patients to be abstinent from alcohol than either of the other two groups (Tonigan et al. 2000). Additional studies have confirmed the effectiveness of this therapy versus usual care. For example, in a randomized, controlled study of disulfiram and TSF in the treatment of cocaine and alcohol dependence (Carroll et al. 1998), both disulfiram and TSF were independently associated with significantly better retention in treatment as well as longer duration of abstinence from alcohol and cocaine use than was found with the control therapy. The study found that the best outcomes were for the groups that received combined TSF and disulfiram. Similar results were found by Thevos et al. (2001) with alcoholic women who received TSF over 12 weeks in a random

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assignment comparison with motivational counseling. Women who received CBT or TSF had better outcomes than women who received the control condition (Thevos et al. 2001).

Individual drug counseling Similar in several ways to TSF, the drug dependence treatment field has employed a structured form of individual counseling that uses many of the same practical elements, but not a formal spiritual component (Woody et al. 1990). Individual counseling to foster abstinence and general adjustment, delivered in a structured manner over 12–24 sessions, has been extensively studied. In almost all studies, patients who received this form of counseling (even those who initially did not want it) had better during- and posttreatment outcomes (Fiorentine and Anglin 1997; McLellan et al. 1988), with those who attended a greater frequency of sessions typically showing the best results (McLellan 2002; Moos 2003; Simpson 2004). Importantly, there are very few studies that have shown positive effects from group drug counseling. Indeed, in one large trial among cocaine-dependent patients it was only individual counseling and not group counseling that was associated with improved outcomes (CritsChristoph et al. 1999). This is important in that group drug counseling is by far the most prevalent component of treatment in the national treatment system (SAMHSA 2002).

Adjunctive Interventions and Services Although medications and formal therapies to bring about and sustain cessation of substance use have been the most extensively studied components of care, there are additional types of interventions and services that have also been shown to be effective in initiating and sustaining abstinence from alcohol and other substances.

Voucher-based reinforcement of abstinence Higgins et al. (1993, 1994a, 1994b) brought laboratory principles of behavioral change to the treatment of cocaine dependence. In a now classic set of studies in a clinical laboratory setting, cocaine-dependent patients seeking outpatient treatment were randomly assigned to receive either standard drug counseling and referral to AA or a multicomponent behavioral treatment in which vouchers for desirable goods and services, provided by community shops and stores, were provided contingent upon drug-negative urine tests. The voucher-based reinforcement of abstinence retained more patients in treatment, produced more abstinent patients and longer periods of abstinence, and produced greater improvements in personal function than the standard counseling approach. In the decade since the publication of these early studies, the technique of providing positive reinforcement that is contingent upon drug-free urine tests has been replicated and extended in alcohol-, cocaine-, opiate-, or methamphetamine-dependent patients—all with similarly positive findings (Higgins et al. 1994a). Moreover, because voucher-based reinforcements have been criticized for their expense and administrative problems, investigators have tested partial reinforcement schedules using a lottery system in which drug-free urine tests afford patients an opportunity to draw for a range of prizes of small to large value (Petry 2000). This procedure has reduced costs in real-world settings and appears to provide an enjoyable and treatment-compatible means of delivering the reinforcers. A very promising extension of the voucher-based reinforcement procedure has been developed and studied by Silverman et al. (1996, 1998). These investigators operate a data entry center where recovering patients may learn data entry skills and earn wages for data entry, contingent upon their providing a drug-free urine sample. This procedure appears to be practical and potentially useful as a means of extending the principles of contingency management practices into real-world settings.

Clinical case management and wraparound services Most patients admitted to substance abuse treatment have significant problems in one or more areas of life function, such as medical status, employment, family relations, and/or psychiatric function (McLellan and Weisner 1996). The severity of these addiction-related problems generally is predictive of response during treatment as well as posttreatment outcome (i.e., more or worse problems predict early dropout and poor response). Studies have documented that specialized services—also called wraparound

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services—such as primary medical care, housing, employment training, psychiatric care, and parenting assistance for these addiction-related problems can be effective adjuncts to standard addiction-focused care in either residential or outpatient settings and in either the rehabilitative or continuing care stages of treatment. From a conceptual or clinical perspective, there has been debate regarding whether patients should first acquire stable sobriety so that they will be more likely to follow through with treatment plans incorporating these services, or whether these services should be provided early in the course of rehabilitative care to increase the attractiveness and impact of that care and in turn increase patient engagement. There is no definitive answer to this question at this writing. From a practical perspective, most specialty care treatment programs do not have access to many of the types of professional services that would be useful to their clients, and for this reason most field studies of so-called wraparound services have employed clinical case managers to link patients to available services in the community, to take patients to those services and encourage follow-through, and to advocate on the part of the patients for access and availability of the services (McLellan et al. 1998). Studies of case management with alcohol- and drug-addicted patients show mixed results. Although there are clearly many studies that have found improved patient function with the addition of case management to standard addiction services, the effectiveness of this form of care management seems to be more related to the availability and attractiveness of the services that are being managed than to the theoretical or methodological aspects of the case management process itself (see McLellan et al. 1998 for review). For these reasons, this review treats special services as the active ingredients and case management as the vehicle for linking those services to the patient. It must be admitted that case management and service provision are inextricably linked, and it could be argued that clinical case management itself should be discussed as an evidence-based form of care delivery. A study by Milby et al. (1996) illustrated the importance of providing supplemental social support services to homeless, substance-dependent (typically cocaine and alcohol) individuals who sought health care services (not explicitly drug abuse treatment) from the Birmingham Health Care for the Homeless Coalition. In that study, 176 subjects were recruited and randomized into usual care (primarily 12-step group counseling) and enhanced (addition of employment, housing, and psychiatric services to usual care) conditions conducted in separate facilities. Enhanced care patients attended therapy more regularly and at 6-month follow-up were two times more likely to be employed and four times less likely to be homeless than the usual care patients. It appears that the supplemental services included as part of addiction treatment were associated with significant and broad improvements. Not all studies of wraparound services have required clinical case management. Similar findings have been seen from adding wraparound services to standard addiction treatment through special computer systems or special training of counselors. Better outcomes have been seen when the services were matched to the problems presented by the patients and when those services were requested by the patients. The effects of adding specialized health and social services to standard addiction treatments typically show improvements of 20%–40% over standard care, and these findings have been seen in Veterans Administration patients (McLellan et al. 1993), in publicly supported inner-city treatment programs (Hser et al. 1997; McLellan et al. 1997), among patients in the Kaiser Permanente health care system (Weisner et al. 2001), among welfare to work clients (Gutman et al. 2003), and in criminal justice settings (Cornish et al. 1998; Inciardi et al. 1997). In a recent example, Carise et al. (2005) developed a computer-assisted method of teaching counselors to link the problems presented by patients during treatment admission to free or low-cost community health and social services (derived from the United Way's First Call for Help). These researchers performed a randomized, controlled field trial comparing patients from 10 outpatient programs. Half of the subjects received essentially standard care, while the counselors in the other programs were shown how to use the computer linking procedure. Results showed that patients of counselors who had been trained to link community services to the admission problems were more likely to receive services, the services were more likely to match the problems presented at admission, and the patients were more

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likely to engage and complete care and less likely to have positive urine tests during treatment.

Linking Patients to Alcoholics Anonymous In contemporary substance abuse treatment, AA has become synonymous with the continuing care stage of treatment. Virtually all alcohol dependence rehabilitation programs and most cocaine dependence rehabilitation programs refer patients to AA programs with instructions to get a sponsor, "share and chair" at meetings, and attend 90 meetings in 90 days as a continued commitment to sobriety. Research studies conducted to date have generally found that only about 25%–35% of those who attend one meeting of AA go on to active participation (e.g., attend 90 meetings, acquire a sponsor). However, for those who do attend, there is every indication that this peer support component of rehabilitation is valuable for maintaining rehabilitation (for a review, see Humphreys 2003; Humphreys et al. 2004). Although there has always been consensual clinical agreement about the value of AA and other peer support forms of treatment, there is increasing evidence showing that patients who have an AA sponsor or who have participated in the fellowship activities have much better abstinence records than patients who have received the same rehabilitation treatments but have not continued in AA. There are now many controlled studies and large field studies of AA participation showing that participation in posttreatment self-help groups is related to better outcome among cocaine- or alcohol-dependent individuals (McLatchie and Lomp 1988; Morgenstern et al. 2001b).

POSTTREATMENT MONITORING Substance abuse treatment may be the only area of medical care in which there is specialty care without corresponding primary care. That is, substance abuse patients are very rarely referred to specialty care from a primary care physician (less than 4% of all substance abuse admissions), and perhaps more importantly in this context, almost none of those who complete specialty care addiction treatment are referred back to a primary care physician for continuing care management. There are few clinicians who believe that patients who complete specialty care are truly cured of their addiction. Most realize the need for some form of continuing care, but as has been indicated, AA has been essentially the only option for that continuing care. In this regard, clinical researchers have been studying alternative methods for extending the positive effects of outpatient rehabilitative care. Consistent with a disease management perspective, several groups have shown the clinical benefits associated with either brief telephone monitoring telephone calls, e-mail and Internet contact, or home visits on a decreasing schedule of frequency for 6–12 months after completion of outpatient addiction rehabilitation (see McKay 2005 for review). McKay and his colleagues have been studying alcohol- and cocaine-dependent patients during and following their participation in a 4-week intensive outpatient program. They employed research assistants to deliver several forms of brief, clinically oriented telephone monitoring calls for 24 months following the end of the intervention. In almost all cases, those who received the brief, inexpensive monitoring calls achieved better substance use outcomes (McKay et al. 1997, 1999). McKay is currently evaluating a longer-term, telephone-based adaptive alcoholism treatment package in a study funded by the National Institute on Alcohol Abuse and Alcoholism (McKay 2001, 2005). In this study, patients who achieve initial engagement and stabilization in the intensive outpatient program are randomized to standard care only, 18 months of monitoring and feedback by telephone, or an 18-month telephonebased, adaptive, stepped-care protocol that also provides motivational interviewing, CBT relapse prevention, or return to the intensive program, as needed.

ORGANIZATIONAL INFRASTRUCTURE OF THE ADDICTION TREATMENT SYSTEM Almost all addiction treatment in this country is provided by specialty sector programs funded primarily through the State Block grant, the Department of Veterans Affairs, Medicaid, private medical insurance, and other sources (SAMHSA 2002). Most of this care is carved out from general health plans and is provided by these specialty programs through myriad reimbursement arrangements—but more than

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70% of care involves government funds rather than private insurance (McKusick et al. 1998). Thus, efforts to improve addiction treatment through implementation of some of the evidence-based components of care reviewed here will be governed in a significant way by the ability of the specialty care system to absorb or adopt these new treatment methods. In this regard, the substance abuse treatment system has been particularly affected by the general rise in costs of health care. Because of these growing costs, employers and government purchasers have turned to managed care organizations to reduce their health care expenditures. Although cost reduction and treatment streamlining efforts have affected all areas of health care, it is widely acknowledged that the addiction and mental health treatment systems have been disproportionately affected (Institute of Medicine 2006). For example, in 1990 there were more than 16,000 substance abuse treatment facilities operating in the United States; approximately 55% of those were residential or inpatient hospital, approximately 15% were methadone maintenance programs, and about 30% were outpatient programs. Figures from 2002 indicate that there are now fewer than 14,000 programs; only 10% are residential or inpatient hospital, about 12% are methadone maintenance programs, and approximately 78% are abstinence-oriented outpatient programs (SAMHSA 1997, 2002). Despite a widely perceived growth in need for substance abuse treatment, there are fewer programs in operation and fewer patients in treatment today than there were in 1990 (for a review see McLellan and Meyers 2004). In addition to outright closure, administrative restructuring is also quite prevalent, with about 20%–30% of programs undergoing some form of organizational takeover each year, leaving them under a different administrative structure. Perhaps because of this high level of reorganization, directors of these programs also change regularly. Less than half of program directors surveyed in a recent national sample had been in their jobs for even a year (McLellan et al. 2003). This does not mean that they are new employees. Indeed, at least 80% of program directors had been working within their program prior to their appointment as director, usually in a clinical position. About 20% of those program directors had no college degree, half to two-thirds had bachelor's degrees, and about 20% had master's degrees. Less than 2% were physicians. Beyond their administrative structures, the nature of treatment staffs and the composition of contemporary treatments are also indications of readiness to adopt and ability to provide evidence-based treatments. In this regard, the modal treatment program in the United States employs 6–10 counselors, each treating an active caseload of 50–80 clients. Apart from counselors, there are very few other professional disciplines represented in most of these programs. For example, only about 50% of the nation's treatment programs have even a part-time physician on staff. If methadone maintenance programs are excluded from this group, the proportion drops to about 35%. In fact, only about 50% of U.S. addiction treatment programs even perform an on-site physical examination at intake (Institute of Medicine 2006). Outside of methadone programs, less than 15% of programs employ a nurse, and even fewer employ even a part-time social worker or psychologist. Annual turnover rates for these staff are in the 50% range—approximately the same as seen in the fast food industry (McLellan et al. 2003). Only about 30% of programs have access to well-developed clinical information systems and Internet services. Another 20% have no electronic information services of any type. The remaining 50% have some form of computerized administrative information system dedicated to billing or administrative record keeping available for the administrative staff—but very few have an integrated clinical information system for use by the majority of treatment staff (for a review see McLellan and Meyers 2004). As might be expected from the staffing complement in these programs, the great majority of what goes on in treatment programs is some form of group counseling. Essentially all treatment programs in the United States employ group counseling but only about 40% provide individual counseling. Typical types of groups include orientation groups (in which patients introduce themselves and learn about group therapy), relapse prevention groups, and general drug education groups. Although some reports of

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national surveys of drug abuse treatment program directors have suggested that a wide range of services are available through the programs, most studies of patients in treatment reveal that very few patients actually receive medical or social services beyond general counseling. In summary, these data confirm the already widely acknowledged gap between the type of evidence-based, quality services that could be delivered and the kind of care that is possible to deliver given the current infrastructure. Given the existing infrastructure, it is doubtful if any of the medications reviewed here could be prescribed or administered in most of the treatment programs. Similarly, given the level of training and background needed to effectively provide most of the evidence-based therapies reviewed here, only a minority of existing programs have the staffing and training capabilities to adopt these therapies. Thus, it is disheartening to end this quite positive summary of promising evidence-based clinical practices with the stark but unfortunately realistic conclusion that most of them simply cannot be staffed or delivered in a sustainable manner within the contemporary treatment system.

KEY POINTS Addiction treatment is best considered as at least three separate stages—each with distinct goals and methods: 1) detoxification or stabilization is designed to eliminate the acute effects of substance use and prepare the patient for life change; 2) rehabilitation is designed to continue the initial abstinence and to help the patient develop a life that will be enjoyable without substances; and 3) continuing care follows formal treatment and consists of mutual help groups (usually Alcoholic Anonymous [AA]), professional therapy as needed, and often telephone monitoring calls designed to prevent relapse. Within the rehabilitation and continuing care stages of treatment there is now an impressive array of treatment components that have shown U.S. Food and Drug Administration–level evidence of effectiveness. Medications include naltrexone, buprenorphine, and methadone for opiate dependence; naltrexone, acamprosate, and disulfiram for alcohol dependence; and disulfiram for cocaine dependence. Therapies include cognitive-behavioral therapy; motivational enhancement therapy, behavioral couples therapy, 12-step facilitation, community reinforcement and family training, and individual drug counseling. Adjunctive interventions and services include voucher-based reinforcement for abstinence, clinical case management and wraparound social services, linking of patients to AA, and posttreatment monitoring (telephone, Internet, and home visit). Despite these very promising new developments, most addiction treatment is delivered within a specialty care treatment system that does not have the personnel, information management, or administrative support to implement most of these practices. Although there will be a continuing need for new and more sophisticated treatment interventions and components, there is a pressing need for financial and organizational development to permit the treatment system to provide the kind of quality care that is now possible.

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disorders. Am J Addict 10(suppl):51–59, 2001 Stout RL, Rubin A, Zwick W, et al: Optimizing the cost effectiveness of alcohol treatment: a rationale for extended case monitoring. Addict Behav 24:17–35, 1999 [PubMed] Substance Abuse and Mental Health Services Administration (SAMHSA): Uniform Facility Data Set (UFDS): data for 1996 and 1980–1996 (DHHS Publ No SMA-98-3176). Washington, DC, U.S. Government Printing Office, 1997 Substance Abuse and Mental Health Services Administration (SAMHSA): National Survey of Substance Abuse Treatment (NSSAT): data for 2000 and 2001 (DHHS Publ No SMA-98-3176). Washington, DC, U.S. Government Printing Office, 2002 Thevos A, Thomas S, Randall C: Social support in alcohol dependence and social phobia: treatment comparison. Res Soc Work Pract 11:458–472, 2001 Tonigan JS, Connors GJ, Miller WR: Participation and involvement in Alcoholics Anonymous, in Treatment Matching in Alcoholism. Edited by Babor T, DelBoca F. New York, Hollis Press, 2000, pp 14–31 Vocci FJ, Elkashef A: Pharmacotherapy and other treatments for cocaine abuse and dependence. Curr Opin Psychiatry 18:265–270, 2005 [PubMed] Volkow ND, Hitzemann R, Wang GJ, et al: Long-term frontal brain metabolic changes in cocaine abusers. Synapse 11:184–190, 1992 [PubMed] Wagner E, Austin BT, Von Korff M: Organizing care for patients with chronic illness. Milbank Q 74:511–544, 1996 [PubMed] Weisner CM, Mertens J, Parthasarathy S, et al: Integrating primary medical care with addiction treatment: a randomized controlled trial. JAMA 286:1715–1723, 2001 [PubMed] Wesson DR: Pharmacotherapy of addictive disorders, in SAMHSA Treatment Improvement Protocol 24 (DHHS Publ No SMA 06–1221). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2006, pp 162–179 White W: Slaying the Dragon: The History of Addiction Treatment and Recovery in America. Bloomington, IL, Chestnut Health Systems, 1998 White W: Transformational change: a historical review. J Clin Psychol 60:461–470, 2004 [PubMed] Winters J, Fals-Stewart W, O'Farrell TJ, et al: Behavioral couples therapy for female substance-abusing patients: effects on substance use and relationship adjustment. J Consult Clin Psychol 70:344–355, 2002 [PubMed] Woody GE: Research findings on psychotherapy of addictive disorders. Am J Addict 12 (suppl 2):S19–S26, 2003 Woody GE, McLellan AT, Luborsky L, et al: Psychotherapy and counseling for methadone-maintained opiate addicts: results of research studies. NIDA Res Monogr 104:9–23, 1990 [PubMed] Zarkin GA, Dunlap LJ, Hicks KA, et al: Benefits and costs of methadone treatment: results from a lifetime simulation model. Health Econ 14:1133–1150, 2005 [PubMed] Zweben A, Zuckoff A: Motivational interviewing and treatment adherence, in Motivational Interviewing: Preparing People for Change, 2nd Edition. Edited by Miller RW, Rollnick S. New York, Guilford, 2002, pp 12–26

SUGGESTED READING Humphreys K, Wing S, McCarty D, et al: Self-help organizations for alcohol and drug problems: toward evidence-based practice and policy. J Subst Abuse Treat 26:151–158, 2004

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Institute of Medicine: Improving the Quality of Health Care for Mental and Substance-Use Conditions: Quality Chasm Series. Washington DC, National Academies Press, 2006 McKay JR: Is there a case for extended interventions for alcohol and drug use disorders? Addiction 100:1594–1610, 2005 McLellan AT, O'Brien CP, Lewis DL, et al: Drug addiction as a chronic medical illness: implications for treatment, insurance and evaluation. JAMA 284:1689–1695, 2000 O'Brien CP: Anti-craving medications for relapse prevention: a possible new class of psychoactive medications. Am J Psychiatry 162:1423–1431, 2005 Project MATCH Research Group: Matching Alcoholism Treatments to Client Heterogeneity: Project MATCH posttreatment drinking outcomes. J Stud Alcohol 58:7–29, 1997 Simpson DD: A conceptual framework for drug treatment process and outcomes. J Subst Abuse Treat 27:99–121, 2004 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 8. Neurobiology of Alcohol

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Clifford M. Knapp, Domenic A. Ciraulo, Henry R. Kranzler: Chapter 8. Neurobiology of Alcohol, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.345885. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Neurobiology of Alcohol Clifford M. Knapp, Ph.D. Domenic A. Ciraulo, M.D. Henry R. Kranzler, M.D.

NEUROBIOLOGY OF ALCOHOL: INTRODUCTION Ethanol is a small molecule that readily distributes into highly perfused tissues such as the brain. Peak levels of ethanol are attained approximately 30 minutes after ingestion of an alcoholic drink. A single drink of ethanol produces a biphasic effect with a rapid stimulatory phase associated with an increase in blood ethanol concentrations followed by a depressant phase as the blood concentration diminishes. Although the ethanol from a single drink is readily metabolized in two steps involving the enzymes alcohol dehydrogenase and aldehyde dehydrogenase, this process follows zero-order kinetics. Accordingly, there is a decrease in the percentage of ethanol metabolized per given unit of time, as the dose of this agent is increased. Because of its comparatively low toxicity per unit volume, ethanol can be consumed in large amounts and, consequently, individuals with impaired control over their drinking may remain highly intoxicated for extended periods. Serious disruption in the performance of many of the activities of daily living can occur as a result of the behavioral disinhibition and impairments of judgment, cognition, and fine motor skills associated with high levels of intoxication. Repeated exposure to ethanol is associated with the development of tolerance to many of its effects. The continual use of ethanol can also lead to the development of physical dependence and the consequent onset of withdrawal symptoms following the discontinuation of ethanol consumption. When compared with most pharmacological agents, the potency of ethanol is extremely low, with its effects becoming apparent only in the millimolar range. Most drugs, in contrast, are active at micromolar or even nanomolar concentrations. The low potency of ethanol raises questions as to the specificity of its actions. The effects of ethanol on behavior appear to be mediated by its effects on a variety of proteins in the nervous system. These include proteins associated with -aminobutyric acid (GABA)A receptors, the glutamate receptors (including the N-methyl-D-aspartate [NMDA],

-amino-

3-hydroxy-5-methylisoxazole-4-propionic acid [AMPA], and kainate receptors), nicotinic receptors, cannabinoid CB1 receptors, voltage-gated calcium ion channels, and calcium-activated potassium (BK) channels. The exact nature of the interaction of ethanol with these proteins largely remains to be elucidated. There is limited evidence, however, that ethanol may interact with specific amino acids at discrete locations on the sequence of amino acids that form NMDA receptors (Honse et al. 2004; Smothers and Woodward 2006), the adenylyl cyclase enzyme (Yoshimura et al. 2006), and possibly a particular subunit of the GABAA receptor (Jung and Harris 2006). Some authors have stressed the relationship between blood alcohol concentrations and the effects of ethanol on specific neuronal systems in the brain as a key to understanding the behavioral effects of ethanol (Wallner et al. 2006). The behavioral effects correlate with the concentration of ethanol achieved in the brain, which is directly related to blood alcohol concentration. Mild intoxication produced by the consumption of one or two standard drinks (a standard drink is a glass of wine, a bottle of beer, or a shot of spirits) occurs with ethanol levels of 5–10 mmol/L and may involve mild disruption of cognitive processing and mood changes, ranging from mild mood elevation to dysphoria. Moderate

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drinking leads to ethanol concentrations as high as 20 mmol/L; however, the legal limit for driving is now frequently set at blood levels of 17 mmol/L (0.08 mg/dL). Ethanol levels greater than 100 mmol/L may produce coma and death. Ethanol concentrations in the range of 10–50 mmol/L might be most relevant in the identification of proteins that mediate the actions of ethanol in all but the most severe states of intoxication. In many studies, ethanol concentrations greater than 100 mmol/L have been used to assess the effects of ethanol on receptors and ion channels. This has led some investigators to question certain claims that have been made in the past concerning the effects of ethanol on GABA and other neurotransmitter systems (Krystal et al. 2006). Recent evidence indicates that even small doses of ethanol (0.25–0.5 g/kg) can substantially reduce glucose metabolism in the brain without producing detectable alterations in cognitive performance (Volkow et al. 2006). The full implications of ethanol-induced alterations in brain metabolism on neuronal function have still not been fully characterized. Chronic ethanol use appears to have effects on glucose utilization that are evident during the detoxification of alcoholic individuals. Volkow et al. (1994) showed that glucose metabolism in several brain regions, including the frontal cortex, orbitofrontal cortex, and basal ganglia, was lower at the start of detoxification of alcohol-dependent individuals than in control subjects. Over the course of a 30-day withdrawal period, glucose metabolism increased in frontal regions; however, metabolism was found to remain lower than control levels in the basal ganglia. Supported by National Institute on Alcohol Abuse and Alcoholism grant K24 AA13736 (Kranzler).

CAMP PATHWAYS The second messenger cyclic adenosine monophosphate (cAMP) plays a key role in the regulation of cellular activity by acting through cAMP-dependent protein kinase A (PKA) to phosphorylate a host of proteins, including those that regulate gene expression, receptor function, and ion channel function. The activation of G protein–coupled receptors can elevate or decrease intracellular concentrations of cAMP by altering activity of the different types (isoforms) of adenylyl cyclase. Alterations of cAMP levels within the cell, in turn, modulate PKA activity. PKA is composed of different regulatory and catalytic subunits. Ethanol administration can enhance the activity of some isoforms of adenylyl cyclase (Tabakoff and Hoffman 1998; Yoshimura et al. 2006) that have been shown to enhance PKA activity (Ortiz et al. 1995). Recent abstinence from ethanol is associated with a decrease in platelet adenylyl cyclase activity, but increases in the activity of these enzymes occur in association with a history of alcohol dependence (Hoffman et al. 2002). The selective deletion of the PKA regulatory RII

subunit from mice resulted in an increase in ethanol

consumption and a decrease in the sedative effects of ethanol (Thiele et al. 2000b). Infusion of a PKA inhibitor, Rp-cAMP, into the nucleus accumbens (NAcc) elevated ethanol intake in rats (Misra and Pandey 2005). This inhibitor also reduced levels of the phosphorylated form of the gene transcription factor, cAMP response element–binding protein (CREB), and protein levels of neuropeptide Y (NPY) in the NAcc. This may be of significance because both CREB and NPY have been implicated in the regulation of ethanol consumption (Hayes et al. 2005; Misra and Pandey 2003; Pandey et al. 2004). In mice that were haplodeficient for CREB (i.e., those with partial deletion of the CREB gene), ethanol consumption increased (Pandey et al. 2004). These mice showed decreased levels of phosphorylated CREB and expression of NPY in brain structures that include the amygdala, hippocampus, and NAcc (Pandey et al. 2004). Ethanol-induced PKA activity may have broad influences on neuronal function, many of which are presently poorly understood. NMDA receptor function varies with the phosphorylation state of the receptor, and PKA plays a major role in this variation. Activation of dopamine D 1 receptors can enhance the activity of PKA, which then leads to enhanced phosphorylation of CREB. The alteration of CREB activity not only appears to influence the regulation of ethanol consumption but has also been implicated in the reinforcing actions of many other abused substances, including cocaine and morphine (McClung and Nestler 2003; Walters and Blendy 2001).

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NEUROTRANSMITTER SYSTEMS AND ETHANOL Dopamine Dopaminergic neurons in the mesolimbic region project from the ventral tegmental area (VTA) to the NAcc. The NAcc may be crucially important in producing the rewarding actions of ethanol (Weiss and Porrino 2002). Ethanol administration enhances dopamine release in the NAcc (Di Chiara and Imperato 1988; Yim and Gonzales 2000), which may result from ethanol-induced increases in the firing rate of dopamine cells located in the VTA (Brodie et al. 1999; Gessa et al. 1985). The repeated administration of ethanol may result in sensitization of dopamine VTA neurons to the effects of ethanol on dopamine cell firing (Brodie 2002). However, during acute withdrawal from ethanol, spontaneous activity of dopamine cells in the VTA is decreased (Shen and Chiodo 1993), as is dopamine release in the NAcc (Weiss et al. 1996). Dopamine D2 receptor–deficient mice, "knockout mice," show less preference for ethanol than do the wild-type mice that can express this receptor (Thanos et al. 2005b). Transfer of D 2 receptor deoxyribonucleic acid (DNA) by viral vector into the NAcc of mice lacking this receptor leads to an increase in ethanol consumption and preference. In contrast, transfer of D 2 receptor DNA into wild-type mice and mice heterozygous for the D2 receptor gene reduces ethanol consumption. These results suggest that the D2 receptor regulates ethanol drinking and that either high or minimal receptor availability is associated with reduced levels of drinking. There is some evidence that low D 2 availability in the striatum may be related to alcohol use disorders. Volkow et al. (2002) have shown that subjects with early-onset alcohol dependence have lower D2 availability in the caudate and putamen than do control subjects. Individuals with alcohol use disorders have also been shown to have lower D2 receptor levels in the ventral striatum than do controls (Heinz et al. 2004). D2 receptor concentrations in the ventral striatum have been found to correlate negatively with both alcohol craving and ethanol cue-induced activation of the medial prefrontal cortex and the anterior cingulate (Heinz et al. 2004).

Serotonin In monkeys, high rates of ethanol consumption are associated with low cerebrospinal fluid (CSF) levels of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA) (Higley et al. 1996). Evidence implicating serotonin in the development of alcoholism includes the observation that concentrations of 5-HIAA in CSF may be lower in early-onset alcoholic individuals than in those whose alcohol use disorders had a late onset (Fils-Aime et al. 1996). Extracellular serotonin levels are regulated by the activity of serotonin transporters, which mediate the reuptake of this neurotransmitter into presynaptic neurons. Studies in rodents indicate that ethanol administration may lead to significant elevations in serotonin levels in the hippocampus (Daws et al. 2006) and striatum (Thielen et al. 2001). However, evidence from mutant mouse models suggests that the effects of ethanol on serotonin levels in the hippocampus may not result from a direct interaction of alcohol with serotonin transporters (Daws et al. 2006). The availability of brainstem serotonin transporter sites, as labeled by the radioligand [I-123]2 -carbomethoxy-3 -(4-iodophenyl) tropane ([I-123] -CIT), was found to correlate positively with the mean daily intake of ethanol by monkeys (Heinz et al. 2003). Binding of ligands to serotonin transporters, however, was reduced in the brainstem of alcoholic individuals (Heinz et al. 1998; Szabo et al. 2004) and in other regions, including the frontal cortex, midbrain, thalamus, and amygdala (Szabo et al. 2004). However, Brown et al. (2007) showed that when a new radioligand—[11C]-3-amino4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile—with high specific binding for the serotonin transporter was used, there were no differences in binding to this transporter protein between alcoholdependent and control subjects. The extent of binding to serotonin transporters in the raphe nucleus by [I-123] -CIT was dependent upon the genotype of a polymorphic site in the promoter of the gene encoding the transporter (Heinz et al. 2000). Studies that carefully control for genetic factors may be

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needed to clarify the relationship between alcoholism and serotonin transporter availability. Ethanol consumption may also be modulated by the serotonin type 3 (5-HT3 ) receptor. Administration of the 5-HT3 antagonist ondansetron results in a reduction of ethanol consumption by individuals with early-onset alcoholism (Johnson and Ait-Daoud 2000; Kranzler et al. 2003). The administration of 5-HT3 antagonists, including ondansetron, also reduced ethanol intake in animals (Tomkins et al. 1995). This effect is not seen when a 5-HT3 antagonist is administered to mice that are missing the gene for the 5-HT3A receptor subtype (Hodge et al. 2004). Infusion of the 5-HT3 antagonist tropisetron into the NAcc reduces ethanol-induced increases in dopamine release (Yoshimoto et al. 1992) and ethanol consumption (Jankowska and Kostowski 1995). This suggests 5-HT3 receptors may modulate ethanol drinking via an action on dopamine release in the NAcc. There is some evidence that 5-HT1B receptors can modulate the dopamine-releasing actions of ethanol. Results of a study by Yan et al. (2005) suggest that infusion of 5-HT1B receptor agonists into the VTA significantly prolong the time during which ethanol administration produces an increase in dopamine levels in the NAcc. In contrast, their findings indicate that ethanol-induced dopamine release is decreased by the intrategmental infusion of 5-HT1B antagonists. In animal models of alcohol consumption, the administration of serotonin 5-HT1B receptor agonists can suppress ethanol intake (Higgins et al. 1992; Tomkins and O'Neill 2000). Rats consume more ethanol after being given an injection of a viral vector containing 5-HT1B DNA, which increases the expression of 5-HT1B receptors in the NAcc (Hoplight et al. 2006). However, the effects of deletion of 5-HT1B receptors from mice have been inconsistent. Some investigators (Crabbe et al. 1996), but not others (Gorwood et al. 2002), have found that 5-HT1B knockout mice consumed more ethanol than wild-type mice. Although these findings suggest that 5-HT1B receptors may play a role in modulating ethanol self-administration, it is unclear how expression levels of 5-HT1B receptors are related to this effect.

Nicotinic Receptors The stimulant effects of ethanol are attenuated in healthy subjects who have been pretreated with the nicotinic receptor antagonist mecamylamine (Blomqvist et al. 2002). This finding complements those from animal studies that implicate nicotinic receptors in the mediation of the actions of ethanol. In animals, the systemic administration of mecamylamine may decrease ethanol-induced enhancement of locomotor activity (Blomqvist et al. 1992) and suppresses voluntary ethanol consumption (Blomqvist et al. 1996). When infused into the VTA, mecamylamine may block ethanol-induced dopamine release in the NAcc (Blomqvist et al. 1997; Tizabi et al. 2002) and may also reduce ethanol consumption (Ericson et al. 1998). The voluntary intake of ethanol produces an increase in acetylcholine levels in the VTA, an effect that may explain how ethanol may activate nicotinic receptors in the VTA that regulate dopamine release in the NAcc (Larsson et al. 2005). In addition to acting on nicotinic receptors by enhancing acetylcholine release, ethanol may also have more direct effects on these receptors (Aistrup et al. 1999). Ethanol, through actions on presynaptic nicotinic receptors, may enhance the release of GABA (Alkondon et al. 1997; Moriguchi et al. 2007). Potential implications of this effect are discussed in the section after next, "GABAA Receptor Systems." Nicotinic receptors consist of different combinations of subunits, and the precise subunit combination may determine the nature of the receptor response to ethanol (Cardoso et al. 1999; Covernton and Connolly 1997). Nicotinic receptors containing

3 4

subunits are either inhibited or potentiated by low

concentrations of ethanol (Covernton and Connolly 1997). Deletion of the

7

nicotinic subunit from mice

increases their sensitivity to the hypnotic effects of ethanol (Bowers et al. 2005). Even slight variations in the amino acid composition of the

4

subunit may determine the extent to which

4 2 -containing

nicotinic receptors are activated by ethanol (Butt et al. 2003). This suggests that genetic polymorphisms in nicotinic receptors may help determine how individuals differ in their responses to ethanol.

Cannabinoid CB1 Receptors The activation of cannabinoid CB1 receptors may promote the release of dopamine in the NAcc by

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increasing firing rates of dopamine neurons in the VTA (Gessa et al. 1998; Tanda et al. 1997). The administration of the CB1 receptor antagonist rimonabant blocks ethanol-induced firing of tegmental dopaminergic neurons (Perra et al. 2005). This compound also inhibits ethanol-stimulated dopamine release in the NAcc (Cheer et al. 2007). Administration of rimonabant significantly reduces the intake of ethanol in wild-type mice, but not in mice in which the CB1 receptor is deleted (Thanos et al. 2005a). Compared with the ethanol consumption of wild-type mice, the ethanol consumption of mutant mice whose CB1 receptor has been deleted is significantly reduced (Thanos et al. 2005a). These results suggest that the CB1 receptor may regulate the rewarding actions of ethanol as part of the regulatory actions of CB1 receptor systems within the mesolimbic system.

GABAA Receptor Systems Many of the behavioral effects of ethanol appear to result from its interaction with GABAA receptors. Barbiturates and benzodiazepines positively modulate the actions of GABA at these receptors. These agents have several behavioral effects that parallel those of ethanol, including anxiolytic, anticonvulsant, hypnotic, and sedative actions. Injection of the GABAA receptor agonist muscimol into limbic areas produces stimulus properties that substitute for those of ethanol in drug discrimination studies (Hodge and Alken 1996). The sedative and motor-impairing effects of ethanol are potentiated by the concurrent administration of either GABAA receptor agonists, such as muscimol, or positive modulators of the GABAA receptors, such as the benzodiazepines (Frye and Breese 1982; Martz et al. 1983; Tauber et al. 2003). The administration of benzodiazepine inverse agonists will block or reverse the depressant effects of ethanol, as well as suppress its self-administration (Petry 1995; Suzdak et al. 1986). Sedation produced by the infusion of ethanol into the brain is blocked by the administration of the GABAA receptor antagonist bicuculline (Givens and Breese 1990). The hyperexcitability associated with withdrawal from chronic ethanol exposure, including seizures, can be reversed or attenuated by the administration of benzodiazepines. Finally, there is cross-tolerance of benzodiazepines or barbiturates to the depressant effects of ethanol (Khanna et al. 1998). Behavioral studies can only provide indirect evidence that ethanol interacts with GABAA receptor systems. A large body of physiological and biochemical studies has examined the interactions between ethanol and GABAergic systems. GABAA receptors consist of a family of structurally related ionotropic receptors. This family includes a variety of pentameric complexes consisting of subunits that differ in their amino acid structure. Common subunits found to exist in the brain include the types subtypes 1, 2, 4, and 6),

(subtypes 2 and 3),

, and

GABAA receptors identified in the brain consist of two

(including

(subtypes 1, 2, and 3). The most abundant

, two

, and one

subunit (Pritchett et al. 1989).

GABAA receptors containing the

1 subunit may mediate the sedative-hypnotic actions of benzodiazepines and new hypnotic agents, such as zolpidem (Blednov et al. 2003). The presence of 2 subunits in GABAA receptors has been linked to the mediation of the anxiolytic effects of the

benzodiazepines (Morris et al. 2006). Deletion of the

1

subunit gene attenuates the sedative actions of

ethanol in male mice (Blednov et al. 2003), although this effect has not been seen in some strains of 1 subunit knockout mice (Kralic et al. 2003). In rats, infusion of a selective 1 subunit antagonist into the ventral pallidum, which receives extensive output from the NAcc, blocks both the sedative and reinforcing effects of ethanol (Harvey et al. 2002; June et al. 2003). In humans, genetic variation in the amino acid composition of the

2

subunit has been associated with differences in the subjective effects of

ethanol (Pierucci-Lagha et al. 2005). GABAA receptors containing

1 x 2

subunit combinations are abundant in the postsynaptic sites of the

brain and exhibit sensitivity to benzodiazepines. Of these, the

1 2 2

combination binds readily to

zolpidem, and brain sites that show dense binding of zolpidem have been linked to the actions of ethanol (Criswell et al. 1993, 1995). Whether ethanol interacts directly with postsynaptic GABAA receptors at concentrations that produce moderate levels of intoxication has been questioned because several studies have shown that ethanol enhances the activity of GABAA receptors only at concentrations associated with extremely high levels of intoxication (Krystal et al. 2006). An alternative mechanism through which ethanol may indirectly interact with GABAA receptors may involve the process of alcohol-

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evoked GABA release. Acute ethanol administration increases the release of GABA from presynaptic sites in some brain regions, including the central nucleus of the amygdala, a structure implicated in the rewarding effects of ethanol (Siggins et al. 2005). Electrophysiological data also suggest that ethanol can promote GABA release in the cerebellum (Carta et al. 2004). In some regions, such as the hippocampus, this effect may be regulated by presynaptic GABAB receptors, which may limit GABA release as part of a negative feedback system. A second mechanism through which ethanol may interact with GABAA receptors is by increasing neurosteroid concentrations in the brain (Morrow et al. 1999). Neurosteroids, such as allopregnanolone, are synthesized in the brain from cholesterol (Hu et al. 1987). They may increase the activity of GABAA receptors by binding to specific sites on the

and

subunits of these receptors (Hosie et al. 2006). The

acute administration of ethanol can increase concentrations of allopregnanolone in the plasma, cerebral cortex, and hippocampus (Barbaccia et al. 1999; Morrow et al. 2001; VanDoren et al. 2000). This may occur through the stimulation of neurosteroid synthesis, an effect that may, at least in part, involve the effects of ethanol on the hypothalamic-pituitary-adrenal (HPA) axis (Follesa et al. 2006). In humans, the administration of finasteride, a compound that inhibits neurosteroid synthesis, attenuates the subjective effects of a moderate dose of ethanol (Pierucci-Lagha et al. 2005). GABAA receptors containing

4 3

,

6 3

, and 4 2

subunit combinations have been shown by

some investigators to be sensitive to the effects of low concentrations of ethanol (Sundstrom-Poromaa et al. 2002; Wallner et al. 2003), though in a recent study this effect could not be replicated for the subunit combination (Borghese et al. 2006). GABAA receptors containing 6

subunits and either

4 3

4

or

subunits have extrasynaptic locations and regulate tonic (rather than phasic) currents (Hanchar et al.

2004). These extrasynaptic receptors represent a smaller proportion of GABAA receptors in the brain than do those located in the synapse. Receptors containing the cerebellar granule cells, whereas those composed of the

4 3

6 3

combination are present in

combination are more widespread in the

brain and appear in areas such as the hippocampus, striatum, and frontal cortex (Wallner et al. 2006). GABAA receptors containing

4

or

6

subunits in combination with the

subunits may mediate the

anxiolytic motor coordination, impairment, and the sedative effects of low-dose ethanol. Prolonged exposure to ethanol may result in decreased sensitivity (i.e., tolerance) to the sedative and many other actions of ethanol. Tolerance to the action of ethanol may occur in association with a decrease in GABAA-mediated function (Grobin et al. 1998). Acute forms of tolerance to the sedativehypnotic effects of ethanol, which occur in a single drinking session, may be related to the phosphorylation of the

isoform of protein kinase C (PKC) (Wallace et al. 2007). Chronic tolerance, it

has been suggested, may result from an alteration in the subunit composition of GABAA receptors that are present in the brain. Such changes in subunit expression are seen in animal studies that either examined the presence of subunit proteins by immunoreactivity or measure levels of messenger ribonucleic acids (mRNAs), which are responsible for the synthesis of the subunits (Grobin et al. 1998; Mahmoudi et al. 1997). These changes include a decrease in the expression of cerebral cortex and the cerebellum, and an increase in

2

subunits in the

4,

6 , and 1–3 subunits in these regions. This pattern of change, however, has not been detected for humans with a history of alcoholism. Evidence

concerning the effects of chronic ethanol use on the relative amounts of different GABAA subunits in the human brain is not consistent. One group of researchers has reported that levels of mRNA for the

3

receptor subunit may be increased in the frontal cortex of alcoholic individuals (Mitsuyama et al. 1998). Another group found increases in the

1

subunit levels in this region (Lewohl et al. 1997) but failed to

see this change when tissue from the superior frontal cortex of noncirrhotic alcoholic patients was examined (Lewohl et al. 2001). In another study, levels of

2

subunit mRNAs were decreased in the

superior frontal cortex (Lewohl et al. 2000). Some researchers, however, have been unable to find changes in the frontal cortex in the expression of mRNA for any GABAA receptor subunits (Flatscher-Bader et al. 2005; Mayfield et al. 2002). The significance of findings on the nature of GABAA subunit expression in alcoholic individuals is confounded by postmortem studies in which investigators are unable to control for genetic differences

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between control and alcoholic groups, and variables such as between-group differences in the cause of death and the state of health before death. Examination of the effects of chronic ethanol on GABAA subunit expression in nonhuman primates allows for the control of some of these confounding factors. Chronic self-administration of ethanol decreased the expression of

2,

4,

1,

prefrontal cortex of these animals, mRNAs were decreased for

and 3 subunit mRNAs in the orbital frontal cortex of cynomolgus monkeys (Hemby et al. 2006). In the dorsolateral 2,

1,

and

1,

3,

1,

2,

subunits, although no

changes were observed for subunits in the anterior cingulate. These reductions in GABAA subunits may contribute to the tolerance that develops to ethanol's effects. Tolerance to the effects of ethanol may also be related to alterations in the trafficking of GABAA receptor subunits between the cell membrane surface and the interior of the cell. This is evidenced by the finding that chronic exposure to ethanol enhances the internalization of

1

subunits in cerebral cortical neurons

(Kumar et al. 2003).

Glutamate Receptor Systems NMDA receptors Activation of NMDA receptors by glutamate and other excitatory amino acids enhances calcium and sodium flow into neurons, with a resultant increase in excitatory postsynaptic potentials. NMDA receptors contain four subunits: two NR1 and two NR2 subunits. NR2A and NR2B subtypes exist, and, in some cases, other subunits, such as the NR3 subunit, may also be present. Glutamate may activate NMDA receptors by binding to the NR2 or comparable subunit. The functioning of NMDA receptors is dependent on the binding of the amino acid glycine to the NR1 subunit. NMDA receptor–mediated flux is regulated by a voltage-dependent magnesium block. Consequently, these receptors become active only when a certain level of neuronal depolarization is reached. Competitive antagonists directly block the binding of glutamate to the NMDA receptor. Ketamine, phencyclidine, and many other agents act as uncompetitive antagonists at the NMDA receptor by binding to sites within the ion channel of the receptor complex. Several studies indicate that there is overlap in the stimulus properties of ethanol and uncompetitive NMDA receptor antagonists (Hodge et al. 2001; Hölter et al. 2000; Hundt et al. 1998). In animal studies, the administration of both competitive and uncompetitive antagonists reduces responding for ethanol (Rassnick et al. 1992; Shelton and Balster 1997). However, these agents will also reduce responding for saccharin solutions, which argues against the specificity of their actions (Shelton and Balster 1997). The administration of both uncompetitive and competitive NMDA receptor antagonists decreases ethanol consumption at doses that produced only small changes in food intake (McMillen et al. 2004), which is consistent with the idea that NMDA receptors regulate ethanol consumption. From a functional standpoint, acute ethanol administration appears to inhibit NMDA receptor activity. At concentrations as low as 10 mmol/L, ethanol can inhibit NMDA receptor–mediated influx of calcium in cultured cerebellar granule cells (Hoffman et al. 1989). The acute administration of ethanol may reduce excitatory postsynaptic potentials mediated by NMDA receptors in the hippocampus (Lovinger et al. 1989, 1990), with significant inhibition being detected at an ethanol concentration of 25 mmol/L. In the core of the NAcc, NMDA currents are reduced by ethanol at concentrations ranging between 11 and 200 mmol/L (Nie et al. 1994). Ethanol in concentrations of 25–75 mmol/L inhibits NMDA excitatory postsynaptic potentials in medium spiny neurons of the shell of the NAcc (Zhang et al. 2005). There is limited evidence that the inhibitory effects of ethanol are regulated by discrete sites located on NR1 (Smothers and Woodward 2006) and NR2A (Honse et al. 2004) subunits. The sensitivity of NMDA receptors to glutamate and other agonists is regulated by the phosphorylation and dephosphorylation of receptor subunits. Kinases, such as PKA and tyrosine kinases, phosphorylate the receptor, whereas phosphatases, such as PP1, can dephosphorylate the receptor. The hypnotic effect of ethanol is greatly enhanced in mutant mice with deletions of the gene for Fyn-tyrosine kinase (Miyakawa et al. 1997; Yaka et al. 2003). However, presence of the Fyn mutation does not appear to

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alter voluntary ethanol consumption (Yaka et al. 2003). The NR2B subunit may be a target of Fyn-tyrosine phosphorylation. Involvement of this subunit in mediating ethanol's sedative effects is suggested by the finding that the administration of ifenprodil, a selective antagonist of the NR2B subunit, increases the duration of loss of the righting reflex in wild-type mice (Yaka et al. 2003). The presence of a dopamine D 1 receptor agonist leads to a marked reduction in the inhibitory actions of ethanol on NMDA-induced currents in the NAcc (Maldve et al. 2002). This may result from D1 receptor– mediated phosphorylation of the NR1 subunit. In cAMP-regulated phosphoprotein 32KD (DARPP-32) knockout mice, D1 agonist stimulation fails to alter the sensitivity of NMDA receptors to the inhibitory effects of ethanol (Maldve et al. 2002). The reinforcing effects of ethanol are attenuated in DARPP-32 knockout mice (Risinger et al. 2001), which may indicate that DARPP-32–mediated phosphorylation of the NMDA receptor is involved in the neuroadaptation that promotes ethanol consumption. NMDA receptors may be up-regulated during ethanol withdrawal (Haugbøl et al. 2005). In the amygdala, chronic ethanol treatment produces an increase in NMDA-stimulated currents, possibly indicating that NMDA receptor up-regulation is related to enhanced sensitivity of the NMDA receptor systems (Floyd et al. 2003). Treatment with NMDA receptor antagonists such as memantine reduces ethanol withdrawal seizures, suggesting a role for the NMDA receptor in the onset of withdrawal symptoms (Bienkowski et al. 2001). Chronic ethanol administration increases mRNA and protein levels for NMDA receptor subunits in various brain regions, including the amygdala, cerebellum, frontal cortex, and hippocampus (Darstein et al. 2000; Floyd et al. 2003; Kalluri et al. 1998). Similarly, in postmortem tissues, there is greater density of putative NMDA receptor binding sites in frontal cortical tissues obtained from alcoholic individuals than from controls (Freund and Anderson 1996). In rats treated chronically with ethanol, concentrations of NMDA receptor subunits in the cerebral cortex and hippocampus returned to near-control levels 48 hours after the start of withdrawal (Kalluri et al. 1998). Chronic ethanol exposure increases the size and density of clusters of the NR1 and NR2B subunits in synapses of hippocampal neurons (Carpenter-Hyland et al. 2004). Thus, chronic ethanol administration appears to remodel the pattern of distribution of synaptic NMDA receptor subunits in neurons. A recent study by Zhou et al. (2007) indicates that, in addition to altering NMDA subunit expression and NMDA receptor function, chronic ethanol administration may also alter the structure of dendritic spines within the NAcc. Both continuous and intermittent access to ethanol reduced dendritic spines of medium spiny neurons of the NAcc. Intermittent ethanol exposure was associated with the appearance of large-sized spines. Continuous access to ethanol was also associated with an up-regulation of NR1 subunits. Ethanol-induced alterations in dendritic spine morphology may be related to changes in the postsynaptic proteins that regulate NMDA receptor function. These proteins include Homer and Shank, which are involved in the anchoring of NMDA receptors and regulate their function. Deletion of the Homer-2 protein in mice enhanced the hypnotic effects of ethanol and increased place aversion to environments associated with ethanol administration (Szumlinski et al. 2005). Ethanol exposure may also alter the function of NMDA receptors by changing the trafficking of NMDA receptor subunits. Treatment with ethanol increases the internalization of NR2A subunits into hippocampal neurons. This, in turn, produces NMDA receptors that consist predominantly of NR2B subunits, which are associated with the form of synaptic plasticity known as long-term depression, which plays a role in memory (Liu et al. 2004). The up-regulation of NMDA receptors that results from chronic ethanol exposure may be one factor that contributes to the increased neuronal excitability that occurs during withdrawal from ethanol. A second factor in the development of hyperexcitability during withdrawal may be increased extracellular levels of excitatory amino acids in the brain. Glutamate may be elevated in both the hippocampus (Dahchour and De Witte 2003) and the striatum (Rossetti and Carboni 1995; Saellstroem et al. 2006) during ethanol withdrawal. These elevations may involve positive feedback loops in which glutamate stimulates NMDA receptors to facilitate further release of this amino acid (Rossetti et al. 1999). Interestingly, nicotine

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administration also increases glutamate release in the NAcc in animals withdrawn from ethanol (Saellstroem et al. 2006).

AMPA/Kainate receptors AMPA and kainate receptors are glutamate-activated receptors (GluRs) that regulate sodium currents and in some cases also calcium currents. These receptors overlap in their sensitivity to certain agonists, but are composed of distinct subunits, with GluR1–4 units forming the AMPA receptors and GluR5–7 forming the kainate receptors in combination with kainic acid (KA) 1–2 subunits (Dingledine et al. 1999). Ethanol reduces non–NMDA glutamate receptor–mediated currents in the central nucleus of the amygdala (Zhu et al. 2007). These currents are increased by the repeated administration of ethanol. In the core of the NAcc, ethanol slightly reduces kainate-induced currents but has no effect on AMPA-induced currents (Nie et al. 1994). In the hippocampus, ethanol potently inhibits currents produced by kainate receptors, but not those associated with the activation of AMPA receptors (Carta et al. 2003). Although ethanol has not been shown to alter the activity of AMPA receptor systems, these systems, nevertheless, may play a role in alcoholism. The AMPA receptor subunits GluR2 and GluR3 are elevated in tissues obtained from individuals with a history of alcohol abuse, when compared with control subjects (Breese et al. 1995). Topiramate, which has AMPA/kainate-blocking properties (Gryder and Rogawski 2003; Poulsen et al. 2004), reduces ethanol consumption in alcohol-dependent individuals (Johnson et al. 2003). It is unknown whether this effect involves actions at kainate receptors, AMPA receptors, or both types of receptor. AMPA receptor systems may regulate ethanol-seeking behaviors. Reinstatement of responding for ethanol, a measure of the motivation to seek ethanol, is blocked by the administration of an AMPA/kainate receptor antagonist (Bäckström and Hyytiä 2004; Sanchis-Segura et al. 2006). Reinstatement responding induced by ethanol-related cues is blunted in mice missing the GluR3 subunit (Sanchis-Segura et al. 2006). Mice missing this subunit, however, did not differ from wild-type mice with respect to the self-administration of ethanol.

Metabotropic receptors Metabotropic receptors are activated by glutamate, but in contrast to glutamatergic ionotropic receptors, their actions are mediated by G proteins. Group I metabotropic receptors include the metabotropic GluR1 (mGluR1) and mGluR5 subtypes, and Group II receptors include the mGluR2/3 subtypes. The Group II receptors are located on presynaptic glutamatergic neurons. The Group I metabotropic receptors and NMDA receptors can each alter the activity of the other receptor type. For example, activation of NMDA receptors can potentiate the activity of mGluR5 receptors (Alagarsamy et al. 2005), and NMDA receptor–mediated synaptic transmission is dependent on activation of mGluR5 receptors (Harney et al. 2006). Ethanol may decrease the activity of mGluR5-type receptors via a mechanism involving the kinase PKC (Minami et al. 1998; Netzeband and Gruol 1995). Both the mGluR1 and mGluR5 receptors have been implicated in the regulation of the rewarding effects of ethanol. The drug acamprosate, which is approved for the treatment of alcohol dependence, may act as an antagonist at the mGluR5 receptor (Harris et al. 2002). Ethanol-induced elevations of dopamine levels in the NAcc are blocked by the administration of mGluR1 or mGluR5 antagonists (Lominac et al. 2006). In animal studies, the administration of mGluR1 and mGluR5 antagonists may reduce ethanol self-administration (Cowen et al. 2005; Lominac et al. 2006), although mGluR1 antagonists have not consistently had this effect (Hodge et al. 2006; Schroeder et al. 2005). The mGluR5 antagonist 6-methyl-2(phenylethynyl) pyridine alters ethanol intake in wild-type mice but not in animals in which the

isoform of PKC has been deleted

(Olive et al. 2005). This is consistent with other findings implicating PKC-mediated phosphorylation in the inhibitory actions of ethanol on mGluR5 receptors (Minami et al. 1998).

Neuropeptides

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Opioid receptor systems The endogenous opioid system plays a role in the reinforcing effects of ethanol and a variety of other drugs that are self-administered by animals and abused by humans, including nicotine, cocaine, amphetamines, and cannabinoids. Three classes of opioid receptors, , peptides to produce their biological effects (Kieffer 1995). The

, and , interact with opioid

opioid receptor mediates the effects of

morphine and related opioid agonists (Yu 1996). It has a putative secondary structure of seven transmembrane domains common to G protein–coupled receptors, with functional coupling to adenylyl cyclase. Ethanol, like nicotine, cocaine, amphetamines, and cannabinoids, releases dopamine in the NAcc (Di Chiara and Imperato 1988; Tanda et al. 1997). In addition,

opioid receptors in the VTA modulate NAcc

dopamine activity and ethanol-preferring (AA) rats have a significantly higher density of

opioid

receptors in the VTA (and related limbic brain regions) than ethanol-avoiding (ANA) rats (De Waele et al. 1995). The

opioid receptor is also a G protein–coupled receptor with functional coupling to adenylyl cyclase,

and it too has been shown to modulate ethanol consumption (Froehlich et al. 1991; Krishnan-Sarin et al. 1995). In rats selectively bred for high levels of ethanol drinking, the selective

antagonist ICI 174864

was found to be more potent than naloxone in suppressing ethanol consumption (Froehlich et al. 1991; Krishnan-Sarin et al. 1995). The more highly selective and longer-acting

antagonist, naltrindole

hydrochloride, also produced a dose-dependent suppression of drinking in rats selectively bred for ethanol consumption (Krishnan-Sarin et al. 1995). In research done by Gianoulakis and Gupta (1986), concentrations of endogenous opioids, which bind to and

opioid receptors, are correlated with ethanol exposure. Acute ethanol treatment of ethanol-

drinking mice increased the hypothalamic release of

-endorphin. In humans, individuals with alcohol

use dependency showed decreased basal plasma (Aguirre et al. 1990) and CSF (Genazzani et al. 1981) concentrations of -endorphin. Furthermore, nonalcoholic adults with a family history of alcoholism (i.e., high risk) had basal concentrations of

-endorphin that were comparable with those of abstinent

alcoholic persons but significantly lower than those of low-risk individuals (Gianoulakis et al. 1989). Following ethanol administration,

-endorphin levels increased among high-risk subjects, resulting in

levels comparable with those seen following ethanol administration among low-risk subjects (Gianoulakis et al. 1989). Furthermore, ethanol induced a dose-dependent increase in plasma -endorphin levels in high-risk but not low-risk subjects (Gianoulakis et al. 1996). Enkephalins may also play a role in the reinforcing effects of ethanol (Li et al. 1998; Mendez and Morales-Mulia 2006). The efficacy of opioid antagonists (i.e., naltrexone, nalmefene) in the treatment of alcoholism (Srisurapanont and Jarusuraisin 2005) provides further evidence that the rewarding properties of ethanol are, in part, mediated by the opioid system.

Neuropeptide Y NPY is a 36-amino acid peptide neurotransmitter. Mice deleted for the gene encoding NPY showed a preference for drinking ethanol-water solutions over water (Thiele et al. 1998). These mice were also less sensitive to the hypnotic and sedative effects of ethanol than NPY wild-type mice. In contrast, mice manipulated to overexpress NPY showed less preference for ethanol and greater sensitivity to the sedative and hypnotic effects of ethanol (Thiele et al. 1998, 2000a). Studies of specific NPY receptors show that Y1 receptors inhibit voluntary ethanol consumption and some of ethanol's intoxicating effects, such that mice deleted for the gene encoding this receptor show increases on these measures (Pandey et al. 2003; Thiele et al. 2002). In contrast, the Y2 receptor serves as a presynaptic autoreceptor that inhibits NPY release, so that mice deleted for the gene encoding this receptor show reduced ethanol consumption (Pandey et al. 2003). These findings have led to the suggestion that NPY Y1 agonists and Y2 antagonists may be of value in the treatment of alcoholism (Cowen et al. 2004).

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Other peptide neurotransmitters Other peptides that have been linked to the actions of ethanol are corticotropin-releasing hormone (CRH), urocortin, leptin, cholecystokinin, melanocortins, and galanin (reviewed in Cowen et al. 2004). Preclinical studies have linked the CRH system to the effects of a variety of substances of abuse, including alcohol (Sarnyai et al. 2001). CRH, which plays a central role in the response to stress by regulating the HPA axis, exerts its effects through CRH1 and CRH2 receptors. In an acute free-choice paradigm, Sillaber et al. (2002) found that mice homozygous for a CRH1 receptor gene deletion (CRH –/– ) did not differ from wild-type mice with respect to their consumption of fluids, including ethanol. However, following habituation to 8% ethanol and exposure to a repeated social defeat stress, when tested again 3 weeks later, CRH –/– animals consumed more than twice the volume of ethanol daily that did their wild-type littermates. Although subsequent exposure to a swim stress slightly decreased ethanol consumption acutely in both groups of animals, CRH –/– mice subsequently showed increased drinking, whereas there was no increase in drinking among the wild-type mice. The doubling of ethanol intake persisted among the CRH –/– mice for more than 6 months. The rate of ethanol metabolism did not differ between the groups of mice, excluding this as a possible explanation for the observed effects on drinking behavior. However, further analysis did reveal increased expression of the NR2B subunit of the NMDA receptor, without alteration of the expression of any other ionotropic glutamate subunit.

ETHANOL INTERACTIONS WITH ION CHANNELS Voltage-gated calcium ion channels regulate neuronal excitability and neurotransmitter release by regulating calcium flow into neurons in response to membrane potential changes. Several varieties of voltage-gated calcium channels have been identified, including the L, N, P/Q, R, and T types. Studies of the effects of ethanol on calcium channels in isolated cell preparations indicate that ethanol can inhibit the activity of L-type (Mullikin-Kilpatrick and Treistman 1995), N-type (Solem et al. 1997), P/Q-type (Solem et al. 1997), and T-type (Littleton et al. 1992; Mu et al. 2003; Twombly 1990) calcium channels. The functional implication of ethanol's actions on voltage-gated calcium channels is just beginning to be characterized. Dihydropyridine-sensitive (L-type) binding sites are increased in ethanol-dependent rats (Dolin et al. 1987), and L-channel antagonists can prevent withdrawal symptoms in these animals. N-type and P/Q-type channels have been implicated in the regulation of neurotransmitter release (Reid et al. 2003). The hypnotic effects of ethanol are diminished in mutant mice that lack the N-type calcium channel (Newton et al. 2004), which show both decreased ethanol preference and levels of ethanol consumption compared with wild-type mice. In contrast to the other voltage-gated channels, T-type channels have low voltage thresholds for activation. These channels have been implicated in the generation of burst responses in thalamic neurons that produce spindle waves during Stage II sleep (Kim et al. 1995). Low concentrations of ethanol may enhance T-type currents in the thalamus, although higher concentrations of ethanol block these currents (Mu et al. 2003). The chronic self-administration of ethanol reduces T-type calcium currents in dorsal-lateral geniculate nucleus cells in the thalamus of monkeys (Carden et al. 2006), an effect that may play a role in the disruptive effects of ethanol on sleep (Carden et al. 2006). Inwardly rectifying potassium channels can decrease neuronal excitability. G protein–coupled, inwardly rectifying potassium channels (GIRKs) may be activated by intoxicating concentrations of ethanol (Lewohl et al. 1999). Mutant mice, from which the GIRK2 type of potassium channel is deleted, consume more ethanol than do wild-type mice (Blednov et al. 2001). Large-conductance, BK channels are voltage-dependent potassium channels that are also activated by increases in intracellular calcium. BK channels may be abundant in the medium spiny neurons of the NAcc (Martin et al. 2004). BK channel subunits have been identified in several other brain regions, including the amygdala, cerebellum, hippocampus, and neocortex (Edgerton and Reinhart 2003; Faber and Sah 2002; Hicks and Marrion 1998; Kang et al. 1996). These channels modulate the shape and

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frequency of action potentials and control neurotransmitter release (Shao et al. 1999). Ethanol activates BK channels in the NAcc (Martin et al. 2004) at concentrations associated with intoxication. Although the behavioral significance of ethanol-induced activation of BK channels is not well understood, in the nematode Caenorhabditis elegans BK channels may be the only proteins through which ethanol acts to produce intoxication (Davies et al. 2003).

CONCLUSION Ethanol can alter the activity of cAMP second messenger pathways by stimulating some isoforms of adenylyl cyclase. This effect can alter the phosphorylation state of receptor systems, most notably the NMDA receptor system. This action may also influence the function of CREB and NPY systems, which may play a critical role in regulating drinking behaviors. Another neuropeptide, CRH, through actions involving both the HPA axis and extra-HPA systems, may also play a key role in ethanol consumption, possibly by interacting with the glutamate system through NMDA receptor effects. Like many other drugs of abuse, ethanol promotes the release of dopamine within the mesolimbic system. This action may be linked to the rewarding actions of ethanol. The dopamine-releasing effects of ethanol may be enhanced as a result of repeated exposure to this agent. Nicotinic receptors located in the VTA may mediate some of the dopamine-releasing actions of ethanol. Cannabinoid CB1 and serotonin 5-HT3 and 5-HT1B receptors may also facilitate mesolimbic-dopamine release associated with ethanol use. Whereas ethanol intake, the

and

opioid receptors also appear to facilitate dopamine release following

opioid receptor appears to inhibit this effect.

The anxiolytic, hypnotic, motor-impairing, and sedative actions of ethanol most likely result from activation of GABAA receptor systems. Mechanisms that mediate the actions of ethanol on these systems remain a subject of intense investigation. Proposed mechanisms include ethanol-induced presynaptic release of GABA, increases in neurosteroid concentrations in the brain, and direct interactions between ethanol and GABAA receptors that contain 4 or

6

subunits in combination with the

subunit.

Each of the major types of glutamate receptors may play a role in alcoholism. The NMDA receptor systems are subject to the inhibitory actions of ethanol. These actions produce some of the stimulus effects associated with ethanol use and may be tied to the rewarding actions of ethanol. mGluRs, particularly the mGluR5 receptor, may regulate ethanol self-administration, possibly through an interaction with NMDA receptors. Although they may not directly interact with ethanol, AMPA receptors may regulate ethanol-seeking behavior. Kainate receptors in select brain regions are subject to the inhibitory actions of ethanol, but the behavioral implications of this effect remain to be determined. Ethanol exposure alters the functioning of L-, N-, P-, and T-type voltage-dependent calcium channels. Ethanol-induced alterations of L-type calcium channels may play a role in the development of ethanol withdrawal symptoms. N- and T-type calcium channels may mediate some of the sedative effects of ethanol and its impact on the quality of sleep experienced. Recent evidence suggests that BK channels may play an important role in ethanol intoxication. The decreased sensitivity of GABAA receptors and the increased sensitivity of NMDA receptor systems have been implicated in the development of neuronal hyperexcitability that occurs during the early phases of ethanol withdrawal. Withdrawal symptoms can be attenuated by the administration of either positive modulators of GABAA receptor systems, such as the benzodiazepines, or NMDA receptor antagonists, such as memantine. Alterations in subunit expression that occur with prolonged ethanol exposure may play a role in ethanol withdrawal. Ethanol withdrawal, however, may also involve more subtle changes, such as alterations in the local trafficking of receptors through the plasma membrane and in gene expression. As discussed in this chapter, considerable knowledge has accrued concerning the neurobiology of ethanol drinking behavior and ethanol's behavioral effects. This growing understanding of the neurobiology of alcohol can be expected to continue to inform the search for medications to treat alcohol use disorders, reflecting an iterative process of preclinical and clinical development.

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KEY POINTS The antianxiety, motor-impairing, and sedative-hypnotic effects of ethanol may be produced by the activation of -aminobutyric (GABA)A receptors. Ethanol may interact with GABAA receptors by enhancing GABA release, increasing brain neurosteroid levels, and/or by directly acting on GABAA receptors that contain 4 or

6

subunits.

Decreased GABAA receptor sensitivity and N-methyl-D-aspartate (NMDA) receptor up-regulation may play important roles in the development of physical dependence on ethanol. Ethanol-induced dopamine release within the nucleus accumbens may produce the reinforcing effects of alcohol. Cannabinoid CB1 , nicotinic,

opioid, and serotonin 5-HT3 receptors may alter the reinforcing effects

of ethanol by facilitating dopamine release. Endogenous opioid peptides, including the enkephalins, may promote ethanol consumption while other peptides, such as neuropeptide Y, may have inhibitory effects on alcohol-seeking behaviors.

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SUGGESTED READING Koob GF: Alcoholism: allostasis and beyond. Alcohol Clin Exp Res 27:232–243, 2003

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Sommer W, Hyytiä P, Kiianmaa K: The alcohol-preferring AA and alcohol-avoiding ANA rats: neurobiology of the regulation of alcohol drinking. Addict Biol 11:289–309, 2006 Weiss F, Porrino LJ: Behavioral neurobiology of alcohol addiction: recent advances and challenges. J Neurosci 22:3332–3337, 2002 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 9. Clinical Management of Alcohol Abuse and Depe...

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Hugh Myrick, Tara Wright: Chapter 9. Clinical Management of Alcohol Abuse and Depend ence, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.346212. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Clinical Management of Alcohol Abuse and Dependence Hugh Myrick, M.D. Tara Wright, M.D.

CLINICAL MANAGEMENT OF ALCOHOL ABUSE AND DEPENDENCE: INTRODUCTION Alcohol abuse and dependence are prevalent and costly problems in the United States today. Data from the Epidemiologic Catchment Area Study indicate that the lifetime prevalence of alcohol dependence is 14.7% (Regier et al. 1990). More strikingly, approximately 100,000 Americans die each year from alcohol-related disease or injury (McGinnis and Foege 1999). It has been estimated that alcohol-related problems account for at least 15% of health care expenditures and cost the U.S. economy an excess of $185 billion in medical costs, loss of life and property, and reduced productivity (Harwood 2000). Unfortunately, alcohol dependence is underdiagnosed and difficult to treat. In as few as 1–2 years following treatment, only about 20%–30% of treated patients have maintained abstinence, with most returning to heavy drinking. Clearly, there is a critical need for the development of more effective therapies for the treatment of alcoholism.

DIAGNOSTIC ISSUES Intoxication Depending on the individual, effects of alcohol may be observed after as little as one standard drink. Most states in this country have designated a blood alcohol level of 0.08 g/dL as the legal limit of intoxication. Table 9–1 lists diagnostic criteria for alcohol intoxication as defined by the DSM-IV-TR (American Psychiatric Association 2000). In nonalcoholics, a blood alcohol level of 0.40 g/dL is associated with a 50% risk of mortality. In determining how quickly a person's blood alcohol level will decrease, one can use the rule of thumb that the body metabolizes approximately 1 drink (approximately 0.015 g/dL) per hour.

Abuse Alcohol abuse is diagnosed in individuals who have repetitive problems in interpersonal, legal, or psychosocial domains within a 12-month period, but do not meet criteria for alcohol dependence. Table 9–2 presents the DSM-IV-TR criteria used to diagnose alcohol abuse.

Dependence The diagnosis of alcohol dependence is met when an individual continues to drink despite significant alcohol-related problems. There is a pattern of repeated alcohol consumption that can result in tolerance, withdrawal, and compulsive drinking behavior in which the person cannot stop drinking, despite attempts to do so. Although tolerance and withdrawal symptoms are not necessary for the diagnosis of alcohol dependence, some studies indicate a more severe clinical course for patients with histories of either of these physiological components, especially withdrawal (Schuckit et al. 1998). Table 9–3 outlines the DSM-IV-TR criteria used to diagnose alcohol dependence.

Withdrawal Alcohol withdrawal typically begins 6–8 hours after the last drink, peaks 24–28 hours after the last drink, and generally resolves within 7 days (Myrick and Anton 2004). The manifestation of alcohol

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withdrawal varies widely, and possible manifestations are outlined in Table 9–4. Only about 5% of individuals with alcohol dependence will develop more than mild to moderate withdrawal symptoms. Chronic medical conditions, nutritional deficiencies, and electrolyte abnormalities often contribute to and complicate the picture of alcohol withdrawal. Alcohol withdrawal seizures, usually grand mal in type, are estimated to occur in 5%–15% of patients. An individual with a history of alcohol withdrawal seizures is considered to be at significant risk for seizures during subsequent withdrawal periods. Although it is not life threatening, alcohol hallucinosis occurs in 3%–10% of patients with severe alcohol withdrawal. Hallucinations can be auditory, visual, or tactile in the presence of a clear sensorium. Delirium tremens (DTs), or alcohol withdrawal delirium, are characterized by agitation, tremulousness, autonomic instability, fevers, auditory and visual hallucinations, and disorientation, and are the most severe complication of alcohol withdrawal. DTs are estimated to occur in 5% of patients admitted for alcohol withdrawal (Mayo-Smith et al. 2004) and must be considered a medical emergency, given that without prompt and adequate treatment the mortality rate of this condition can be as high as 20%.

IDENTIFICATION Essential steps in identifying individuals with alcohol use disorders include understanding the high prevalence of these disorders and the generally low rate at which they are identified and treated. It has been reported that only 20% of people with significant alcohol use disorders are identified as having such, and only 20% of those identified individuals will actually receive treatment (Kaner et al. 1999). Several questionnaires are available for the detection of drinking-related problems. A positive response to any of the questions on the CAGE (named for its four questions; Ewing 1984) should lead the clinician to further investigate problem drinking with the patient. The Alcohol Use Disorders Identification Test (AUDIT) (Saunders et al. 1993), a 10-item questionnaire, and the 10- and 25-item Michigan Alcohol Screening Test (MAST) (Conley 2001) are also frequently used to indicate potential alcohol problems. Because patients may underreport their drinking, biomarkers of heavy alcohol use can play an important role in identifying individuals at risk for alcohol use disorders. Table 9–5 outlines biological markers that may be indicative of heavy drinking. -Glutamyltransferase (GGT) has typically been recognized as a liver enzyme whose elevation may be indicative of alcohol use. The sensitivity of GGT in detecting alcohol abuse is 40%–60%, with a specificity of about 80%. A limitation of GGT is that it may not be particularly sensitive to relapse. The carbohydrate-deficient transferrin test (%CDT), which is a newer tool for identifying heavy alcohol use, measures the relative percentage in serum of the carbohydrate-deficient form of an iron transport protein. The diagnostic specificity of the %CDT for recent heavy drinking is approximately 70% in patients with non-alcohol-induced liver cirrhosis, 88.2% in hepatitis patients, and 93.5% in patients with a nonspecific elevation of GGT (Hock et al. 2005), making it a more sensitive and specific indicator of alcohol consumption. The combination of a %CDT and GGT measurement further enhances the detection of problem drinking.

MEDICAL COMPLICATIONS Alcohol was identified as the third leading actual cause of death in the United States in 2000, contributing to 85,000 deaths, or 3.5% of all deaths in that year (Mokdad et al. 2004). The mortality risk is calculated to be 33% higher for hazardous drinkers (four to six drinks daily for men and two to four drinks daily for women) and 47% higher for harmful drinkers (more than six drinks daily for men and more than four drinks daily for women) compared with abstainers or lower-level drinkers. A major cause of early mortality among alcoholic individuals is heart disease, occurring at an earlier age and at a higher rate in these individuals than in their nonalcoholic counterparts. Although lightto-moderate alcohol consumption has been associated with a lower risk of myocardial infarction or cardiac death in men and postmenopausal women, heavier alcohol consumption has been associated with a significantly increased risk of cardiac diseases, including cardiomyopathy, dysrhythmias, and hypertension.

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The consequences of heavy alcohol consumption on the liver are well documented and can occur as a progression from steatosis ("fatty liver") to alcoholic hepatitis and cirrhosis. Steatosis, marked by an excessive buildup of fat inside liver cells, is the earliest stage of alcoholic liver disease and can occur with heavy drinking for as little as a few days. Steatosis can be reversed with abstinence. Alcoholic hepatitis, acute inflammation of the liver caused by excessive alcohol intake, can be accompanied by nausea, lack of appetite, vomiting, fever, abdominal pain and tenderness, jaundice, and, sometimes, mental confusion. Up to 70% of all alcoholic hepatitis patients may eventually go on to develop permanent scarring of the liver (cirrhosis). In addition, the combination of alcohol use and infection with hepatitis C virus can be particularly dangerous. It has been estimated that patients infected with hepatitis C who consume alcohol are 31 times more likely to develop cirrhosis than those who abstain from alcohol use (Henry et al. 2002). A substantial proportion of individuals with cirrhosis will progress to liver cancer. Another leading cause of death among alcoholic patients is cancer. A large meta-analysis found that alcohol consumption particularly increases the risks for cancers of the oral cavity, pharynx, esophagus, and larynx. Statistically significant increases in risk also exist for cancers of the stomach, colon, rectum, liver, female breast, and ovaries (Bagnardi et al. 2001). The authors found that concurrent tobacco use, which is common among drinkers, enhances alcohol's effects on the risk for cancers of the upper digestive and respiratory tract.

TREATMENT OF ALCOHOLISM Alcohol Withdrawal Patients being treated for alcohol withdrawal often need adjunctive management of a variety of medical conditions. A physical examination should be performed with particular emphasis placed on assessing for cardiac conditions such as arrhythmia or heart failure, liver disease, pancreatic disease, gastrointestinal bleeding, infections, or neurological impairment. Vital signs should be stabilized while electrolyte and nutritional disturbances are corrected. Nutritional deficits are common in persons with chronic alcohol use. These deficits include hypomagnesemia, hypophosphatemia, and hypokalemia. Deficits are secondary to dietary habits and alcohol-related changes in the digestive tract. Most individuals with alcoholism are vitamin deficient and therefore could benefit from oral multivitamin preparations containing folic acid for a few weeks. The replacement of thiamine is particularly important, given its role in Wernicke's encephalopathy. All patients being treated for alcohol withdrawal should immediately be given 100 mg/day of thiamine and throughout the withdrawal period. It is important to also remember that thiamine should be provided prior to glucose administration in order to prevent precipitation of Wernicke's encephalopathy by depletion of thiamine reserves.

Inpatient versus outpatient treatment Alcohol detoxification can be safely and effectively accomplished on both an outpatient and inpatient basis. Although there have been studies evaluating inpatient versus outpatient detoxification, no specific criteria have been rigorously tested.

Inpatient treatment Inpatient treatment of alcohol withdrawal provides the safest setting for detoxification. Trained staff can ensure that patients will be carefully monitored and appropriately supported. The use of an inpatient facility may also be of greater benefit in providing continuity of care, given that individuals often begin the process of rehabilitation while in the hospital. In addition, inpatient detoxification offers the patient a separation from the environmental stimulation for alcohol and/or other drug use during the treatment period. Despite the lack of research-based criteria, certain patients are more likely to respond favorably to inpatient treatment. Individuals with an established history of significant withdrawal symptoms, patients

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who have recently been drinking at very high levels, or patients with a history of withdrawal seizures or DTs are better served by inpatient treatment. A serious concomitant medical illness or psychiatric illness also favors the need for inpatient treatment. In addition, patients who have already experienced multiple detoxification treatments may be at an increased risk of complications and should therefore be considered for inpatient detoxification (Brown et al. 1988).

Outpatient treatment An increasing number of alcohol detoxification treatments are taking place outside the hospital setting. The shift from inpatient to outpatient treatment may in some ways reflect the changing health care environment, which has limited access to inpatient settings. As a result, increased attention is being focused on the efficacy and safety of outpatient detoxification. In a review of the literature on ambulatory detoxification, Abbott et al. (1995) found that less than 10%–20% of patients required admission to an inpatient unit. The completion rates for ambulatory detoxification programs ranged from 35% to 95% with most programs showing completion rates above 70%. In most studies reviewed, 50% of patients continued in alcohol rehabilitation treatment. Most importantly, this review found no reports of mortality or serious medical complications during outpatient treatment, except for one program that reported a seizure occurring after the start of detoxification. Although no specific criteria have been formulated to determine patient selection for outpatient alcohol detoxification, there are important factors about candidates' suitability for outpatient treatment that should be assessed (Table 9–6). Candidates for outpatient detoxification should have only mild to moderate withdrawal symptoms, no concomitant medical or severe psychiatric illnesses that could interfere with the withdrawal process, and no history of withdrawal seizures or DTs; potential outpatient candidates should also have a sober significant other to serve as a reliable support person. Patients should be seen daily to reassess withdrawal symptoms, the occurrence of medical complications, and to monitor the treatment regime.

Pharmacological treatment Benzodiazepines are considered by research studies and consensus reports to be the drugs of choice to treat alcohol withdrawal (Anton and Becker 1995; Institute of Medicine 1990). More specifically, in North America, benzodiazepines are the mainstay of alcohol withdrawal treatment and are considered the standard of care, as judged by multiple reviews on this topic (Mayo-Smith MF et al. 2004; Ntais et al. 2005). In general, there are two dosing strategies for treating alcohol withdrawal. The first option entails using a fixed dosing schedule. A loading procedure is recommended for inpatients in severe alcohol withdrawal. In this treatment strategy, 10 mg or more of diazepam or another long half-life benzodiazepine is administered every hour until either symptoms are suppressed or the patient becomes oversedated. Often, only 1–2 days of medication is used and tapering is not required. In the most recent trials (Myrick et al. 2005; Ntais et al. 2005), symptom-triggered treatment is employed, as measured by the Clinical Institute of Withdrawal Assessment for Alcohol Scale, Revised (CIWA-Ar) to indicate the need for a benzodiazepine (Saitz et al. 1994). Symptom-triggered treatment allows for reduced total doses of benzodiazepines. With lower doses of benzodiazepines, patients display less sedation and are able to more readily engage in other treatment activities. The CIWA-Ar appears to be a useful instrument for quantifying alcohol withdrawal and an effective guide for determining the need for ancillary "rescue" medication dosing. Based on reviews and meta-analyses, no one single benzodiazepine appears to be superior to others in the treatment of alcohol withdrawal (Mayo-Smith 1997). The selection of a specific benzodiazepine should be made on the basis of clinical factors such as age, status of liver function, and the presence or absence of a history of seizures. An agent's kinetic profile, in terms of half-life and simplicity of liver metabolism, has been used as the rationale to promote one benzodiazepine over another. Longer half-life agents may cause problems ranging from oversedation to coordination difficulties and confusion

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in individuals with liver impairment. Many alcoholic patients present with liver dysfunction, which indicates that the use of shorter half-life agents such as oxazepam and lorazepam is favored. Because lorazepam is available in multiple methods of administration, including oral, sublingual, and intramuscular, all of which have good absorption, it may be a particularly effective agent, in contrast to chlordiazepoxide or diazepam.

Treatment of complicated withdrawal More severe complications of alcohol withdrawal include withdrawal seizures and DTs. Primary alcohol withdrawal seizures are self-limited and usually require only supportive treatment. However, benzodiazepines are considered the treatment of choice. The issue of what method should be used in the treatment of DTs is somewhat controversial. Benzodiazepines are often prescribed to decrease both autonomic hyperactivity and the risk of alcohol withdrawal seizures and to control agitation. Despite these beneficial effects, benzodiazepines may contribute to the behavioral dyscontrol and confusion that accompanies DTs. Low doses of antipsychotic agents such as haloperidol are also used for the treatment of DTs.

Relapse Prevention Disulfiram Disulfiram is an alcohol deterrent drug that has been in use for over 50 years. It interrupts the metabolism of alcohol by irreversibly inhibiting aldehyde dehydrogenase, thereby blocking the breakdown of acetaldehyde to acetate. When a patient taking disulfiram drinks alcohol, the accumulation of acetaldehyde results in facial flushing, nausea and vomiting, headache, and changes in blood pressure. The patient's fear of this disulfiram-alcohol reaction, particularly after experiencing it, is presumed to serve as a strong reinforcement for abstinence. A large placebo-controlled trial of disulfiram treatment found no significant differences in rates of abstinence or time to first drinking day (Fuller et al. 1986). Patient nonadherence was likely a main contributor of the negative finding, considering that only 20% of 577 subjects who completed the study were compliant with disulfiram treatment. However, among patients who drank and had a complete set of assessment interviews, those in the 250-mg disulfiram group reported significantly fewer drinking days than those in the 1-mg or no-disulfiram groups. A significant relationship between adherence to drug regimen and complete abstinence was found in all groups. Fuller et al. (1986) concluded from their findings that disulfiram may help reduce drinking frequency after relapse, but it does not enhance counseling in aiding alcoholic patients to sustain continuous abstinence or delay the resumption of drinking. They also suggested that older, more motivated men seemed to be more compliant and to do better with disulfiram. Adherence is an obstacle in determining the generalization of disulfiram's effectiveness. Wright and Moore (1990) have shown that supervised disulfiram treatment and incentive-driven interventions are associated with decreased alcohol consumption and increased rates of abstinence. A detailed meta-analysis revealed that evidence for the efficacy of disulfiram is lacking overall, but that some evidence is available for disulfiram being effective when given under supervision (Berglund et al. 2003).

Naltrexone After it was shown to reduce drinking frequency and the likelihood of relapse to heavy drinking, naltrexone was approved by the U.S. Food and Drug Administration (FDA) in 1994 for the treatment of alcohol dependence (O'Malley et al. 1992; Volpicelli et al. 1992). Although its mechanism of action is not fully understood, naltrexone's competitive antagonism at the opioid receptor is hypothesized to block the release of dopamine induced by the consumption of alcohol and therefore reduces alcohol craving and loss of control by reducing the rewarding effects of alcohol. A large meta-analysis including 27 randomized, controlled trials of naltrexone revealed that short-term

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treatment with naltrexone decreased relapse with a risk ratio of 0.64, with the number needed to treat (NNT; i.e., the number of patients treated to achieve a better outcome over placebo response) being 7 (Srisurapanont and Jarusuraisin 2005). The analysis also showed that, in a comparison with the placebo group, naltrexone lowered the risk of treatment withdrawal in alcohol-dependent patients by 28% (NNT = 13). The efficacy of naltrexone was recently supported by the Combining Medications and Behavioral Interventions for Alcoholism (COMBINE) trial, a federally funded, randomized, controlled trial involving 1,383 recently abstinent alcoholics from 11 U.S. academic sites and that evaluated the efficacy of naltrexone, acamprosate, or both, in comparison with each other and placebo, with health care provider–delivered medical management, and with or without a specialized alcohol counselor, delivered combined behavioral intervention (Anton et al. 2006). In this trial, individuals that were given naltrexone plus medical management; or naltrexone, medical management, and combined behavioral intervention; had a higher percentage of days abstinent than those receiving placebo and medical management only. Naltrexone also reduced the risk over time of heavy drinking days. Not all studies of naltrexone have revealed positive results (Gastpar et al. 2002; Krystal et al. 2001), which suggests there may be subtypes of individuals who are more likely to respond to naltrexone. The drug may be preferentially effective among alcoholics whose disease is mostly characterized by reward craving, given that it is believed to work by blocking endogenous opioids, thereby diminishing the pleasant effects of alcohol consumption. King et al. (1997) investigated the effects of naltrexone on subjective response to alcohol in a double-blind, placebo-controlled trial. They found a differential response to naltrexone, based on subjects' paternal history of alcoholism and levels of stimulation experienced during alcohol drinking. Work recently conducted by researchers reveals that variants of the

opioid receptor, which may alter

the affinity of the receptor for endogenous ligands, may also affect response to naltrexone. In a post-hoc study that combined three previously collected data sets, subjects of European descent with one or two copies of the 118G variant allele and who were treated with naltrexone had significantly lower rates of relapse and took a longer time to return to heavy drinking than those homozygous for this allele (Oslin et al. 2003). These differences were not found among subjects assigned to placebo. Given potential genetic variabilities in the response to naltrexone, meta-analyses may underestimate the effect size for naltrexone because of the heterogeneity of patients (Heilig and Egli 2006). Because compliance is clearly critical in the success of naltrexone, a long-acting injectable naltrexone is also available. Garbutt et al. (2005) performed a randomized, double-blind, placebo-controlled trial of extended-release, injectable naltrexone in 624 actively drinking, alcohol-dependent adults who received either a monthly intramuscular injection of 380 mg of long-acting naltrexone, 190 mg of long-acting naltrexone, or a matching volume of placebo combined with 12 sessions of low-intensity psychosocial intervention. Compared with placebo, 380 mg of long-acting naltrexone resulted in a 25% decrease in the event rate of heavy drinking days, and 190 mg of naltrexone resulted in a 17% decrease. The same study also revealed that men more than women and those with lead-in abstinence exhibited greater treatment effects. A crucial consideration for the clinician and the patient is that naltrexone is an opioid antagonist and can therefore induce withdrawal in an opioid-dependent individual. Special consideration must also be taken with pain control, because naltrexone will block the effects of opioid analgesics. In a supervised hospital setting, the antagonist properties of naltrexone can be overridden with increased doses of opioid analgesics.

Acamprosate Acamprosate was approved by the FDA in 2004 for the treatment of alcohol dependence but has been available by prescription in France since 1989. It is reported to assist in the maintenance of abstinence and decrease negative symptoms associated with the acute postwithdrawal period in recently detoxified

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alcohol-dependent individuals. Acamprosate is structurally similar to -aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system, and is thought to exert its therapeutic effect by modulating the excitatory glutamate amino acid system (N-methyl-D-aspartic acid; NMDA) in the brain. By functioning to increase GABAergic activity and/or inhibiting glutamatergic activity via modulation of the NMDA receptor, acamprosate may ameliorate alcohol withdrawal symptomatology (Boeijinga et al. 2004). Multiple trials performed in Europe and elsewhere support the efficacy and safety of acamprosate. Mann et al. (2004) performed a large meta-analysis, involving 4,087 individuals, of 17 randomized, placebocontrolled trials of acamprosate. They found that continuous abstinence rates at 6 months were significantly higher in the acamprosate-treated patients. At 12 months, the overall pooled difference for continued abstinence between subjects treated with acamprosate and those given placebo was 13.3%. The effect sizes in abstinence rates at 3, 6, and 12 months were 1.33, 1.50, and 1.95, respectively. Bouza et al. (2004) also performed a meta-analysis comprising 13 studies of acamprosate and 19 studies of naltrexone. They too found that acamprosate helped maintain abstinence in alcoholdependent individuals who had stopped drinking. Not all studies of acamprosate have shown efficacy over placebo. Findings of the COMBINE study, mentioned earlier (Anton et al. 2006), did not support the efficacy of acamprosate under intent-to-treat analyses. There has been much speculation about the reasons for this discrepancy in results. Differences in study populations and designs may be contributing factors. For instance, in many of the European clinical trials, acamprosate was initiated while the patients were hospitalized for alcohol detoxification and many patients had lengthy hospital stays for rehabilitation. In contrast, the COMBINE patients were initiated on study drugs as outpatients, after attaining a minimal 4 days of abstinence (Anton et al. 2006). However, over 50% of participants had more than 4 days of reported abstinence prior to randomization. Additionally, a combined analysis of many studies conducted in Europe did not find predictors of response, including alcohol withdrawal symptoms or severity of alcohol problems (Verheul et al. 2005). In summary, at present, it is unclear which alcoholic individuals will be more likely to respond to acamprosate, but the weight of the data does suggest that those with a strong commitment to abstinence who take the medication for several weeks while abstaining might have better outcomes in the long run than those who are not given acamprosate. Because acamprosate is poorly absorbed, it is generally given in high doses of approximately 2 g/day, in three doses. Acamprosate has been found to be generally well tolerated by patients in all of the clinical trials to date. Diarrhea is the most common side effect noted, but headache, dizziness, and pruritis have also been reported, to a much lesser degree.

Combination therapy Attention has recently focused on the use of naltrexone and acamprosate in combination. Although studies have shown that the two medications are safe and well tolerated in combination, the results supporting the combination's superior efficacy over naltrexone alone are mixed. Some trials have shown superior efficacy (Feeney et al. 2006; Kiefer and Wiedemann 2004), but the COMBINE trial did not show a superior effect of naltrexone and acamprosate over naltrexone alone (Anton et al. 2006).

Nonpharmacological treatment options Treatment modalities that have been used for alcohol use disorders include psychodynamic psychotherapy, cognitive-behavioral therapy (CBT), motivational enhancement therapy, 12-step facilitation (TSF), contingency management, network therapy, group therapy, and family therapy. Motivational interviewing, or motivational enhancement therapy (MET), is a brief, time-limited intervention and therapeutic approach, in which the clinician works with the patient to build trust by showing empathy. Areas of resistance to change are noted, and the patient is encouraged to discuss why altering drinking patterns might be beneficial. Modifications of motivational enhancement have been used in brief physician interventions. The clinician asks about drinking behavior, reviews alcohol-

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related problems, and emphasizes the adverse effects of alcohol. One paradigm incorporates two 15-minute physician visits separated by a month. These interventions are followed by two 5-minute telephone conversations with a nurse to reinforce the lessons learned. In addition, the patient keeps a diary of his or her drinking pattern and establishes realistic goals that are set in a contract. Evaluation of this approach revealed that more than two-thirds of the drinking patients agreed to participate in therapy, and excellent outcomes of reduced drinking and alcohol problems were maintained over a 4-year period (Fleming et al. 2002). Project MATCH (Matching Alcoholism Treatments to Client Heterogeneity) was a multisite clinical trial designed to investigate if patient–treatment matching improved treatment outcomes. Over a 12-week period, 1,726 subjects were randomly assigned to TSF, CBT, or MET. Interaction effects with selected patient characteristics were studied, including severity of alcohol involvement, cognitive impairment, psychiatric severity, conceptual level, gender, meaning seeking, motivational readiness to change, social support for drinking versus abstinence, sociopathy, and typology of alcoholism. Subjects were recruited from two parallel study arms: one with alcohol-dependent patients who received outpatient therapy and one with patients who received aftercare therapy following inpatient or day hospital treatment. Overall, study subjects showed significant and sustained improvement in increased percentage of abstinent days and decreased number of drinks per drinking days, with few clinically significant outcome differences among the three treatments in either treatment arm. There was no difference in sustained abstinence among treatments in the aftercare arm. However, outpatients who received TSF were more likely to remain completely abstinent in the year following treatment than outpatients who received the other treatments. With regard to matching patient characteristics with specific treatments, client anger demonstrated the most consistent interaction in the trial, with significant matching effects evident at both the 1-year and 3-year follow-ups. Clients identified as having high levels of anger fared better in MET than in CBT or TSF. Conversely, clients with low levels of anger performed better after treatment in CBT and TSF than in MET. The overarching conclusion of this study appears to be that once patients have reached a point at which they are willing to consider abstinence, their motivation and characteristics are likely to be better predictors of outcome than any specific aspect of the treatment program (Project MATCH Research Group 1997, 1998).

SPECIAL POPULATIONS Comorbid Populations The co-occurrence of substance abuse and psychiatric disorders is a complex and common phenomenon. The National Institute of Mental Health Epidemiologic Catchment Area (ECA) study and the National Comorbidity Study (NCS) are two large epidemiological surveys that have evaluated the prevalence of comorbid psychiatric and substance use disorders in community samples. In the ECA study, 45% of individuals with alcohol use disorders had at least one co-occurring psychiatric disorder (Regier et al. 1990). Likewise, in the NCS, 78% of alcohol-dependent men and 86% of alcohol-dependent women met lifetime criteria for another psychiatric disorder, including drug dependence (Kessler et al. 1996). The co-occurrence of psychiatric and alcohol use disorders is clinically important because comorbidity has a negative impact on the course, treatment outcome, and prognosis of both syndromes. The accurate diagnosis and differentiation between substance-induced states and primary psychiatric diagnoses are two of the more difficult tasks in assessing patients with co-occurring psychiatric symptoms and substance use disorders. Clinicians often differentiate substance-induced transient symptoms from psychiatric illness through observation during a period of abstinence. However, the duration of abstinence necessary for accurate diagnosis should be based on both the diagnosis being assessed and the substance used. Sustained psychiatric symptoms during lengthy periods of abstinence, a family history of the particular psychiatric disorder, and the onset of psychiatric symptoms before the onset of substance abuse and dependence all suggest a primary psychiatric illness. Although the treatments for psychiatric and substance use disorders have largely consisted of separate clinical services, the integration of services is paramount to the optimal treatment of individuals with

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comorbid conditions. Such programs often include a mix of group and individual therapy. CBTs are among the most efficacious treatments for anxiety disorders and substance use disorders (Anton et al. 1999). Brown et al. (1997) demonstrated that alcoholic persons with depressive symptoms had improved outcomes at 3- and 6-month follow-up visits after treatment with CBT for depression, compared with a control group given treatment in the form of relaxation training. Individuals with comorbid psychiatric and substance use disorders can also benefit from participation in 12-step groups such as Alcoholics Anonymous and Narcotics Anonymous. The ideal approach to the pharmacological treatment of comorbid conditions is to use an agent that has no abuse potential, is safe and well tolerated, and may be efficacious for both disorders. Data support the use of selective serotonin reuptake inhibitor (SSRI) agents for the pharmacotherapeutic treatment of comorbid alcohol dependence and major depression. Higher doses of SSRIs and tricyclic antidepressants may be required because of the possibility that alcohol use has induced hepatic microsomal activity. The use of SSRIs in the area of subtyping alcoholics shows promise, but much work remains to be done (Kranzler et al. 1996; Pettinati et al. 2000). Although lithium is accepted as the gold-standard agent in the treatment of bipolar disorder, anticonvulsant agents have shown some promise in the treatment of substance use disorders and comorbid bipolar and substance use disorders (Myrick et al. 2004). Research investigating the use of psychiatric medications in combination with alcohol-treatment medications such as naltrexone and acamprosate would be useful.

Adolescents Alcohol is the most the common substance of abuse among adolescents. In 2005, 47% of twelfth graders reported past-30-days drinking and 29.2% reported binge drinking (five or more drinks in a row, per occasion) within the past 2 weeks (Johnston et al. 2006). Diagnostic criteria for alcohol use disorders are based on adult symptom patterns, which may not fit for some heavy-drinking teenagers. The diagnostic criteria of preoccupation, loss of control, and reckless behavior while using can occur in teenagers, but medical problems and severe withdrawal are unlikely (Brown and D'Amico 2001). When evaluating adolescents with possible alcohol use disorders, educational status, family functioning, peer relationships, legal status, and use of free time should be assessed, in addition to direct questions about the use of alcohol and other drugs and possible psychiatric disorders. Investigating areas of academic performance, school attendance, disciplinary problems, and any history of abuse can be particularly important because it helps the practitioner ascertain the adolescent's risk of an alcohol use disorder. There is a high level of co-occurrence of substance use and other psychiatric disorders in adolescents. Psychosocial treatments for alcohol use disorders in adolescents should be adapted for this specific population. If at all possible, family participation should be viewed as a prerequisite for successful treatment for any adolescent with a substance use disorder. Motivational therapy, CBT, behavioral therapies (including operant-conditioning methods as well as behavioral contingency contracts and parent management training), family therapy, and 12-step approaches may all be useful options. In employing 12-step approaches, it is important to help the family identify a support group that is geared specifically toward adolescents. Multisystemic therapy involves working with teenagers, parents, schools, community resources, and peers to decrease problem behaviors (Henggeler et al. 1995). As with adults, the aim of pharmacotherapy in adolescents with substance use disorders includes detoxification, interfering with the physiological and subjective effects of the substance, and treatment of co-occurring psychiatric disorders. A small, open-label trial of naltrexone in adolescents found that it was well tolerated and reduced craving and drinking among adolescents who were dependent on alcohol (Deas et al. 2005).

Women Differences have been identified in the incidence, development, and consequences of alcohol dependence in women as compared with men; women more often drink alone, binge less, have more

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regular drinking patterns, and drink smaller quantities. For women in relationships, drinking patterns are more likely to match that of their significant others. After equivalent doses of alcohol, women have been shown to have higher blood ethanol levels than men. Likely contributors to this include lower levels of alcohol dehydrogenase in the gastric mucosa and livers of women compared with men, as well as the lower adjusted total body water content and smaller volume of distribution in women (Frezza et al. 1990). The faster progression from first drink to significant problems with alcohol in women as compared with men has been termed the telescoping effect (Frezza et al. 1990). Women reach criteria for alcohol dependence from onset of drinking more quickly than men and progress to liver disease with lower levels of drinking over a shorter period of time than do men. In addition, women who develop cirrhosis from alcohol dependence have a higher rate of mortality than their male counterparts. Women's risk of breast cancer is also increased by moderate to heavy alcohol consumption. Alcohol use disorders in women can lead to sexual dysfunction, menstrual cycle abnormalities, and amenorrhea (Blume and Russell 2001). Alcohol may also increase the risk of spontaneous abortion. Fetal alcohol syndrome, resulting from heavy use of alcohol during pregnancy, is characterized by growth deficiencies, facial abnormalities, and significant impairments in the neurodevelopment of the fetus (Jones and Smith 1973). In addition, studies suggest that even low to moderate levels of drinking during pregnancy are associated with alcohol-related birth defects. Women with alcohol use disorders are more likely to present for treatment of other problems, such as marital or relationship difficulties, physical illness, or emotional problems (Weisner and Schmidt 1992). Related to this, they are more likely to seek treatment in psychiatric or primary care settings than in traditional substance disorders treatment programs (Beckman and Kocel 1982). Estimates indicate that women make up approximately 25% of patients in traditional treatment centers for alcohol dependence in the United States (U.S. Department of Health and Human Services 1990). It is important to recognize potential gender-specific barriers that may have an impact on treatment initiation and completion. Such barriers include lack of gender and cultural appropriateness in program content, fear of legal consequences (particularly loss of child custody), lack of child care and transportation, inadequate or no health insurance coverage, caretaker roles for dependent family members, and societal intolerance and stigmatization of substance-dependent women (Chasnoff 1991). Some evidence suggests that genderspecific services can improve treatment retention, substance use outcomes, and possibly psychosocial functioning in women when compared with traditional mixed-gender programs, but further research is warranted (Brady and Ashley 2005; Greenfield et al. 2007).

Older Adults According to the annual national survey on drug use and health sponsored by the Substance Abuse and Mental Health Services Administration (SAMHSA 2004), 49.9% of individuals between the ages of 60 and 64 years and 35.3% of individuals ages 65 years and older reported past-month alcohol use. In addition, 6.5% of people ages 65 years and older reported binge drinking (5 or more drinks on one occasion, on at least 1 day in the past month) and 1.8% reported heavy drinking (5 or more drinks on the same occasion, on each of 5 or more days in the past 30 days). Standard drinking guidelines for adults 65 years and older state that individuals should not consume more than 1 standard drink per day or 7 standard drinks per week (National Institute for Alcohol Abuse and Alcoholism 1995). There are several barriers to diagnosing alcohol use disorders among older adults. Many problems caused by alcohol can mimic other disorders common in this age group, such as dementia and depression. Other barriers include patient reluctance to divulge this information and clinician failure to adequately screen in this subset of the population. Identification and treatment are of utmost importance because even relatively moderate amounts of alcohol can increase the risk for health problems such as hypertension, sleep problems, and malnutrition (SAMHSA 1998). Other consequences may include acute pancreatitis, alcohol-induced cirrhosis, or alcohol-related cardiomyopathy, in addition to an increased risk of trauma from falls or motor vehicle accidents (Oslin 2004). Because individuals

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generally take more prescription and over-the-counter medications with increasing age, the risk for interactions with alcohol and drugs is certainly heightened. Alcohol use is one of the leading risk factors for developing adverse drug reactions and is known to interfere with the metabolism of many medications, such as digoxin and warfarin (Fraser 1997).

CONCLUSION Alcoholism is a devastating illness that leads to huge societal losses. Despite the fact that alcoholism is underdiagnosed, effective identification strategies are available and need to be further utilized in medical settings. Over the past decade, there have been exciting developments in the treatment of alcohol withdrawal and relapse prevention. In particular, there have been advancements not only in the treatment strategies for alcohol withdrawal but also the location in which detoxification may occur. There has also been much progress made in the prevention of relapse to alcohol use. Improvements include the approval of a new medication for alcohol dependence, the use of combined treatments for alcohol dependence, and increased research in the use of nonpharmacological treatment strategies. Despite these advances, more effective interventions for individuals with alcohol use disorders are needed. An increased understanding of the neurobiological underpinnings of alcohol dependence, including the role of pharmacogenetics, may lead to enhanced effectiveness of future treatment strategies.

KEY POINTS Detection and referral rates of alcoholic patients are low. The biomarker carbohydrate-deficient transferrin test alone, or in combination with -glutamyltransferase, may be used to identify heavy alcohol use and monitor drinking status during alcohol treatment. Treatment of alcohol withdrawal has primarily become an outpatient procedure. The Clinical Institute of Withdrawal Assessment for Alcohol Scale, Revised, appears to be a useful instrument for quantifying alcohol withdrawal and guiding the need for ancillary rescue medication dosing. U.S. Food and Drug Administration–approved medications for the treatment of alcohol dependence include disulfiram, naltrexone, and acamprosate.

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SUGGESTED READING Anton RF: Carbohydrate-deficient transferrin for detection and monitoring of sustained heavy drinking. What have we learned? Where do we go from here? Alcohol 25:185–188, 2001 Anton RF, Swift RM: Current pharmacotherapies of alcoholism: a U.S. perspective. Am J Addict 12 (suppl 1):S53–S68, 2003 Oslin DW, Berrettini W, Kranzler HR, et al: A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-dependent patients. Neuropsychopharmacology 28:1546–1552, 2003 Pettinati HM, Volpicelli JR, Kranzler HR, et al: Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 24:1041–1049, 2000 Smothers BA, Yahr HT, Ruhl CE: Detection of alcohol use disorders in general hospital admissions in the United States. Arch Intern Med 164:749–756, 2004 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 10. Neurobiology of Stimulants

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Margaret Haney: Chapter 10. Neurobiology of Stimulants, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.346622. Printed 1 0/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Neurobiology of Stimulants Margaret Haney, Ph.D.

NEUROBIOLOGY OF STIMULANTS: INTRODUCTION Cycles of amphetamine and cocaine abuse have occurred throughout the world for more than a century. In the United States, use of methamphetamine, which is the primary type of amphetamine abused, has dramatically increased. The number of admissions for methamphetamine treatment increased nearly fourfold from 1994 to 2004. In many areas of the country, the number of patients enrolled for methamphetamine treatment surpasses the number of patients in treatment for cocaine and heroin. Cocaine also remains a major public health issue, based on arrest statistics and drug treatment records. In fact, emergency room visits related to cocaine use increased by more than 22% between 1994 and 2001 (Office of National Drug Control Policy 2001; Substance Abuse and Mental Health Services Administration 2006a, 2006b). Although pharmacotherapies are available to facilitate treatment for heroin, alcohol, and tobacco dependence, there are currently no medications approved for the treatment of cocaine or methamphetamine use. Progress in our understanding of the relationship between the cellular and molecular consequences of chronic stimulant exposure and the behaviors comprising compulsive stimulant use will be essential to the development of effective treatment medications for these drugs. Thus, continued efforts at the preclinical level, combined with human laboratory investigations that detail the mechanisms by which prospective medications interact with cocaine or methamphetamine, are needed to develop effective pharmacological adjuncts for the treatment of cocaine and methamphetamine dependence.

ACUTE STIMULANT EFFECTS Among the most important behavioral effects of cocaine and methamphetamine are their mood-altering properties. Cocaine and methamphetamine, whether smoked, snorted, or injected, dose-dependently increase measures considered to describe euphoria, such as ratings of "high" and "good drug effect." Furthermore, these stimulants are highly reinforcing, meaning that they reliably maintain behavior leading to their administration. For rats or monkeys, these behaviors include pressing a lever associated with drug administration, and for humans, they include seeking out and purchasing drugs. The robust reinforcing properties of cocaine and methamphetamine are primarily mediated by their effects on mesolimbic and mesocortical dopamine pathways, involving sites such as the ventral tegmental area (VTA), nucleus accumbens (NAcc), ventral pallidum, and prefrontal cortex.

Neurobiological Mechanism Cocaine binds to the dopamine transporter and inhibits the reuptake of synaptic dopamine (Ritz et al.1987). Reuptake is the primary mechanism by which dopamine is inactivated. By blocking reuptake, cocaine administration results in dose-dependent increases in extracellular levels of dopamine (Wise et al. 1995). Methamphetamine has a more complex mechanism of action, both decreasing dopamine reuptake and promoting dopamine release via the dopamine transporter (Saunders et al. 2000). Methamphetamine is taken up intracellularly, enhancing dopamine release and also increasing cytoplasmic concentrations of dopamine, which undergo oxidation and may produce toxicity (Hanson et al. 2004). Another important difference between methamphetamine and cocaine is their duration of action: cocaine is rapidly

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metabolized, whereas methamphetamine metabolism is relatively slow, with effects lasting several hours longer than cocaine. Given these differences, medications that show promise in treating dependence for one stimulant may not be effective for the other. It is important to note that cocaine has been studied to a far greater extent than has methamphetamine, so many of the studies discussed here focus on cocaine. Furthermore, although methamphetamine is the primary type of amphetamine that is abused, laboratory studies have often used dextroamphetamine, which has behavioral and dopaminergic effects similar to methamphetamine but has a different pattern of effects on serotonin, norepinephrine, and glutamate, particularly following repeated administration (Shoblock et al. 2003). Thus, methamphetamine data are presented when available. For both cocaine and methamphetamine, routes of administration that result in abrupt increases in extracellular dopamine are most reinforcing. Although oral cocaine use might produce the same magnitude increase in dopamine as that of cocaine that is smoked or used intravenously, the rapid change in dopamine levels that occurs by these latter routes is more reinforcing (Volkow et al. 2003). This is why smoking methamphetamine ("ice") or cocaine ("crack") has greater abuse liability than snorted or oral routes of administration. In addition to dopamine transporters, both cocaine and methamphetamine potently block norepinephrine and serotonin transporters, yet neither norepinephrine nor serotonin appears to specifically mediate the reinforcing effects of these drugs. As shown in Table 10–1, the reinforcing effects of cocaine and methamphetamine appear to be primarily mediated by their effects on dopamine.

CONSEQUENCES OF REPEATED STIMULANT EXPOSURE Repeated use of cocaine and methamphetamine produces disruptions in homeostatic mechanisms, resulting in a range of enduring neuroadaptations, some of which persist even after prolonged abstinence. Consequences of chronic stimulant use can include addiction, sensitization, tolerance, dependence, and neurotoxicity, and the neurobiological mechanism for each of these consequences is distinct. One way stimulants produce long-term adaptations is by modulating gene expression and reconfiguring neural networks that influence behavior. Examples of such adaptations include altered dendritic branching and receptor function (Xi et al. 2002). Repeated stimulant exposure modifies transcription factors, such as the Fos family, which bind to regulatory elements in gene promotors. In particular, it is hypothesized that

FosB, a stable and long-lasting protein stimulated by chronic dopamine receptor

activity, mediates many of the effects of chronic cocaine use on gene expression (Nestler 2005).

FosB

is selectively induced in the NAcc and the striatum after repeated stimulant administration, and it persists even in the absence of further drug use. Mice bred to have high levels of

FosB in the NAcc have

enhanced motivation to self-administer cocaine, based on the progressive ratio schedule of reinforcement (McClung et al. 2004); this finding suggests a potential role for

FosB in the long-term

behavioral consequences of chronic stimulant use.

Addiction Addiction is characterized by compulsive drug seeking and drug taking, with a loss of control over drug use. This loss of control includes both difficulty regulating drug intake and maintaining abstinence, thereby defining addiction as a chronic relapsing disorder. Most individuals addicted to cocaine or methamphetamine, for example, relapse within 1 year of initiating abstinence. Stimulant drugs are generally abused in repeated bouts, called binge-crash cycles, which impinge on the reward pathway with a longevity and intensity that does not occur with natural rewards. One overarching hypothesis posited to explain these cycles is that for addicted individuals, the saliency of drug cues are enhanced, whereas those of other reinforcers, such as food or sex, are diminished. Furthermore, impulse control exerted by the frontal cortex may be lessened by chronic stimulant use, thus shifting motivation and behavior to acquisition of an immediate and robust drug reinforcer over

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non-drug reinforcers (see Volkow et al. 2003).

Neurobiological mechanism Stimulant-induced increases in extracellular dopamine and glutamate play a critical role in the cascade of events that lead to addiction, including changes in gene expression and synaptic plasticity. Neural areas involved in the loss of control and compulsive use of stimulant drugs include those involved in reward (NAcc, ventral pallidum), motivation (orbitofrontal cortex), memory (amygdala, hippocampus), and impulse control (prefrontal cortex, cingulate gyrus). With regard to cocaine, neuroimaging data in humans and nonhuman primates demonstrate that the reinforcing effects of cocaine are negatively related to dopamine D 2 receptor levels: cocaine abusers have lower D2 receptor availability than control volunteers (Martinez et al. 2004; Volkow et al. 1993). In drug-naïve, nonhuman primates, low levels of D 2 receptor availability predict high rates of cocaine self-administration. Following repeated cocaine self-administration, D 2 receptor availability is decreased by 15%–20%, and a subset maintained these low levels even following months of abstinence (Nader et al. 2006). These data suggest that some individuals may have a vulnerability to finding cocaine particularly reinforcing, and that repeated cocaine use exerts long-term changes in dopamine receptors, which may play a role in maintaining cocaine's robust reinforcing effects. Dopaminergic medications have been tested as potential pharmacotherapy for cocaine dependence much as opioid agonists and antagonists have been used in the treatment of opioid abuse. In terms of an agonist approach to stimulant treatment, D 1 -type dopamine receptor agonists show more promise than those acting at the D2 -type receptor. Acute pretreatment with a D1 agonist produced dose-dependent decreases in the euphoric effects of smoked cocaine, as well as a decrease in the reported quality and potency of cocaine (Haney et al. 1999). Maintenance on D 2 receptor agonists, by contrast, did not appear promising in either laboratory studies (Haney et al. 1998) or clinical trials (Malcolm et al. 2000). In terms of dopaminergic antagonists, maintenance on the nonselective antagonist, flupenthixol, did not alter cocaine self-administration in human laboratory studies, and at higher doses was associated with extrapyramidal side effects (Evans et al. 2001). Acute administration of the D 1 antagonist, ecopipam, decreased the euphoric effects of cocaine in a laboratory setting (Romach et al. 1999), yet maintenance on ecopipam actually enhanced cocaine's reinforcing and subjective effects compared with placebo (Haney et al. 2001a). These data emphasize the importance of studying the chronic administration of potential treatment medications, given that this is how they would be used clinically. Various medications can produce opposite effects when given acutely versus chronically. Other neurotransmitter systems may also influence cocaine or amphetamine use. The excitatory neurotransmitter glutamate, for example, interacts closely with mesolimbic dopamine. Glutamate projections from the prefrontal cortex convey information regarding memory, drive, and motivation, and are integrated by the NAcc to generate goal-directed movement (Carelli 2002). Glutamate acts by binding both ligand-gated, ionotropic receptors ( -amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor [AMPA], kainite, N-methyl-D-aspartate [NMDA]) and G protein–coupled metabotropic (mGlu) receptors, which are classified into three main groups (groups I–III). In rats, NMDA receptor antagonists increased cocaine self-administration (Pierce et al. 1997). Data from the human laboratory have consistently demonstrated that the NMDA antagonist memantine enhanced ratings of cocaine-induced good drug effect and high (Collins et al. 1998, 2006, 2007). Memantine also increased ratings of good drug effect when combined with oral methamphetamine in humans (Hart et al. 2002). These data do not suggest that NMDA antagonists would be useful in decreasing cocaine or methamphetamine use clinically. Group II mGlu receptors act as inhibitory autoreceptors that regulate the release of glutamate and dopamine in the NAcc. Acute administration of a group II mGlu receptor agonist decreased the reinforcing effects of cocaine in monkeys (Adewale et al. 2006). No data in humans are currently

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available, but this study suggests that more studies with these compounds should be conducted, particularly using procedures in which medication is administered chronically. Modafinil, which is a glutamate-enhancing agent (among its other actions) used to treat narcolepsy, appears to show promise in clinical and laboratory studies of cocaine dependence (Dackis et al. 2005; Hart et al. 2007b). The precise mechanism for modafinil's mechanism of action with regard to cocaine is still not clear. The inhibitory neurotransmitter -aminobutyric acid (GABA) also interacts with dopamine neurons in the NAcc and the VTA, and pharmacological manipulation of GABA alters dopamine activity and the self-administration of both cocaine and methamphetamine in rats (Cousins et al. 2002; Ranaldi and Poeggel 2002). Data from the human laboratory demonstrate that GABA agonists, such as gabapentin or baclofen, decrease cocaine craving and some of its positive subjective effects, but fail to robustly alter cocaine self-administration (Haney et al. 2006; Hart et al. 2004, 2007a) or cocaine use in the clinic (Bisaga et al. 2006; S. Shoptaw, personal communication, 2007). Other GABAergic medications, however, do show promise for cocaine abuse treatment: the GABA reuptake inhibitor tiagabine had positive effects in one clinical trial (Winhusen et al. 2005). Furthermore, topiramate, which both enhances GABA and blocks AMPA glutamate receptors, appeared to improve abstinence rates by decreasing the likelihood of relapse to cocaine use (Kampman et al. 2004). In terms of treating methamphetamine use, baclofen, but not gabapentin, improved outcome in a recent clinical trial (Heinzerling et al. 2006). These data demonstrate that medications useful in treating dependence on methamphetamine might not work for cocaine dependence treatment, and vice versa. Although cocaine and methamphetamine potently inhibit serotonin reuptake, maintenance therapy using selective serotonin reuptake inhibitors such as fluoxetine or sertraline has not been shown to improve treatment outcome in cocaine abusers (Walsh and Cunningham 1997) and actually worsened clinical outcome in methamphetamine-dependent patients (Vocci and Ling 2005). Perhaps selective modulation of one or more of the 14 subtypes for the serotonin receptor would show promise, but currently there are few specific compounds available to test in humans. Thus, further work is needed to clarify whether selective serotonergic agonists or antagonists will prove useful as pharmacotherapies for cocaine or methamphetamine abuse. Overall, these data demonstrate that dopamine plays a primary role in mediating the reinforcing effects of stimulants. Because of the intricate interactions between dopamine and other neurotransmitters, cocaine and amphetamine use can be modulated by medications acting on a range of neurochemical sites, particularly those modulating glutamate and GABA.

Cue- and stimulant-induced drug seeking The persistence of stimulant addiction may reflect altered patterns of synaptic connectivity similar to what occurs during normal memory foundation. Exposure to the cues—or "people, places, and things" —associated with cocaine or methamphetamine use often produces an overwhelming desire for the drug. Associations between these cues and drug use are typically formed on hundreds of occasions and can influence the motivation to use drugs even after years of abstinence. The interconnected regions making up the limbic system, which is highly concentrated in dopamine neurons, are essential to both the initial subjective and reinforcing response to stimulants, as well as to the long-term association between this response and memory. Brain sites such as the basolateral amygdala and hippocampus, which mediate the association between environmental stimuli and reinforcer effects, are essential to the influence of stimulant-related cues on drug seeking. More specifically, presentation of the cues associated with cocaine or amphetamine use increases both extracellular dopamine levels in the NAcc and the amygdala and increases drug-seeking behavior (Everitt and Wolf 2002). Fast-scan cyclic voltammetry, which measures subsecond changes in dopamine in the NAcc, shows that extracellular dopamine increases in the seconds before animals respond to receive cocaine and after they receive cocaine. In fact, electrical stimulation of the VTA, mimicking what occurs when animals are preparing to self-administer cocaine, triggers lever-pressing for cocaine

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(Phillips et al. 2003). Blockade of dopaminergic neurons in the amygdala attenuate drug- and cue-induced reinstatement (Bossert et al. 2005). Conventional reinforcers, such as palatable food, increase dopamine in the NAcc and in other areas of the extended amygdala, which helps form the association between the reinforcer and the stimuli associated with it (Schultz 1998). Repeated exposure to the palatable food habituates the dopamine response. Yet stimulants elicit a prolonged increase in dopamine that does not habituate. This lack of habituation may be one reason drug-related stimuli gain excessive control over behavior (Di Chiara 1998). That is, stimulants, by enhancing dopamine action to a greater extent than nondrug reinforcers, may lead to excessive strengthening of the behaviors associated with drug use, perhaps explaining the long-term influence of drug-related cues on drug use. Drug seeking can also be elicited by stimulant use. For example, an individual in treatment for methamphetamine use who lapses and uses a small amount of methamphetamine is very likely to relapse or return to the same patterns of methamphetamine use that were occurring before treatment began. Glutamate projections from the prefrontal cortex to the NAcc also appear to play an important role in cocaine- and cue-induced drug seeking. Either cocaine or cocaine-paired cues increases extracellular dopamine in the dorsal prefrontal cortex, activating prefrontal glutamatergic projections to the NAcc (Hotsenpiller et al. 2001). The amygdala and ventral subiculum also send glutamatergic projections to the NAcc. In fact, directly stimulating glutamatergic pathways to the NAcc elicits drug-seeking behavior in rats (Bossert et al. 2005). Cocaine has minimal effects on glutamate release in the NAcc in naïve animals, but following chronic cocaine exposure, basal glutamate levels in the NAcc are decreased, and glutamate release in response to cocaine is enhanced. Administration of glutamate agonists or a brief electrical stimulation of the VTA, basolateral amygdala, or NAcc reinstates cocaine-seeking behavior (Hayes et al. 2003; Vorel et al. 2001). Blocking or normalizing glutamatergic input to the NAcc decreases both cocaine- and cue-induced glutamate release and cocaine seeking (Bäckström and Hyytiä 2006; Baker et al. 2003; Baptista et al. 2004; Bowers et al. 2004; McFarland et al. 2004). Thus, these preclinical data suggest that one mechanism by which environmental cues or stimulants trigger cocaine- or amphetamine-seeking may be via glutamatergic projections from limbic structures to the NAcc. In humans, functional imaging and cerebral blood flow studies show that cocaine-related cues are associated with both cocaine craving and increased activity in the amygdala, insula, and prefrontal cortical regions (Bonson et al. 2002; Childress et al. 1999). In fact, there is a correlation between cue-induced dopamine release in the dorsal striatum (not the ventral striatum where the NAcc is) and self-reported craving (Volkow et al. 2006). The dorsal striatum receives projections from the substantia nigra and is hypothesized to reflect the habitual nature of compulsive drug seeking, in which exposure to a drug or to drug cues elicits well-learned sequences of behavior. The dorsal striatum is the primary entry into the basal ganglia. Although the ventral striatum is innervated by the prefrontal cortex and limbic structures, the dorsal striatum is preferentially innervated by associative and sensorimotor cortical areas (Gerdeman et al. 2003). Some hypothesize that the ventral striatum continues to play an important role in chronic stimulant use, but the dorsal striatum contributes to the habit-forming aspect of compulsive drug use. In rats, elevated dopamine levels in the dorsal striatum are associated with chronic cocaine self-administration (Ito et al. 2002), and inactivation of the dorsal striatal structures attenuates drug seeking after abstinence (Fuchs et al. 2006). These data support a role for the dorsal striatum in mediating habitual drug-taking behavior.

Stress-induced drug seeking Stressful stimuli also increase the likelihood of craving and relapse in stimulant users (Sinha et al. 2006). Data from preclinical studies show that there is a large degree of overlap among the brain regions involved in cue-, cocaine-, and stress-induced drug seeking, but there are also some

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distinctions. Preclinical studies suggest that extrahypothalamic corticotropin-releasing factor (CRF) and noradrenaline in the central amygdala and the bed nucleus of the stria terminalis mediate stressinduced drug seeking (Xi et al. 2004). Exposure to stress increases sensitivity of VTA glutamatergic neurons to CRF, which activates dopaminergic neurons in the NAcc and dorsal prefrontal cortex. Blockade of CRF release elicited by either stressful stimuli (Shaham et al. 2003) or cocaine (Przegalinski et al. 2005) decreases cocaine seeking in rats. Decreasing stress-induced norephinephrine release with 2 -adrenoceptor

agonists also decreases drug seeking. These preclinical data suggest that it may be

possible to target the neurochemical response to stress to decrease relapse to cocaine or methamphetamine use.

Impulsivity and decision making Another consequence (and often precursor) to chronic cocaine or methamphetamine use is impaired impulse control. Frontal cortical structures mediating decision making and impulse inhibition—which are closely linked to the NAcc, amygdala, and VTA—appear to be affected by chronic stimulant exposure (Jentsch and Taylor 1999). Compared with non–drug users, individuals who abuse cocaine and methamphetamine have alterations in dopamine D 2 receptors and metabolic activity in the frontal cortex that persist for months after detoxification. Imaging studies have revealed dysfunction in the prefrontal and dorsolateral prefrontal cortex in stimulant-dependent patients that is consistent with a possible alteration in brain circuits mediating decision making. It is important to note that decision making improved with length of abstinence (Franklin et al. 2002; Paulus et al. 2002), so the effect is not necessarily permanent. In studies of brain injury, damage within the frontal cortex leads to a preferential response for small, immediate reinforcers over larger, delayed reinforcers, and leads to persistent responding, even in the absence of reinforcement. Some brain-injured patients recover cognitive function, but they continue to make choices that bring immediate reward even at the risk of incurring negative outcome, such as a loss of reputation or job (Bechara 2005). Similarly, stimulant-dependent patients often make decisions consistent with immediate rather than delayed reward. In methamphetamine users, a recent study suggests fMRI activation in prefrontal, parietal, and insular cortices during a decision-making task predicted relapse in methamphetaminedependent individuals. Those showing low activation in these brain sites were significantly more likely to relapse within a year than those showing high activation (Paulus et al. 2005). These data demonstrate an important role for decision making in relapse susceptibility, and implicate the frontal cortex in mediating aspects of addiction.

Summary By understanding the neurobiology of the factors influencing relapse, it may be possible to decrease the likelihood that an abstinent methamphetamine or cocaine user who returns to an environment where he or she always used drugs would relapse to drug use, or, even if the individual did use some drug (i.e., lapse), would not return to levels of drug use that preceded his attempt to quit (relapse). An additional approach may be to use medications that decrease the response to stress, so that a frustrating or upsetting event would be less likely to precipitate a relapse. Preclinical studies demonstrate an essential role of mesolimbic dopamine and glutamate in cue-, stimulant-, or stress-induced drug seeking. Yet, although the neurobiological mechanisms of drug seeking in rats have been well described, the relevance of this model to clinical relapse is still a matter of debate (Katz and Higgins 2003). Compared with rodents, primates have a distinct limbic circuitry and a more prominent cortical role in addiction (Bradberry and Rubino 2006). Therefore, much of the neurochemistry of drug seeking may need to be replicated in primates before inferences to humans are drawn. Data on decision making in chronic stimulant users are compelling. These studies show that impaired decision making may predict relapse. It is important to note that drug abstinence improves decision

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making for many but not for all, suggesting that impaired decision making may be present in some individuals before the onset of drug use.

Sensitization In laboratory animals, repeated exposure to cocaine or amphetamine can result in sensitization or a heightened behavioral and dopaminergic response to subsequent stimulant administration. Sensitization, also referred to as reverse tolerance, may also occur following repeated exposure to stressful stimuli. Sensitization to the convulsant, locomotor, and reinforcing effects of stimulant drugs has been demonstrated. The development of sensitization appears to involve transient glutamatergic adaptations in the VTA. Specifically, the ability of drugs to modulate AMPA receptor subunits in the VTA may mediate the development of sensitization. These transient adaptations in the VTA induce secondary, long-term adaptations in the NAcc, resulting in altered dopamine receptor sensitivity (Carlezon and Nestler 2002). Although sensitization in rodents has been well characterized, the relevance of this phenomenon to stimulant abuse has not been clearly demonstrated. Unlike rodents, nonhuman primates that self-administer cocaine in patterns that mimic human cocaine abusers do not show an enhanced dopaminergic response to cocaine (Bradberry and Rubino 2006). An enhanced dopamine response has also not been demonstrated in humans. In fact, cocaine abusers had lower extracellular dopamine levels following stimulant administration compared to non–drug users (Volkow et al. 1997). If sensitization is relevant to stimulant addiction, it may occur when an individual is starting to use drugs. A recent neuroimaging study has demonstrated that exposure to oral amphetamine in drug-naïve research volunteers resulted in enhanced psychomotor effects and dopamine release in response to subsequent amphetamine administration, with the effects persisting for at least 1 year (Boileau et al. 2006). The relationship between these measures and abuse liability is not known, but it may be that prior amphetamine use enhances the effects of subsequent use. One consequence of stimulant use in which sensitization has been shown to play an important role is in the development of behavioral pathology. Acute paranoia, which is one of the most common symptoms of cocaine and methamphetamine use, typically abates as the drug wears off. However, more extreme pathology can include psychosis, characterized by paranoia, impaired reality testing, and hallucinations that are virtually indistinguishable from schizophrenia (Post and Kopanda 1976). Methamphetaminerelated psychosis may last as long as several days or weeks, whereas cocaine-related psychosis tends to have a briefer duration (Jackson 1989). Chronic stimulant abusers who have experienced drug-induced psychosis report that this state readily recurs with readministration of even a small dose of the drug, and laboratory investigations support these findings; amphetamine psychosis has been replicated reliably in volunteers who were given small but frequent doses of the drug over time (Griffith et al. 1972). Thus, sensitization appears to play a role in the behaviorally toxic consequences of stimulant abuse.

Tolerance Repeated exposure to drugs of abuse can also produce tolerance, in which larger doses are needed to produce an effect that was previously obtained at a lower dose. In humans, acute tolerance to many of cocaine's effects develops during a single episode of cocaine use. That is, the first dose produces larger cardiovascular and subjective effects than do subsequent doses, despite sustained elevations in cocaine plasma levels (Foltin and Fischman 1991). During a binge, cocaine users will often use large amounts of cocaine in an attempt to achieve the effect obtained by the first dose. There is little evidence to support longer-term tolerance to cocaine or amphetamine's reinforcing effects in nonhuman or human laboratory studies (Nader et al. 2006; Ward et al. 1997). One criterion for stimulant dependence cited in the DSM-IV-TR is tolerance (American Psychiatric Association 2000); yet experienced stimulant abusers do not appear less sensitive to the reinforcing effects of cocaine or methamphetamine than those who have less experience using stimulants. Thus, although tolerance to

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certain stimulant effects, such as anorexia, has been demonstrated, tolerance to the reinforcing effects of cocaine or amphetamine does not appear to occur under conditions in which these drugs are abused.

Dependence Pharmacological dependence is defined as the presence of withdrawal symptoms upon termination of drug use. Stimulants, unlike opiates or alcohol, do not produce neuroadaptations in areas mediating somatic and autonomic function; therefore, abstinence is not associated with physical withdrawal symptoms. However, both clinical observations and controlled laboratory studies demonstrate that abstinence following the repeated use of methamphetamine or cocaine is associated with increased depression, fatigue, anxiety, and irritability (Foltin and Fischman 1997; Weddington et al. 1990). In recently abstinent methamphetamine abusers, ratings of depression and anxiety significantly covaried with relative glucose metabolism in limbic regions implicated in mood, such as the cingulate gyrus, amygdala, and insula (London et al. 2004). Thus, stimulant withdrawal is primarily characterized by disorders in mood, which typically resolve in a relatively short period of time. In laboratory animals, abstinence following unlimited stimulant self-administration coincides with decreased extracellular dopamine and serotonin and increased dynorphin levels in the NAcc, which are hypothesized to mediate mood symptoms during stimulant withdrawal. Stimulant withdrawal is also associated with increased extracellullar levels of CRF in the central nucleus of the amygdala, which also may contribute to the negative affect and decreased sensitivity to natural reinforcers accompanying withdrawal (Koob et al. 1997). In humans, the specific consequences of chronic stimulant use on serotonin and dopamine pathways are difficult to study directly. Yet there is indirect evidence supporting alterations in serotonin pathways during withdrawal. Serotonin stimulates prolactin and cortisol release, so one method of assessing central serotonergic function is to measure plasma prolactin and cortisol following the administration of the serotonin releaser and reuptake inhibitor, d-fenfluramine. Cocaine users, who smoked a controlled amount of cocaine in the laboratory, had a blunted neuroendocrine response to d-fenfluramine that lasted for at least 2 weeks of cocaine abstinence, as compared to non-drug-abusing controls. By contrast, there was no disruption in the hormonal response to the D 2 agonist, bromocriptine, during cocaine abstinence, even shortly after a cocaine binge (Haney et al. 2001b). A deficit of central serotonin transmission during stimulant withdrawal is consistent with the hypothesized etiology of clinical depression. Thus, a selective disruption in serotonin pathways following chronic cocaine use may provide a neurochemical basis for changes in mood commonly reported during stimulant withdrawal.

Toxicity An additional consequence of chronic exposure to stimulants, particularly methamphetamine, may be dopaminergic and serotonergic neurotoxicity; noradrenergic neurons appear resistant to amphetamine neurotoxicity (McCann and Ricaurte 2004). In laboratory animals, repeated administration of large doses of methamphetamine is associated with decreased tissue concentrations of dopamine and serotonin, decreases in dopamine uptake sites, and inhibition of the dopamine precursor tyrosine hydroxylase and the serotonin precursor tryptophan hydroxylase (Seiden and Sabol 1996). Most laboratory animal studies demonstrating neurotoxicity use higher doses and more frequent dose administrations than those used by humans, so one has to be cautious in interpreting the relevance of these studies to human methamphetamine abuse. However, one study in nonhuman primates utilizing methamphetamine doses comparable with those abused by humans, reported significant decreases in the dopamine transporter and in brain dopamine axonal markers (Villemagne et al. 1998). Furthermore, brain imaging studies in detoxified methamphetamine abusers showed decreased D2 receptors and dopamine transporters in the striatum that appeared to last at least several months after last drug use. Decreased dopamine transporters correlated with slower motor speed and poorer verbal memory (Volkow et al. 2001a). Detoxified methamphetamine abusers also had lower serotonin

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transporter density, and the density was inversely correlated with the duration of methamphetamine use (Sekine et al. 2006). Although it is possible that the altered dopamine receptor and transporter levels reflect neuroadaptations rather than dopamine terminal degeneration, the persistence of these effects and the decrease in structural indicators of nerve terminals suggest that dopamine transporter levels were not simply down-regulated (Johanson et al. 2006). Nonetheless, studies of methamphetamine users have shown that some dopaminergic terminal markers recover after prolonged abstinence (Volkow et al. 2001b). More studies on the precise behavioral and physiological consequences of long-term methamphetamine use on dopamine and serotonin are needed. Recently, investigators have sought to determine why methamphetamine is not associated with parkinsonism. Studies measuring dopamine levels in autopsied brains of chronic methamphetamine users and patients with Parkinson's disease found that methamphetamine users had greater depletion in the caudate than in the putamen, which is opposite to the pattern seen in Parkinson's patients. These data suggest methamphetamine abuse may have a more profound effect on caudate function than on putamen (motoric) function (Moszczynska et al. 2004). Parkinson's patients also have decreased putamen and globus pallidus volume, whereas chronic methamphetamine users show enlarged basal ganglia (Chang et al. 2005), thus demonstrating an additional difference between the etiology of Parkinson's disease and the consequences of methamphetamine abuse. Cocaine has not been shown to produce the same degree of dopaminergic neurotoxicity as methamphetamine. In laboratory animal studies evaluating doses of cocaine and d-amphetamine that produced comparable levels of weight loss, behavioral activation, and lethality, amphetamine administration resulted in axonal degeneration in the neostriatum and frontal cortex but cocaine did not (Ryan et al. 1988). There is also little evidence of toxicity to dopaminergic nerve terminals in cocaine overdose patients compared with drug-free and age-matched controls (Staley et al. 1997). However, cocaine may have neurotoxic effects outside of dopamine pathways. Chronic cocaine administration has been shown to produce axonal degeneration in the lateral habenula. Furthermore, cocaine abusers (who often abuse other drugs as well) tend to show deficits in cerebral blood perfusion and cerebral glucose metabolism that persist after detoxification from cocaine. These abnormalities, which mimic certain neurological disorders, may play a role in cocaine's behavioral toxicity (Majewska 1996).

Neurobiological mechanism Depending on dose and route of administration, methamphetamine-induced release of dopamine may be auto-oxidized to 6-hydroxydopamine, which results in neurodegeneration. In fact, the magnitude of dopamine release correlates with the amount of neurotoxicity. Thus, the destruction of both serotonin and dopamine neurons has been shown to be reduced or prevented in laboratory animals if the following steps are taken prior to methamphetamine administration: 1) dopamine reuptake blockers are administered, 2) dopamine synthesis inhibitors or antagonists are administered, or 3) brain dopamine levels are depleted (Seiden and Sabol 1996). Antioxidants protect dopamine from damage induced by methamphetamine, suggesting that treating methamphetamine abusers during early withdrawal with antioxidants may attenuate pathology. Neurotoxicity with repeated methamphetamine abuse may also be the result of increased glutamate release, which underlies the neuron-damaging effects of a range of central nervous system insults. Toxic doses of methamphetamine increase glutamate efflux in the striatum, where neurotoxicity occurs, but not in the NAcc, where neurotoxicity does not occur (Abekawa et al. 1994). NMDA antagonists prevent both dopaminergic and serotonergic neurotoxicity (Johnson et al. 1989), suggesting that these medications also have potential for decreasing methamphetamine toxicity. Another source of neurotoxicity may involve glia. Data in mice show that methamphetamine prompts microglia to mount an immune response to dopamine neurons (Thomas et al. 2006). Human imaging studies show that the striatum is expanded in former methamphetamine abusers, which the authors

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conclude reflects a glial response (Chang et al. 2005).

CONCLUSION There are a range of consequences to repeated stimulant abuse, including addiction, sensitization, dependence, tolerance, and neurotoxicity, and each consequence has a distinct etiology and time course. It is clear that whatever environmental, sociological, or psychological factors influence an individual's decision to initiate cocaine or amphetamine use, repeated stimulant use can produce long-term brain changes that make it a difficult behavior to control (Nestler 2005). Circuits affected include those involved with reward, motivation, learning, inhibitory control, and executive function (Volkow and Li 2005). Sensitivity to natural reinforcers decreases, further boosting the likelihood that individuals will return to drug use. Thus, relapse is the cardinal feature defining addiction, and likely reflects the strength of internal and external cues linked to drug use and possibly drug-induced alterations in decision making and impulse control. No medications have been approved for the treatment of cocaine or amphetamine dependence, yet the substantial advances in our understanding of the complex neuroadaptations following cocaine or amphetamine abuse have formed the basis for studies attempting to reverse or treat certain aspects of addiction. The far-reaching effects of stimulant abuse on a range of neurochemical systems illustrate the difficulty of this task. Furthermore, the development of treatment medications is complicated because chronic drug exposure impinges on experience-dependent learning and memory formation. Pharmacotherapeutic interventions will not cure a chronic relapsing disorder such as stimulant abuse, but may decrease craving, initiate or prolong abstinence, or block the acute stimulant effects of the drug being abused. These effects may provide a window of opportunity during which behavioral and psychosocial interventions will be most efficacious.

KEY POINTS The robust reinforcing properties of cocaine and methamphetamine are primarily mediated by their effects on dopamine in the ventral tegmental area, nucleus accumbens, ventral pallidum, and prefrontal cortex. Cocaine and methamphetamine share similar subjective and reinforcing effects, yet important distinctions exist between these two stimulant drugs. Cocaine's effects are relatively short-lasting, resulting in a pattern of more frequent self-administration over a shorter period of time compared with methamphetamine. Furthermore, cocaine inhibits the reuptake of dopamine, whereas methamphetamine also promotes dopamine release, which renders this drug more neurotoxic than cocaine. Chronic use of cocaine and methamphetamine produces long-term neuroadaptations that can increase the probability that people will choose to seek and use drug over other behaviors. A number of factors contribute to this shift in behavior: 1) Exposure to the cues associated with drug use may produce a strong desire to use the drug; stressful stimuli or a lapse to drug use also increases the desire to return to drug use. 2) Chronic stimulant use may alter the prefrontal brain circuits mediating decision making, thereby increasing the likelihood people will choose short-term immediate reinforcers (e.g., smoking methamphetamine) over long-term reinforcers (e.g., working steadily to receive a paycheck). In fact, impaired decision making appears to predict relapse. Repeated stimulant-induced increases in extracellular dopamine and glutamate play a critical role in the cascade of events that lead to addiction, including changes in gene expression and synaptic plasticity. Because of the intricate interactions between dopamine and other neurotransmitters, cocaine and amphetamine use may be modulated by medications acting on a range of neurochemical sites, particularly those modulating glutamate and -aminobutyric acid.

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SUGGESTED READING Kalivas PW, Volkow ND: The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatry 162:1403–1413, 2005 Kelley AE: Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44:161–179, 2004 Nader MA, Czoty PW: PET imaging of dopamine D2 receptors in monkey models of cocaine abuse: genetic predisposition versus environmental modulation. Am J Psychiatry 162:1473–1482, 2005 Sinha R, Garcia M, Paliwal P, et al: Stress-induced cocaine craving and hypothalamic-pituitary-adrenal responses are predictive of cocaine relapse outcomes. Arch Gen Psychiatry 63:324–331, 2006 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 11. Clinical Management: Cocaine

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Thomas R. Kosten, Mehmet Sofuoglu, Tracie J. Gardner: Chapter 11. Clinical Managemen t: Cocaine, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.346875. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Clinical Management: Cocaine Thomas R. Kosten, M.D. Mehmet Sofuoglu, M.D., Ph.D. Tracie J. Gardner, Ph.D.

CLINICAL MANAGEMENT: COCAINE: INTRODUCTION Cocaine and amphetamine are psychoactive agents that increase central nervous system (CNS) activity and produce powerful reinforcing effects (e.g., euphoria, elevated mood, high) that contribute to their high abuse liability. Since the peak of the cocaine epidemic in the mid-1980s, addiction to this stimulant has been a major public health concern. Recently, localized epidemics of amphetamine abuse have developed, particularly in the Western United States. In addition, misuse of prescription stimulants has increased exponentially in the past several years, particularly among adolescents and young adults. The dangers associated with stimulant use are enormous and include increased risk of HIV infection, detrimental effects on the unborn and newborn, and increased crime and violence as well as medical, financial, and psychological problems. Because of these consequences, the task of identifying, characterizing, and developing treatments is more important than ever. Progress has been made in identifying and developing pharmacological and behavioral treatments for stimulant addiction. In this chapter, we review our current understanding of the biological basis for stimulant reinforcement and describe the clinical characteristics resulting from its use, as a foundation for a discussion of the pharmacological and behavioral treatment approaches for stimulant abuse. We conclude by providing specific treatment guidelines for managing stimulant-abusing individuals. Work in this chapter has been supported by the National Institute on Drug Abuse grants K05-DA0454 and P50-DA12762.

NEUROCHEMICAL ACTIONS MEDIATING STIMULANT REWARD A vast behavioral and pharmacological literature demonstrates that the rewarding effects of stimulants are mediated through the mesocorticolimbic dopamine system, which consists of dopamine neurons of the ventral tegmental area and their target projections, including the nucleus accumbens and prefrontal cortex (Johanson and Fischman 1989; Kosten 2002). The reinforcing properties of cocaine and amphetamine are associated with their ability to increase synaptic dopamine levels. Cocaine increases dopamine by binding to the dopamine transporter and inhibiting its activity, whereas amphetamine increases synaptic dopamine concentrations by actions on the vesicular monoamine transporter, causing dopamine release from the vesicles into synapses (White and Kalivas 1998). In addition to dopamine, cocaine and amphetamine have actions on norepinephrine and serotonin neurons, and all are important targets for medication development (Rothman and Baumann 2006a; Rothman et al. 2000). However, behavioral and neurochemical studies indicate that dopamine is the critical neurotransmitter mediating the reinforcing effects of these stimulants and that this action is dependent on rapid entry of cocaine into the brain raising these dopamine levels (Volkow et al. 1996a, 1997).

NEUROBIOLOGICAL EFFECTS OF CHRONIC STIMULANT ABUSE In addition to the acute reinforcing effects, stimulants can produce a constellation of neurochemical, physiological, and neuropsychological impairments following chronic use. Studies examining dopamine receptor function show decreased postsynaptic dopamine receptors and reduced dopamine function

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(Sevarino et al. 2000; Volkow et al. 1992, 1996b). Single photon emission computed tomography and positron emission tomography studies show increases in dopamine transporter in acutely abstinent cocaine abusers relative to control subjects (Malison et al. 1998), decreases in dopamine D2 receptor binding in detoxified cocaine abusers relative to control subjects (Volkow et al. 1996b), and reduced cerebral blood flow and cortical perfusion among chronic cocaine users (Holman et al. 1991, 1993; Kosten et al. 1998; Volkow et al. 1988). Alterations in glucose metabolism have also been observed following stimulant administration. When tested during early withdrawal, there is an increase in glucose metabolism among cocaine users relative to control subjects, but during late withdrawal, there is a decrease in metabolic activity among cocaine addicts (Volkow et al. 1991, 1992). Such reductions in glucose metabolism have also been observed following acute administration of cocaine (London et al. 1990). Given the evidence of disturbances in brain structure and function following stimulant use, it is not surprising that individuals with histories of cocaine abuse also show cognitive deficits. In fact, impairments in verbal learning, memory, and attention have been well documented in cocaine-abusing individuals (Beatty et al. 1995; Bolla et al. 1998; Di Sclafani et al. 2002; Gottschalk et al. 2001), and these neuropsychological deficits have been shown to correlate with reductions in blood flow among cocaine users (Woods et al. 1991). There is also an association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers (Volkow et al. 2001a, 2001b). Thus, chronic stimulant use produces not only neurochemical and physiological alterations but also cognitive impairments.

CLINICAL ASPECTS OF STIMULANT USE The rewarding effects of cocaine and amphetamine are influenced by the route of administration, because some routes (e.g., intravenous administration) produce more immediate onset of euphoria. The preferred methods of self-administering cocaine have been snorting and, more recently, smoking. Amphetamines come in a variety of forms (e.g., pill, liquid, or powder form), but they are usually taken orally or intravenously. The effects of snorted cocaine generally occur within 15–20 minutes, whereas the effects from intravenously injected cocaine can be felt within just a few minutes. A smokeable form of cocaine ("crack"), which changes cocaine hydrochloride into a free base by using baking soda and water, produces euphoria within seconds. Similar to cocaine, a smokeable version of amphetamine ("ice") is also available and, due to its long duration of action, can produce euphoria lasting 12–24 hours. Stimulant use may range from low-dose to high-dose and from infrequent to chronic or binge patterns. Depending on the dosage, pattern, and duration of use, stimulants can produce several drug-induced states that differ in clinical characteristics. Moderate to high doses of stimulants can produce stimulant intoxication that may or may not be pleasant. The intoxicated person may show signs of hyperawareness, hypersexuality, hypervigilance, and psychomotor agitation. Often the symptoms of stimulant-induced intoxication resemble mania. The medical staff needs to monitor intoxicated persons until the symptoms of agitation and paranoia diminish. If these symptoms do not resolve within 24 hours, pharmacotherapy of the psychotic symptoms is indicated (Kosten 2002). With increased dosage and duration of administration, stimulants can also produce a state of mental confusion and excitement known as stimulant delirium. Delirium is associated with becoming disoriented and confused, as well as anxious and fearful. Extreme medical caution is needed when treating delirium, because such symptoms may indicate stimulant overdose. For instance, crack cocaine addicts who overdose need careful monitoring for seizures, cardiac arrhythmias, stroke, and pulmonary complications. Overdose management in the past used chlorpromazine, but this agent can worsen a cocaine withdrawal syndrome of hyperthermia and agitation that resembles neuroleptic malignant syndrome (Kosten and Kleber 1988). High doses of benzodiazepines may be safer alternatives for controlling the delirium and agitation because neuroleptics will worsen the hyperthermia in some cases of overdose and lead to fatality. Acutely, benzodiazepines can also help minimize the need for physical restraints.

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During high-dose stimulant use, something that is often seen during binge episodes, individuals can experience stimulant-induced psychosis characterized by delusions, paranoid thinking, and stereotyped compulsive behavior. When patients are delusional, close clinical monitoring is essential. Although stimulant psychosis generally clears within a few days of drug discontinuation (Spear and Alderton 2003), prolonged psychoses may sometimes occur (Ahmad 2003). It may therefore be necessary to employ short-term treatment with neuroleptics to ameliorate the psychosis. It is more common for amphetamine to induce psychosis than cocaine, perhaps because of the difficulty in maintaining high chronic levels of cocaine in the body (King and Ellinwood 1997). Also, stimulant-induced psychosis in humans is related to the dose and duration of administration of amphetamine and cocaine rather than to psychiatric predisposition (Satel et al. 1991). Stimulant withdrawal, which occurs following cessation of cocaine or amphetamine use, can produce a wide range of dysphoric symptoms. Following binge use, individuals may initially experience a "crash" period characterized by symptoms of depression, anxiety, agitation, and intense drug craving (Gawin and Ellinwood 1988). The crash period is followed by an intermediate withdrawal phase in which the individuals may experience fatigue, a loss of physical and mental energy, and decreased interest in the surrounding environment (Gawin and Ellinwood 1988). During the late withdrawal phase, brief periods of intense drug craving can occur such that objects and people in the addict's life can become a conditioned trigger for craving and relapse. These withdrawal symptoms may be a target for pharmacological agents (see the section "Dopaminergic Agents" section later in this chapter).

TREATMENT FOR STIMULANT ABUSE Although a great deal has been learned about the reward mechanisms underlying stimulant abuse, the development of effective pharmacotherapy has lagged behind. The pharmacological and behavioral treatment approaches used for cocaine abuse also appear to be applicable to the treatment of amphetamine use, but no treatment agents have U.S. Food and Drug Administration (FDA) approval for this use.

Pharmacotherapy More than 60 medications have been investigated for the treatment of stimulant abuse, some of which include dopaminergic agonists (disulfiram, selegiline), antidepressants (desipramine, bupropion), and a cocaine vaccine. To date, none have shown consistent efficacy in the treatment of stimulant use disorders, although many show considerable promise. Studies have been relatively brief and have focused on abstinence initiation rather than on relapse prevention, but even these modest treatment targets have not been attained. Table 11–1 categorizes most of the agents that have been examined by their putative mechanisms.

Dopaminergic agents Based on the theory that chronic cocaine use reduces the efficiency of central dopamine neurotransmission, a number of dopaminergic compounds, including bromocriptine, mazindol, and methylphenidate, have been examined as treatment medications for cocaine abuse. It is thought that these dopaminergic agents, which have a fast onset of action, would correct the dopamine dysregulation and alleviate the withdrawal symptoms that often follow cessation of stimulant use. A review found little efficacy for direct dopamine agonists such as pergolide but some suggestion of efficacy for indirect agents such as sustained-release amphetamine, selegiline, and disulfiram (Kosten et al. 2002a; Malcolm et al. 2000). Although controlled studies found no difference between methylphenidate and placebo treatment groups in cocaine use, sustained-release amphetamine showed more promise (Grabowski et al. 1997, 2001; Schubiner et al. 2002). Selegiline, a monoamine oxidase B inhibitor, blocks the catabolic enzyme that breaks down dopamine, resulting in greater synaptic levels of dopamine. This medication also exhibits amphetamine-like effects and can enhance dopamine release and block dopamine reuptake (Ebadi et al. 2002). Although short-term treatment with selegiline did not alter physiological or subjective effects of cocaine in a

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laboratory study of cocaine users (Haberny et al. 1995), cerebral metabolic and subjective effects of cocaine were evaluated in another study in subjects receiving selegiline, 10 mg/day. Selegiline altered the cerebral metabolic effects of cocaine and attenuated the cocaine "high" (Bartzokis et al. 1999). Disulfiram has an indirect action on dopamine through inhibition of the enzyme dopamine-hydroxylase, which converts dopamine to norepinephrine. Studies with disulfiram have been promising in reducing cocaine abuse (Carroll et al. 1998; George et al. 2000). Compared with psychotherapy alone, disulfiram is associated with greater reduction in cocaine use (Carroll et al. 1998). A recent study replicated previous findings in a cocaine-dependent sample in which the disulfiram (250 mg/day) treatment group achieved greater reduction in cocaine use compared with the placebo group (Carroll et al. 2004). Although results suggest that disulfiram may be an effective medication for reduction in cocaine use, it may not be suitable for treatment in all populations. A combined analysis of two cocaine pharmacotherapies (Carroll et al. 1998; Petrakis et al. 2000) examined possible gender/treatment interactions in response to disulfiram; Nich et al. (2004) reported that men responded to disulfiram in reduction of cocaine use, whereas women did not. Further studies are needed to determine the optimum dosage and duration of treatment with this agent as well as to assess the efficacy of disulfiram related to gender and comorbid conditions such as alcohol use or opioid dependence.

Antidepressants Antidepressants make up the second class of medications used to treat cocaine dependence and are thought to down-regulate synaptic catecholamine receptors—an action opposite to the presynaptic up-regulation caused by chronic stimulant use (Gawin and Ellinwood 1988). Although antidepressants have a relatively benign side effect profile, good patient compliance rates, and lack of abuse liability, only desipramine has shown some efficacy in selected populations; the more common serotonin reuptake inhibitors have been ineffective. Desipramine is the tricyclic antidepressant that has been studied most extensively as a treatment for cocaine dependence. A meta-analysis of placebo-controlled studies by Levin and Lehman (1991) showed that desipramine produced greater cocaine abstinence than placebo, but a more recent review did not concur (Lima et al. 2001). However, secondary analyses of studies with imipramine, desipramine, and bupropion have suggested that depressed cocaine abusers are more likely to show significant reductions in cocaine abuse than nondepressed cocaine abusers (Margolin et al. 1995; Nunes et al. 1991; Ziedonis and Kosten 1991). Furthermore, additional work with desipramine has suggested its efficacy in opioiddependent patients, particularly in combination with contingency management therapies (Kosten et al. 2003; Oliveto et al. 1999). Although early studies suggested some efficacy for fluoxetine, this has not been confirmed in controlled trials (Grabowski et al. 1995).

GABAergic agents -Aminobutyric acid (GABA) agonists are showing promise following initial studies using baclofen (Ling et al. 1998). In a randomized, placebo-controlled trial, the baclofen treatment group had greater reductions in cocaine use than the placebo group, and baclofen was reportedly more effective in a subgroup of individuals with greater cocaine use at baseline (Shoptaw et al. 2003). Tiagabine, a GABA reuptake inhibitor, has also shown promise in reducing the reinforcing effects of cocaine by attenuating cocaine-induced dopamine release. In a clinical trial investigating the efficacy of tiagabine for cocaine use in opioid-dependent patients maintained on methadone, tiagabine dose-dependently attenuated cocaine use as measured with self-reported and urine drug screening (Gonzalez et al. 2003, 2007). In a 10-week, double-blind, placebo-controlled trial of treatment-seeking, cocaine-dependent subjects treated with methadone, clinical efficacy of gabapentin was compared with that of tiagabine for reduction of cocaine use. Tiagabine significantly reduced cocaine-taking behavior compared with placebo- or gabapentin-treated subjects (Gonzalez et al. 2007). Topiramate, another GABA-enhancing medication with a primary therapeutic indication for epilepsy, has yielded promising results for cocaine dependence as well. In a 14-week, double-blind, placebo-

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controlled outpatient study, subjects assigned to topiramate had more negative urine results for cocaine use than those given placebo (Kampman et al. 2004). Results suggest potential efficacy for GABAergic treatments for cocaine dependence, but outcomes must be replicated in additional, larger clinical trials. Most recently, vigabatrin has shown efficacy in clinical studies for cocaine abusers, and placebocontrolled, multisite studies examining it for use in cocaine dependence are under way (Brodie et al. 2005).

Other treatment agents and approaches In addition to the dopaminergic agents and antidepressants, a number of miscellaneous agents, including amantadine, carbamazepine, and buprenorphine, have been examined for cocaine pharmacotherapy. Carbamazepine failed to show therapeutic effects in three controlled studies after an initial enthusiasm (Cornish et al. 1995; Kranzler et al. 1995; Montoya et al. 1995). Buprenorphine also has had more negative than positive findings regarding its efficacy in treating cocaine-abusing opiate addicts (Kosten et al. 1989, 1993; Schottenfeld et al. 1997, 2005). Studies of another agent, amantadine, have reported mixed results (Alterman et al. 1992; Kampman et al. 1996, 2000; Shoptaw et al. 2002). In a trial of cocaine-dependent men treated for 10 days with amantadine, 100 mg two times a day, urine toxicology screens were more likely to be free of cocaine among men taking amantadine at the 2-week and 1-month follow-up visits (Alterman et al. 1992). A further study reported, however, that 100 mg of amantadine administered three times a day was no more effective than placebo in reducing cocaine use (Kampman et al. 1996). Re-analysis of the data found that amantadine effectively reduced cocaine use among subjects with severe cocaine withdrawal symptoms at the start of treatment (Kampman et al. 2000). Although results of clinical trials do not appear to support amantadine as a treatment for cocaine dependence, further controlled studies are needed to determine whether amantadine is efficacious in cocaine users with high withdrawal severity. Recent advances in understanding dopamine neuronal systems and in considering ways to prevent stimulants from getting into the brain have led to innovative approaches for medications. For example, although dopamine seems critical for reinforcement, several groups have shown that mice with the dopamine transporter deleted will still self-administer cocaine, suggesting a role of the serotonergic system (Rocha et al. 1998; Sora et al. 1998, 2001). Recent data support the theory that a balance between dopamine neurons and serotonin neurons is critical in medication development for reduction of stimulant side effects. Elevated synaptic serotonin can attenuate stimulatory effects mediated by dopamine release, such as motor stimulation and drug self-administration (Rothman and Baumann 2006a). In order to normalize neurotransmitter impairments, nonselective biogenic amine transporters that concurrently release both dopamine and serotonin have been examined as a way to reduce stimulant withdrawal symptoms (Rothman et al. 2006). A recent study of PAL-287, a dual dopamine/serotonin releasing agent, suppressed cocaine self-administration in rhesus monkeys (Rothman and Baumann 2006b). Maintaining the ability to suppress ongoing drug-seeking behavior while experiencing minimal abuse liability and few stimulant side effects are advantages that should be further explored. Finally, the effects of

agonists in reducing dopamine activity are opposite to those

observed with cocaine or amphetamine, suggesting they have a role as potential medications (Maisonneuve et al. 1994). Modafinil is a novel stimulant approved by the FDA for the management of daytime sleepiness in narcolepsy; the drug is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions (Dackis et al. 2003, 2005). Generally well tolerated with a low propensity for abuse, modafinil is frequently used for off-label indications such as attention-deficit/hyperactivity disorder (ADHD), depression, and cocaine dependence and withdrawal (Ballon and Feifel 2006, Dackis et al. 2003). Dose-related effects on pre-potent inhibition in healthy volunteers further suggests a positive effect of modafinil in reducing impulse responding (Turner et al. 2003). The effect was also noted in a follow-up study in patients with ADHD (Turner et al. 2004). In the first double-blind, placebo-controlled trial in 62 cocaine-dependent patients, modafinil reduced cocaine use to a greater extent than placebo. The group

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receiving modafinil provided significantly more cocaine-free urine samples compared with those given placebo and were more likely to achieve a protracted period of cocaine abstinence (Dackis et al. 2005). Additional studies are needed to evaluate the efficacy of cocaine use reduction and determine the potential of modafinil to increase impulse control in cocaine abusers. Several other agents have not been addressed in detail due to limited clinical study data. For example, 2

adrenergic receptor agonists such as lofexidine and clonidine, which are used to alleviate short-term

opioid withdrawal, may also have an indication for stimulant abuse, based on animal data (Erb et al. 2000; Shaham et al. 2000). The efficacy of lofexidine in cocaine seeking or stress-induced reinstatement of cocaine seeking has not yet been determined in humans; however, footshock stress-induced reinstatement of heroin and cocaine seeking in rats is attenuated by acute injections of clonidine or lofexidine (Erb et al. 2000; Shaham et al. 2000). Repeated injections of lofexidine in speedball- (cocaine and heroin mixture) seeking rats successfully attenuates stress-induced reinstatement of cocaine and heroin beyond the acute drug withdrawal phase (Highfield et al. 2001). A recent study of lofexidine in naltrexone-treated, opioid-dependent subjects successfully reduced stress-related opioid craving and relapse-related outcomes as well (Sinha et al. 2007). These data therefore support the need for further examination of lofexidine in stress-related craving and relapse, particularly in polydrug abusers. Furthermore, combination therapies that target both drug-related reinforcement and stress-related triggers to drug seeking may be beneficial in addiction relapse prevention. A cocaine vaccine has also been developed for humans and is supported by animal studies in which several different types of vaccines have suppressed cocaine administration (Kosten and Biegel 2002; Kosten et al. 2002b). Now in clinical trials, the vaccine utilizes a cocaine derivative conjugated to a cholera-toxin protein to produce antibodies. In a Phase I safety and immunogenicity trial, the vaccine induced cocaine-specific immunoglobulin G cocaine antibodies both time- and dose-dependently. In addition, the vaccine was tolerated with no serious adverse effects during 12 months of follow-up (Kosten et al. 2002b). Recent results from a Phase-IIa study of two doses of this vaccine yielded promising results among cocaine-dependent persons in early recovery. Subjects who received a higher dose of the vaccine had significantly higher mean antibody titer response and were more likely to maintain cocaine-free urine screenings than those in the lower-dose group (Martell et al. 2005). Results demonstrated that a cocaine-specific vaccine can elicit a sufficient immunological response that reduces cocaine usage and attenuates the self-reported psychological effects of cocaine during use (Martell et al. 2005). It is possible to override the effects by the vaccine by increasing the amount of cocaine usage. The vaccine therefore is primarily for use in cocaine users who are motivated to quit.

Behavioral Therapy The most important component of stimulant treatment involves behavioral therapies. Although a large multisite study showed little difference between drug counseling and two types of more intensive behavioral therapies—cognitive and supportive expressive therapies—these therapies retain patients in treatment and can lead to abstinence (Crits-Christoph et al. 1999). They form the platform for any pharmacotherapy by engaging the patient and facilitating more long-term changes, including prevention of relapse (Carroll 1996, 1997). A specific behavioral approach using positive contingencies to initiate abstinence and prevent relapse has been quite successful for managing cocaine- and amphetamine-abusing individuals (Higgins et al. 1994a, 2000a, 2000b; Petry et al. 2005; Silverman et al. 1996; Weinstock et al. 2007). The goal of this approach has been to decrease behavior maintained by drug reinforcers and increase behavior maintained by non–drug reinforcers by presenting rewards contingent upon documented drug abstinence (positive contingencies) and withdrawing privileges contingent upon documented drug use (negative contingencies). Studies illustrate how positive contingency management procedures facilitate initial abstinence in cocaine-dependent persons. In a 24-week study (Higgins et al. 1994b), cocaine-dependent individuals were randomized to receive either behavioral treatment without incentives or behavioral treatment with

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incentives (i.e., vouchers exchangeable for goods and services) during weeks 1–12. Then during weeks 13–24, clients in both groups received a $1.00 lottery ticket for every drug-free urine test, in addition to behavioral treatment. The group that received the incentives showed significantly greater treatment retention and longer duration of continuous abstinence than the group not receiving the incentives. In a 12-week clinical trial among cocaine abusers receiving methadone maintenance treatment (Silverman et al. 1996), the contingency group also achieved significantly longer duration of sustained cocaine abstinence than did control subjects. Overall, these findings suggest that offering incentives contingent on drug abstinence can be a powerful intervention tool for facilitating cocaine abstinence in cocaine abusers receiving methadone maintenance treatment. Recent studies have further reinforced that abstinence-based incentive procedures are efficacious in improving retention and associated abstinence outcomes in substance abusers. Contingency management interventions implemented in community-based settings, for example, have been successful in improving retention and associated abstinence outcomes (Petry et al. 2005). In addition, combining contingency management with pharmacotherapies such as bupropion may significantly improve treatment outcomes for cocaine addiction (Poling et al. 2006). There is, however, a significantly higher cost associated with the incentives group versus usual-care group (Olmstead et al. 2007). To determine the cost-effectiveness of implementing contingency management to improve patient outcomes in real-world situations, threshold values for patient outcomes in substance abuse treatment need to be determined. Cognitive-behavioral therapy (CBT) is also an efficacious intervention for the treatment of stimulant abuse. In a recent pilot study, CBT was examined in conjunction with pharmacotherapy to evaluate length of treatment, drug-free urinalyses, and reduction of alcohol and cocaine craving. Although CBT-treated subjects remained in treatment longer than subjects who received disulfiram/CBT or naltrexone/CBT, the combination treatment groups achieved significantly greater reductions in cocainepositive urinalyses (Grassi et al. 2007). In a study comparing CBT with contingency management, the latter was efficacious during treatment application. Although contingency management may be useful in engaging substance users, retaining them in treatment, and helping them achieve abstinence, CBT has comparable longer-term outcomes (Rawson et al. 2006). Results of previous research also suggest that cognitive deficits predict low retention in outpatient CBT treatment programs for cocaine dependence (Aharonovich et al. 2003, 2006). Future studies should further examine the potential impact of differences in cognitive functioning on treatment outcomes.

Treatment and Psychiatric Comorbidity The rates of comorbid psychiatric disorders in stimulant abusers are significantly higher than community rates of depression, ADHD, and antisocial personality disorders (Rounsaville et al. 1991; Weiss et al. 1986). Because psychiatric disorders may increase the risk for drug use (e.g., individuals may self-medicate to ease psychiatric symptoms), treatment needs to address both the stimulant addiction and the comorbid disorder. Certain pharmacotherapies may be particularly useful for stimulant abusers with comorbid psychopathology. For instance, treatment with antidepressants has reduced depressive symptoms, cocaine use, and craving in depressed cocaine-addicted individuals (Nunes et al. 1991; Ziedonis and Kosten 1991). Also, methylphenidate has been reported to be effective in treating cocaineaddicted persons with ADHD (Khantzian et al. 1984). Unfortunately, psychiatric comorbidity has not yet shown a specific prognostic significance for behavioral therapies.

TREATMENT GUIDELINES FOR STIMULANT ABUSE Treatment for stimulant abuse requires a comprehensive assessment of the patient's psychological, medical, forensic, and drug use history. Moreover, because information obtained from chemically dependent persons may be incomplete or unreliable, it is important that the patient receive a thorough physical examination, including blood and supervised urine samples for analysis. The clinician needs to be aware that polydrug abuse is common. Patients may ingest large amounts of one or more drugs at potentially lethal doses, and therefore it is important that the physician be aware of the dangers of

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possible drug combinations such as cocaine and alcohol or heroin (Goldsmith 1996). Pharmacological intervention may be necessary during stimulant-induced drug states. For instance, neuroleptics may be useful in controlling stimulant-induced psychosis or delirium, and anticraving agents with a fast onset of action may be helpful during the early withdrawal period. During the late withdrawal phase, when depression may set in, antidepressants may be an appropriate choice for treatment medication. Treatment medications can be given on an inpatient or outpatient basis. However, if medications are used for outpatient treatment, it is critical to warn the patient of the potential adverse interactions between cocaine and the prescribed treatment medication. For instance, high blood pressure could result from the release of epinephrine by cocaine combined with the reuptake blockade by the tricyclic, although later in the course of treatment, tricyclics decrease the sensitivity of the postsynaptic adrenergic receptors (Fischman et al. 1976; Kosten et al. 1992).

CONCLUSION Dopamine neural systems appear to mediate the reinforcing effects of cocaine and amphetamine. It is the powerful rewarding effects that make stimulants addictive and dangerous, creating a range of psychological, social, economic, and medical problems. To date, no effective treatment is available for stimulant dependence, although progress has been made in the development of pharmacological and behavioral techniques for cocaine and amphetamine addiction. GABAergic agents, dopaminergic agents, and antidepressants have shown some promise for reducing drug craving and preventing relapse. Behavioral techniques aimed at maintaining drug abstinence and preventing relapse have also shown favorable results. Although both pharmacological and behavioral interventions may be useful in treating addiction, individuals with significant medical risks, psychiatric comorbidity, and neuroadaptation from heavy stimulant use are particularly likely to benefit from pharmacological treatment (Kosten 2002). Further research is needed to address this issue and identify other effective ways to treat, manage, and prevent stimulant use.

KEY POINTS The rewarding effects of stimulants are mediated through the mesocorticolimbic dopamine system. The reinforcing properties of cocaine and amphetamine are associated with their ability to increase synaptic dopamine levels. Stimulants can produce a constellation of neurochemical, physiological, and neuropsychological impairments following chronic use. Despite advances in pharmacotherapy research, to date there are no U.S. Food and Drug Administration–approved medications for the treatment of stimulant abuse. Combined pharmacotherapy and behavioral interventions may improve treatment outcomes. Pharmacotherapies that target both drug-related reinforcement and stress- and cue-related aspects of drug seeking could be beneficial in relapse prevention. Polydrug use is common and therefore must be taken into consideration when assessing treatment options.

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SUGGESTED READING Carroll BC, McLaughlin TJ, Blake DR: Patterns and knowledge of nonmedical use of stimulants among college students. Arch Pediatr Adolesc Med 160:481–485, 2006 Kosten TR: Future of anti-addiction vaccines. Stud Health Technol Inform 118:177–185, 2005 McCabe SE, Teter CJ, Boyd CJ: Medical use, illicit use and diversion of prescription stimulant medication. J Psychoactive Drugs 38:43–56, 2006 Sofuoglu M, Kosten TR: Emerging pharmacological strategies in the fight against cocaine addiction. Expert Opin Emerg Drugs 11:91–98, 2006 Vocci FJ, Elkashef A: Pharmacotherapy and other treatments for cocaine abuse and dependence. Curr Opin Psychiatry 18:265–270, 2005 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 12. Clinical Management: Methamphetamine

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Richard A. Rawson, Walter Ling: Chapter 12. Clinical Management: Methamphetamine, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.349963. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Clinical Management: Methamphetamine Richard A. Rawson Walter Ling

CLINICAL MANAGEMENT: METHAMPHETAMINE: INTRODUCTION One of the fastest growing illicit drug problems in the world between 1995 and 2005 has been the use and abuse of methamphetamine (MA). According to estimates by the United Nations Office on Drugs and Crime (2005), approximately 26 million people around the world used amphetamines in a 12-month period during 2003–2004. In contrast, approximately 11 million people used heroin and 14 million used cocaine. Statistics on the extent of the MA problem within the United States create a somewhat mixed picture. According to the National Survey of Drug Use and Health, in 2004 an estimated 12 million people had used MA at least once in their lifetime, 1.4 million had used it in the previous year, and 600,000 had used it in the previous 30 days (SAMHSA Office of Applied Studies 2005). Although these estimates have been stable since 2002, the number of previous-month users who met criteria for stimulant abuse or dependence increased from 63,000 in 2002 to 130,000 in 2004. Therefore, according to National Survey of Drug Use and Health data, although the number of new users remains relatively stable, a higher percentage of people who use MA are developing significant clinical disorders as a result of their use. Treatment admission data for adults from the Substance Abuse and Mental Health Services Administration (SAMHSA) indicate that the number of individuals reporting MA as their primary drug of use increased from 41,000 in 1996 to 152,000 in 2005 (SAMHSA Office of Applied Studies 2006a), an increase of 370%. On a percentage basis, treatment admissions for MA, which was cited as the primary drug used, represented 2.5% of total admissions in 1996, and the percentage increased to 8.2% in 2005 (SAMHSA Office of Applied Studies 2006a). The MA problem in the United States has spread from the western states to the midwestern states and, most recently, to the southeastern states since 1997. At present, the only regions in the United States without substantial rates of MA use are the Northeast and major urban centers in the East and Midwest. However, recent media reports have suggested that even in some of these cities (e.g., New York), there is evidence of considerable MA use among some men who have sex with men (MSM) (Jacobs 2006).

HOW METHAMPHETAMINE WORKS MA can be injected, smoked, snorted, or taken orally, and the method of use determines the intensity of the drug's effects. When smoked or injected, the effects of MA are almost instantaneous because it enters the bloodstream very quickly, resulting in the release of high levels of dopamine in the brain and a rapid, powerful, and euphoric "rush" (Matsumoto et al. 2002). In oral use, MA takes about 20 minutes for effects to be felt, whereas effects after nasal insufflation (snorting) are felt after 3–5 minutes (National Institute on Drug Abuse 2002). MA enters the brain and increases the levels of norepinephrine, dopamine, and serotonin in the neuronal synapse by preventing neurotransmitter reuptake (Han and Gu 2006). The combined acute effects are similar to the fight-or-flight response and include increased blood pressure and heart rate; relaxation of bronchioles; activation of fat breakdown; increase in body temperature; locomotor activation; arousal, attention, and appetite effects; and euphoria.

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MA is often compared with cocaine, but there are important differences in their mechanisms of action. Cocaine acts primarily by blocking the reuptake of released dopamine in the synaptic clefts of the mesolimbic dopamine neurons. MA also inhibits reuptake of the released dopamine, but is carried into the dopaminergic neurons and, unlike cocaine, exerts its action intracellularly. MA causes docking of the intracellular dopamine-containing vesicles at the membrane, leading to leakage of dopamine into the synaptic cleft. Additionally, it interferes with dopamine transport into the storage vesicles, thus increasing the cytoplasmic concentration of dopamine, which undergoes oxidation and produces oxidation products that are toxic to the nerve terminals (Hanson et al. 2004; Pierce and Kumaresan 2006; Sandoval et al. 2003). The neurotoxicity of MA is further accentuated by its prolonged half-life and long duration of action, which exceeds 6 hours.

Acute Physiological Effects The acute physiological effects of MA use include increased blood pressure, body temperature, heart rate, and breathing rate (National Institute on Drug Abuse 2006). The positive or rewarding effects include euphoria, reduced fatigue, reduced hunger, increased energy, increased sex drive, and increased self-confidence. Negative acute effects include stomach cramps, shaking, high body temperature, bruxism, stroke, and cardiac arrhythmia, as well as increased anxiety, insomnia, aggressive tendencies, paranoia, and hallucinations. MA-associated psychiatric impairment may be cognitive, intellectual, or affective. The impairment may be acute (intoxication), delayed (withdrawal), or protracted. The severity of psychiatric impairment appears to correlate with duration of use as well as dosage, in terms of total absorbed and peak amounts, which can vary according to route of administration (intravenous administration seems to have greater impact than oral or smoking administration).

Adverse Effects on Health Chronic use of MA may lead to drug tolerance (Matsumoto et al. 2002, National Institute on Drug Abuse 2002), in which larger doses of the drug are required to obtain previous effects, and frequently leads to psychological and physical dependence. Tolerance may also develop to some of the drug's effects, such as appetite suppression, whereas other effects, such as locomotor stimulation, may become greater over time. Repeated, continuous MA use is also associated with physical and psychological damage (McCann and Ricaurte 2004). The alertness provided by casual use of the drug can evolve into paranoia, which is often exacerbated by lack of sleep. Chronic MA use also results in changes in the brain, which may be reflected by cognitive dysfunction concomitant with dependence. These changes in the brain may remain even after use of the drug has ceased. Among the consequences experienced by chronic users is damage to blood vessels in the brain, strokes, respiratory problems including pneumonia, irregular heartbeat, extreme anorexia, cardiovascular collapse, inflammation of the heart lining, liver disease, and death (National Institute on Drug Abuse 2002). A wide range of negative health effects may result from chronic MA use, although some effects can occur even with one-time or occasional use. Adverse effects are listed in Table 12–1 (Albertson et al. 1999).

SCREENING OF METHAMPHETAMINE PROBLEMS Clinicians encountering a possibly stimulant-involved patient who is not forthcoming about self-reporting MA abuse are faced with such a wide array of conditions within the DSM-IV-TR criteria (American Psychiatric Association 2000) that the guidelines may not be sufficiently helpful in isolating the contribution of MA versus the presence of other disorders and psychiatric conditions. The DSM-IV-TR criteria for MA intoxication, for example, include the following conditions: Clinically significant maladaptive behavioral or psychological changes (e.g., euphoria or affective blunting; changes in sociability; hypervigilance; interpersonal sensitivity; anxiety, tension, or anger; stereotyped behaviors; impaired judgment; or impaired social or occupational functioning)

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that developed during, or shortly after, use of amphetamine or a related substance. (American Psychiatric Association 2000, p. 227) If a clinician is relying solely on DSM-IV-TR criteria, the results of a medical workup could be inconclusive regarding an MA-related diagnosis. MA intoxication can produce, for example, either tachycardia or bradycardia, elevated or lowered blood pressure (Haning and Goebert 2007), psychomotor agitation (National Institute on Drug Abuse 2006) or retardation (Volkow et al. 2001)— posing a muddle that defies a definitive diagnosis if regarded without sufficient context. When a patient presents with the symptoms discussed above, consideration should be given to a possible MA-induced state, absent a history of other Axis I or II disorders that preceded MA use. Medications prescribed for a misdiagnosed psychiatric condition would be inappropriate for most MA-intoxicated individuals, especially youth, whose developing brains could be negatively affected by medications commonly prescribed for psychosis. A clinician lacking extensive experience with individuals who abuse MA may be best advised to treat acute symptoms conservatively and rely on the confirming results of a blood test or urine analysis.

METHAMPHETAMINE-RELATED SYNDROMES AND THERAPEUTIC APPROACHES Intoxication and Withdrawal The typical syndrome associated with MA intoxication that leads patients to seek or need medical attention is acute agitation, which may often best be handled by talking down the patient, assuring them that the condition will pass in time, while observing them and ensuring a calm environment. If recent MA administration indicates the possibility of toxicity, measures may be taken to promote clearance of the drug; emetics or lavage may be useful in removing amphetamine pills, but much more common is toxicity from intravenous or smoked MA. Currently, there are no medications that can quickly and safely reverse a life-threatening MA overdose. In severe cases, when potential for harm to self or others is manifest, either a benzodiazepine or an antipsychotic may be used. Although little formal research has established the efficacy of any pharmacotherapeutic regimen for MA overdose, the traditional approach is to provide 5 mg of haloperidol, frequently in combination with 1–2 mg of lorazepam, administered orally or parenterally in repeated doses. Other approaches include providing 1–2 mg of risperidone orally or parenterally, with 1–2 mg of lorazepam orally, administered in several doses over a 12-hour period, with the patient evaluated for 12 hours. Clinicians should observe for and treat possible dehydration and hyperthermia (Brown and Yamamoto 2003). Early abstinence symptoms, primarily severe fatigue, depressed mood, and clouded thinking, resolve in a short time for most MA-dependent individuals (Table 12–2). Indeed, rest, exercise, and a healthy diet may be the most appropriate management approach for the majority of individuals experiencing withdrawal. Extreme agitation and sleep disturbance may respond to short-acting benzodiazepines, but withdrawal-associated depressed mood and the most severe cognitive deficits generally resolve without intervention. Drug craving is currently only managed through behavioral treatment, given that no specific medications have proven effective.

Managing Acute and Persistent Methamphetamine Psychosis MA-induced psychosis symptoms (Table 12–3) can be difficult to distinguish from preexisting disorders or disorders concomitant with drug abuse; thus, the clinician must conduct a thorough assessment of the patient before making a definitive diagnosis and treatment plan. Persons with MA abuse disorders frequently report auditory hallucinations in addition to visual (e.g., flashing lights, peripheral artifacts), olfactory, and tactile sensations (e.g., the sense of bugs crawling on or below the skin). Disorientation, a symptom typical of schizophrenia, is said to not be characteristic of MA psychosis, but in reality it is often difficult to differentiate the two conditions. MA-induced acute psychosis can require more intensive treatment approaches involving use of either a benzodiazepine or an antipsychotic. Such psychosis is generally short-lived, at least as it is documented

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in the United States. In Japan, the Philippines, Korea, and Thailand, however, the symptoms often persist; in one Japanese study, 28% of the patients had psychosis lasting longer than 6 months (Ujike and Sato 2004). As with the treatment of MA intoxication, low-dose antipsychotics may be useful in treating psychosis, but there is no research guidance on efficacy or appropriateness. It is important to note that these drugs have not been carefully tested in adolescents and young adults (Cooper et al. 2006). Long-term effects of exposure to such medications (Curtis et al. 2005) during these formative years are unknown but may be profound and long-lasting. Caution in prescribing antipsychotics for younger patients is justified. Persistent psychosis in the presence of MA abuse has been regarded by some clinicians and researchers as latent schizophrenia made manifest by MA, whereas others assert that MA can produce a persistent psychosis that resembles schizophrenia (Curran et al. 2004). In fact, the set of symptoms of MA psychosis is frequently so similar to that of schizophrenia as to cause the clinician to see the two conditions as equivalent. Research findings appear to support the position that MA abuse can be the genesis of a persistent psychotic state (Iwanami et al. 1994; Sato 1992). Clinicians should be aware of the documented close relationship between MA-induced psychosis and schizophrenia. For example, Chen et al. (2005) showed that relatives of MA users with MA-related psychosis had a significantly higher morbid risk for schizophrenia than the relatives of those MA users who never became psychotic. Conclusions indicated that greater familial propensity for schizophrenia yielded higher likelihood that an MA user will develop psychosis and that the psychosis will be more persistent.

TREATMENT FOR METHAMPHETAMINE ABUSE AND DEPENDENCE Contrary to some popular but errant notions, treatment for MA dependence does work. Although there are some specific populations and clinical issues that may pose special challenges, treatment outcomes for MA-dependent patients are comparable with those for other substance-dependent patients involved in similar treatment programs. For example, research on the Matrix Model and other behavioral strategies (cognitive-behavioral therapy [CBT] and contingency management [CM]) revealed that treatment responses of MA users appeared indistinguishable from those of cocaine users (Obert et al. 2000). However, a number of populations present particular treatment challenges and several clinical issues are particularly important when treating MA-dependent individuals.

Methamphetamine Populations With Unique Clinical Concerns Methamphetamine injectors Recently, some states (e.g., South Dakota and Oregon) have reported elevated rates of MA injection. Smoking and, especially, injecting MA appears to lead to a more difficult drug-related disorder. Injection users tend to report far more severe craving during their recovery and higher rates of depression and other psychological symptoms before, during, and after treatment (Hillhouse et al. 2007). Injection users also have higher dropout rates and exhibit higher rates of MA use during treatment. In a recent sample of MA-dependent users who entered treatment in the Midwest, Hawaii, or California, the rate of hepatitis C infection was 15% (Gonzales et al. 2006). Of the MA injectors, over 45% were infected with hepatitis C. Clearly, preventive efforts that address behaviors that expose individuals to hepatitis C infection (blood-to-blood transfers or sharing drug paraphernalia) should be incorporated into treatment protocols.

Men who have sex with men Use of MA by MSM is one of the most significant public health problems associated with the increased use of MA. Elevated rates of MA use and associated high-risk sexual behavior have been reported in many MSM communities throughout the United States (Halkitis et al. 2005; Patterson et al. 2005; Shoptaw et al. 2005). Rates of HIV seroprevalence have been reported to be threefold higher among MA-using MSM than among non-MA-using MSM (Halkitis et al., in press). A report by the Centers for

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Disease Control and Prevention on the connection between MA-use, high-risk sexual behavior, and HIV transmission in MSM communities suggests that this combination of factors poses a major threat of a renewed increase in rates of HIV infection among MSM (Centers for Disease Control and Prevention 2007). The development of treatment materials for this population has progressed in recent years, with evaluation of MSM-oriented programs showing that successful treatment of MA dependence is an extremely effective HIV prevention strategy (Shoptaw et al. 2005).

Women Women use MA at rates approaching those of men (Brecht et al. 2004; Freese et al. 2000). Use of two other major illicit drugs, heroin and cocaine, is roughly characterized by a 2:1 ratio (men to women; SAMHSA Office of Applied Studies 2006b). In contrast, the male-to-female ratio for MA users approaches 1:1. Surveys among women suggest that they are more likely than men to be attracted to MA for weight loss and to control symptoms of depression. MA-related drug disorders may present different challenges to women's health, may progress differently, and may require different treatment approaches. Over 70% of MA-dependent women report histories of physical and sexual abuse; and women are more likely than men to present for treatment with greater psychological distress (Brecht et al. 2004). Treatment materials that address the extensive historical and current trauma-related problems of these women (e.g., Najavits 2002) are likely to be valuable to people addressing these clinical issues. Many women with young children do not seek treatment or they drop out early because of the fear of not being able to take care of or keep their children, as well as the fear of punishment from authorities. Consequently, women may require treatment that identifies and addresses women's specific needs.

Children and perinatal issues MA poses significant threats to the health of children in communities with high levels of MA availability and abuse. The effects of MA use by pregnant women on their fetuses are currently being studied (Smith et al. 2006). At present, it appears that such use can cause growth retardation, premature birth and, possibly, neurological disorders (Lucas 1997). Children of MA-abusing parents are at high risk of negligence and abuse as a result of the parents' drug preoccupation, erratic behavior, and psychiatric instability. Children who live in environments where MA is manufactured are at particularly high risk for exposure to the toxic precursors of MA (Swetlow 2003).

Adolescents Although patterns of adolescent MA use have been reported to be relatively low in national surveys (lifetime use of 3% by tenth graders and 3.4% by twelfth graders) as measured by the Monitoring the Future study in 2004, in communities where MA-use levels are high, adolescent MA users have been seen in treatment centers in significant numbers (Johnston et al. 2005). Of particular note is the very high rate of MA use among teen girls admitted for substance abuse treatment. One study (Rawson et al. 2005) found that 63.7% of adolescent females seeking treatment reported MA as their primary drug of choice. In several clinical samples, the rates of MA abuse or dependence for girls have been double that of boys (Gonzales et al., in press). MA use among adolescents has been shown to be associated with higher levels of emotional, psychiatric, and delinquency problems compared with adolescents given other drug abuse diagnoses (Rawson et al. 2005).

Noteworthy Clinical Issues Cognitive impairment Chronic use of MA has been documented to produce profound disruption of cognitive functions (Barr et al. 2006). Verbal and working memory, response inhibition, perceptual speed, attention, and fluency are some of the cognitive processes that are known to be impaired in newly abstinent MA users. Although many of these processes appear to recover within the first several weeks of abstinence, clinical experience suggests that residual cognitive impairment can be present for several months following

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discontinuation of MA use. To accommodate these cognitive limitations, treatment strategies should not emphasize extensive information acquisition or intellectually complex activities, because memory impairment will result in poor retention of such material. Treatment programs should employ simple, clear, directive behavioral techniques, accompanied by reminders and repetition that promote acquisition and retention of treatment materials.

Sexual behavior The hypersexuality of MA-using MSM represents a significant HIV transmission threat. However, MSM are not unique in indicating that they associate MA use and sexual behavior. Rawson et al. (2002) reported that in a comparison of four groups of substance-dependent individuals in treatment (alcohol-, opiate-, cocaine-, and MA-dependent individuals), there was a significantly greater association between drug use and sexual behavior among the MA-dependent group than among the other three substancedependent groups. Sexual pleasure and sexual drive, as well as frequency, intensity, variety, and riskiness of sexual activity, were greater for MA-users than for other groups. These reported elevations of sexual associations between drug use and sexual responses applied to both men and women. Frequently, anxieties and concerns over sexual issues are reported by individuals in the early months of recovery from MA. Decreased libido, inability to function sexually, loss of sexual pleasure, and reduced frequency of sexual activity are all common clinical concerns of individuals during the early months of abstinence from MA. Relapse to MA can be a consequence of these patient concerns unless the patient is educated about the transience of these phenomena and reassured that return to a satisfying sexual life is possible in the future.

Overview of Treatment for Methamphetamine Problems Treatment outcomes for MA-dependent patients have been shown to be comparable with those for individuals treated for other substance dependence disorders. Several studies have documented that when using standard community treatments, the response of MA-dependent patients was comparable with patient groups who were admitted for other substance dependence disorders (Copeland and Sorensen 2001; Luchansky et al. 2007). Research on the Matrix Model and other behavioral strategies (CBT and CM) found similar treatment responses for MA users and cocaine users in evaluations of specific behavioral and cognitive behavioral protocols (Huber et al. 1997; Rawson et al. 2006). Clearly, MA users do respond to current psychosocial treatments as implemented in real-world settings. At present, only two specific psychosocial treatment protocols (CM and the Matrix Model) have been evaluated in randomized, controlled clinical trials with MA-dependent participant samples. These studies are reviewed below. However, comparisons of treatment responses by MA users and cocaine users to the specific behavioral protocols mentioned above suggest that there is a very high likelihood that psychosocial treatments with demonstrated efficacy for cocaine dependence can be useful for individuals with MA dependence, although an optimum approach would address clinical concerns that are salient to MA dependence, as noted above. Treatments including CBT (Morgenstern et al. 2001; Rawson et al. 2006), community reinforcement approach (Higgins et al. 2003), 12-step facilitation (Nowinski et al. 1992), and the National Institute on Drug Abuse drug counseling approach (Daley et al. 1999) should be considered for treating MA-dependent individuals.

Behavioral Treatment Contingency management CM applies the principles of positive reinforcement for performance of desired behaviors consistent with MA abstinence. CM typically involves the contingent delivery of a voucher (which can be traded for desired items or privileges) or other incentives for behaviors, such as attendance at treatment sessions or production of a drug-negative urine specimen. CM has been widely applied to other drug dependence disorders, and a meta-analysis of research findings has documented strong evidence of efficacy across many studies, types of disorders, and populations. Petry (2006) has written on how this technique can

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be used efficiently and cost-effectively. The validity of CM for the treatment of MA dependence has been confirmed in a study conducted within the National Institute on Drug Abuse Clinical Trials Network in which a CM procedure was combined with counseling for a group of 113 MA-dependent individuals (Roll et al. 2006). Study participants were randomly assigned to receive a structured counseling program (Matrix Model, see below; n = 62) or structured counseling plus a CM condition (n = 51). In the CM condition, individuals could earn small incentives for providing MA-free urine samples on a variable ratio schedule of reinforcement. Study results indicated that participants who received CM intervention had more drug-free urine test results than counseling-only individuals, the CM group had longer periods of abstinence, and a higher percentage of the CM group were abstinent during the study period. At follow-up, 12 months posttreatment, both CM and standard counseling participants had comparable outcomes. Another study compared the effectiveness of CM and CBT for treating cocaine- and MA-dependent individuals (Rawson et al. 2006) over a 16-week outpatient trial. Stimulant-dependent individuals (N = 177) were randomly assigned to receive one of three therapy programs: 1) group-based, three-timesper-week CBT program (n = 58); 2) CM program for provision of stimulant-free urine samples, with no counseling (n = 60); or 3) combination of CM and CBT conditions (n = 59). Study results demonstrated that all groups had a significant reduction in MA use during treatment, when compared with pretreatment levels. Participants receiving CM were retained for significantly longer than those receiving only CBT, and they provided more drug-free urine samples during treatment. The gains from CM and CBT were sustained at 6- and 12-month follow-ups. Clearly, the CM approach is a validated, powerful tool in the armamentarium.

Matrix Model The Matrix Model is a blended treatment approach that incorporates principles of CBT in individual and group settings, family education, motivational interviewing, and 12-step program participation. This stimulant treatment protocol, organized into a set of manuals and published by SAMHSA, provides the structure and content for a multi-element, three-visit-per-week, 16-week outpatient treatment experience, followed by a weekly social support group for 1 year. Although it is not a pure CBT intervention, Matrix extensively employs CBT principles and strategies. In addition to CBT materials delivered primarily in group sessions, the Matrix Model emphasizes that clinicians employ a style of interacting with patients that incorporates many of the skills taught as part of motivational interviewing. Family members are involved in a set of psychoeducation sessions and conjoint sessions. The Matrix Model has numerous central therapeutic constructs. These include the following: Establishing a positive and collaborative relationship with the client Creating explicit structure and expectations Teaching psycho-educational information (including information on brain chemistry and other research-derived, clinically relevant knowledge) Introducing and applying cognitive-behavioral concepts Positively reinforcing desired behavioral change Educating family members regarding the expected course of recovery Introducing and encouraging self-help participation Monitoring drug use through the use of urinalyses This manualized therapy has been proven effective in reducing MA use during the 16-week application of the intervention, in comparison with a "treatment as usual" program (Rawson et al. 2004). At 6- and 12-month follow-ups, the reductions in MA use achieved by employment of the Matrix Model and treatment-as-usual were substantial and comparable. Shoptaw et al. (2005) have modified the Matrix Model for the treatment of MA-dependent MSM. Their study results suggest that the Matrix approach produces outcomes that are equivalent at 1 year posttreatment to CM only and CBT combined with CM. The CBT group component of the Matrix Model has also been extensively employed as the behavioral treatment platform in pharmacotherapy trials for MA dependence (Johnson et al. 2006).

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Pharmacological Treatment Several compounds have shown some promise as potential medications for MA treatment, particularly bupropion (Wellbutrin) and modafinil (Provigil). Other medications (e.g., methylphenidate, topiramate, lobeline, vigabatrin) are under consideration.

Bupropion Bupropion shows promise as a pharmacotherapy for preventing relapse among MA-dependent individuals. Laboratory studies have indicated that bupropion can reduce the subjective effects of MA and reduces MA cue-induced craving (Newton et al. 2006). Recent research in six community-based clinics in California, Hawaii, Iowa, and Missouri showed that bupropion produced significant reductions in MA use compared with placebo treatment in subjects. The dosage was 150 mg, two times a day. The authors concluded that bupropion, in combination with behavioral group therapy, was more effective for patients with low/moderate MA dependence (i.e., fewer than 18 days of use in the past month).

Modafinil Modafinil is a nonamphetamine stimulant that is prescribed for controlling symptoms of narcolepsy (i.e., daytime somnolence). Although the neuropharmacologic effects of modafinil are not entirely clear, its stimulant properties may reduce the craving, dysphoria, and anhedonia experienced during initial stages of MA abstinence (Menza et al. 2000; Simon et al. 1994). Furthermore, modafinil has been shown to improve cognitive functioning, which may be useful in alleviating the cognitive impairment that has been associated with MA withdrawal.

Methylphenidate Methylphenidate is a stimulant used to treat attention-deficit/hyperactivity disorder. Preclinical research has revealed a potential role for methylphenidate, acting as a dopamine transporter reuptake inhibitor, in counteracting dopamine deficits resulting from MA abuse (Sandoval et al. 2002). A Finnish study reported that treatment with methylphenidate reduced MA injection in an early-stage trial (Tiihonen et al. 2007).

Lobeline Lobeline is a nicotinic receptor antagonist that has been tested as a smoking cessation agent. Lobeline inhibits dopamine reuptake and has been shown to attenuate MA-induced hyperactivity and reduce the self-administration of MA in rodents (Harrod et al. 2001; Miller et al. 2001; Teng et al. 1997). In addition, there is evidence that lobeline may have neuroprotective properties against the effects of MA (Eyerman and Yamamoto 2005). Testing lobeline in humans as a treatment agent is in an early stage of development.

Topiramate Topiramate is an anticonvulsant that has also been approved for migraine prophylaxis. The exact neuropharmacologic mechanisms underlying the benefits of topiramate are not entirely understood. However, it has been shown to reduce alcohol consumption and craving in alcohol-dependent individuals and to reduce cigarette smoking. Kampman et al. (2004) have reported that topiramate reduced cocaine consumption in cocaine-dependent subjects; Johnson et al. (2007) have reported that topiramate appears safe in Phase I interaction studies with MA administration.

Vigabatrin -Vinyl- -aminobutyric acid (GVG) is an anticonvulsant licensed in Europe and Canada (not the United States). It has been shown to block MA-induced increases in dopamine in the nucleus accumbens and thereby blunt the euphoria and positive-subjective effects of MA (Gerasimov et al. 1999). Several open clinical trials involving cocaine-dependent and MA-dependent individuals have revealed positive findings (Brodie et al. 2003, 2005). Systematic study of the safety and efficacy of GVG for the treatment of MA

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dependence is at an early stage of development.

CONCLUSION Abuse of MA increased between 1995 and 2005, creating substantial public health problems and imposing considerable burdens on social service agencies. Those involved in development of prevention and treatment interventions must consider recent epidemiological trends (e.g., increasing numbers of younger users and women users, increased risks for HIV infection among MSM) in order to efficiently reduce MA-associated harm. Research has improved the neurobiological understanding of MA abuse, and emerging knowledge about associated brain processes provides new opportunities for development of pharmacological and behavioral treatments. It is likely that the distribution and use of MA in the United States and around the world has become so extensive that it will continue to be a problem of considerable significance for the foreseeable future.

KEY POINTS Methamphetamine use, abuse, and dependence in the United States has increased from 1995–2005. Chronic methamphetamine use produces significant medical and psychiatric symptoms, including cardiovascular and respiratory system irregularities, neurological abnormalities, skin and dental problems, as well as psychosis, dysphoria, and anhedonia. Symptomatic treatment for methamphetamine-related psychosis, intoxication, and withdrawal using antipsychotics and benzodiazepines is the current accepted practice. Numerous groups require special attention regarding methamphetamine-related consequences. They are methamphetamine injectors, adolescents, women, and men who have sex with men. Current psychosocial treatments with demonstrated efficacy for the treatment of cocaine disorders appear appropriate for treatment of methamphetamine users. These include: cognitive-behavioral therapy, community reinforcement approach, contingency management, 12-step facilitation, and the National Institute on Drug Abuse drug counseling approach. Contingency management and the Matrix Model are the only two psychosocial approaches with data to support their efficacy for the treatment of methamphetamine dependence. Many medications currently show promise as pharmacotherapies for the treatment of methamphetamine dependence, but currently none have clearly demonstrated efficacy.

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9. Rockville, MD, Substance Abuse and Mental Health Services Administration Office of Applied Studies, 2006a. Available at: http://oas.samhsa.gov/2k6/methTx/methTx.pdf. Accessed Feb. 23, 2007 Substance Abuse and Mental Health Services Administration (SAMHSA) Office of Applied Studies: Treatment Episode Data Set (TEDS). Highlights–2005. National admissions to substance abuse treatment services, DASIS series: S-36 (DHHS Publ No SMA-07-4229). Rockville, MD, Substance Abuse and Mental Health Services Administration Office of Applied Studies, 2006b Swetlow K: Children at clandestine methamphetamine labs: helping meth's youngest victims. U.S. Department of Justice Office for Victims of Crime (OVC) Bulletin, June, 2003 Teng L, Crooks PA, Sonsalla PK, et al: Lobeline and nicotine evoke [3H]overflow from rat striatal slices preloaded with [3H]dopamine. Differential inhibition of synaptosomal and vesicular [3h]dopamine uptake. J Pharmacol Exp Ther 280:1432–1444, 1997 [PubMed] Tiihonen J, Kuoppasalmi K, Fohr J, et al: A comparison of aripiprazole, methylphenidate, and placebo for amphetamine dependence. Am J Psychiatry 164:160–162, 2007 [Full Text] [PubMed] Ujike H, Sato M: Clinical features of sensitization to methamphetamine observed in patients with methamphetamine dependence and psychosis. Ann N Y Acad Sci 1025:279–287, 2004 [PubMed] United Nations Office on Drugs and Crime: 2005 World Drug Report. Vienna, United Nations Office on Drugs and Crime, 2005 Volkow ND, Chang L, Wang GJ, et al: Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158:377–382, 2001 [Full Text] [PubMed]

SUGGESTED READING Center for Substance Abuse Treatment: Treatment for stimulant use disorders. TIP Series #33 (DHHS Publ No SMA-99-3296). Rockville, MD, Substance Abuse and Mental Health Services Administration, 1999 Graham AW, Schultz TK, Mayo-Smith MF, et al (eds): Principles of Addiction Medicine, 3rd Edition. Chevy Chase, MD, American Society of Addiction Medicine, 2003 Jaffe JA, Ling W, Rawson RA: Amphetamines, in Kaplan and Sadock's Comprehensive Textbook of Psychiatry. Edited by Sadock BJ, Sadock VA. Baltimore, MD, Lippincott, 2005, pp 1188–1200 Lowinson JH, Ruiz P, Millman RB, et al (eds): Substance Abuse: A Comprehensive Textbook, 4th Edition. Philadelphia, PA, Lippincott Williams & Wilkins, 2004 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 13. Neurobiology of Hallucinogens

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Richard A. Glennon: Chapter 13. Neurobiology of Hallucinogens, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.347177. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Neurobiology of Hallucinogens Richard A. Glennon, Ph.D.

NEUROBIOLOGY OF HALLUCINOGENS: INTRODUCTION Hallucinogenic agents represent an old and very large class of drugs. Nearly every major civilization throughout history has had a preferred drug of abuse or mind-altering substance. In some instances these have been hallucinogens or hallucinogen-related agents or plant products. Various agents can produce hallucinogenic episodes, and terms used to describe such agents include hallucinogens, psychotomimetics, psychedelics, inebriants, and intoxicants. Many agents can be found in this general class of psychoactive agents. More recently, certain hallucinogens have been included in the loose collection of agents termed club drugs, party drugs, or rave drugs. It is clear, however, that membership in these latter categories is not pharmacologically based and that most agents bearing this appellation are not hallucinogens. Do agents as structurally diverse as (+)lysergic acid diethylamide ([+]LSD), phencyclidine (PCP, angel dust), tetrahydrocannabinol (THC; a constituent of marijuana), amphetamine, and mescaline all produce the same (or a common) effect? Do they all work via a common pharmacological mechanism? Studies conducted over the past several decades indicate they do not (see Glennon 2002 for a review). Further obscuring a simple systematic classification of these agents is the emergence of certain designer drugs (not all of which are hallucinogenic and some of which can produce multiple effects) and the recent popularization of older substances (mostly natural products or plant-derived materials) whose human effects have received only limited investigation under controlled clinical settings. Examples of plantderived substances with growing popularity include ayahuasca and Salvia divinorum (with salvinorin A being one of its active constituents). (Examples of hallucinogen-related designer drugs will be provided later in this chapter, in the section titled "Hallucinogen-Related and Other Designer Drugs.") How, then, can these diverse substances be classified? Hollister (1968) wrote that "one can scarcely get any agreement upon the term used to describe this class of drugs" (p. 18) and defined hallucinogenic/psychotomimetic agents on the basis of their overall pharmacological effects. In proportion to other effects, changes in thought, perception, and mood should predominate. Intellectual or memory impairment should be minimal at dosages that produce the effects listed above. Stupor, narcosis, or excessive stimulation should not be an integral effect. Autonomic nervous system side effects should be neither disabling nor severely disconcerting. Addictive craving should be minimal. Although these criteria are very useful in that they allow the classification of certain agents as hallucinogenic by a process of elimination, the description still allows inclusion of a rather diverse variety of pharmacologically distinct agents. Hallucinogenic agents do not represent a behaviorally homogeneous class of agents. Evidence indicates that agents included in the single, general category of hallucinogenic/psychotomimetic agents should be further subclassified to create a clearer picture of the effects that they produce and encourage the development of agents to treat drug abuse. For example, psychotomimetic PCP-related agents probably produce many of their actions through interaction at PCP receptors, cannabinoid receptors may account for some of the actions of various cannabinoids, and hallucinogenic episodes associated with amphetamine psychosis probably involve a catecholaminergic

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mechanism (Glennon 2002). Plant products such as ayahuasca contain a putative hallucinogen and an inhibitor of monoamine oxidase (Riba and Barbanoj 2005), whereas salvinorin A is thought to be a opioid receptor agonist (Prisinzano 2005; Yan and Roth 2004). Without subclassification, many agents remain unclassified and none of the previously mentioned categories would accommodate hallucinogens such as LSD or mescaline. The term classical hallucinogen has evolved to account for some of these agents (Glennon 1999; Lin and Glennon 1994).

CLASSICAL HALLUCINOGENS: CLASSIFICATION The best functional definition of classical hallucinogen is an agent that meets the Hollister (1968) criteria, binds at serotonin type 2 (5-HT2 ) receptors, and is recognized by animals trained to discriminate 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from nondrug, or vehicle, in tests of stimulus generalization (Glennon 1996, 2003). These criteria may comprise many of the remaining agents. Although significant amounts of human data on the effects of hallucinogens on animals are available (Brimblecombe and Pinder 1975; Hoffer and Osmond 1967; Jacob and Shulgin 1994; Lin and Glennon 1994; Shulgin and Shulgin 1991, 1997; Siva Sankar 1975), many putative hallucinogens and the effect they have on humans have been poorly investigated, if at all. There are results from animal studies; however, no reliable animal model of hallucinogenic activity has been developed (Glennon 1992). As a result, animal data must be interpreted cautiously. Nevertheless, a procedure that has become widely accepted for classifying centrally acting agents is the drug discrimination paradigm, usually performed with rats, mice, pigeons, or monkeys as test subjects (Glennon 1994). Under this paradigm, researchers can use a typical two-lever operant-behavioral paradigm to train animals to respond in one manner (e.g., to press one of two levers) under a given set of conditions, and to respond in a different manner (e.g., to press the second of the two levers) under a different set of conditions. Thus, animals can be reliably trained to discriminate administration of a centrally acting agent from vehicle. Typically, the drug stimulus is reliable and robust, and results are replicable from laboratory to laboratory. Once animals have been trained to discriminate a given training drug from vehicle, several types of studies can be conducted. Two of the most useful and widely employed studies are tests of stimulus generalization and tests of stimulus antagonism. In the former, challenge drugs are administered intermittently to the trained animals to determine whether the agents produce stimulus effects similar to (i.e., whether they substitute for, or generalize to) those of the training drug. Results are both qualitative and quantitative; that is, the method allows classification of the type of action produced and also provides information about the potency of a challenge drug relative to the training drug. In tests of stimulus antagonism, the training drug's mechanism of action can be explored by attempting to antagonize the stimulus effects of the drug with various neurotransmitter antagonists. Although such studies are not limited to the investigation of hallucinogenic agents and have been used more for the investigation of nonhallucinogens, they have provided a wealth of information regarding the classification and mechanism of action of hallucinogens. Furthermore, results obtained from such studies can be compared with results of human studies, where such data are available, to corroborate the findings. The strength of the drug discrimination paradigm is that stimulus generalization does not occur between agents that do not produce common stimulus effects. For example, animals trained to discriminate (+)LSD do not recognize PCP or THC, animals trained to discriminate (+)amphetamine do not recognize mescaline, and so on. Using this procedure, several classical hallucinogens, including (+)LSD, DOM, mescaline, and 5-methoxy-N,N-dimethyltryptamine, have been used as training drugs (Glennon 1996). Moreover, animals trained to one of these agents recognize each of the other agents, further attesting to the similarity of their stimulus effects. Several hundred agents have now been examined in rats trained to discriminate DOM from vehicle, and this research has aided the classification of the agents. Table 13–1 shows categories and examples of classical hallucinogens, and Figure 13–1 shows chemical

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structures of selected examples. The agents in Table 13–1 seem to share a common component of action in that they are recognized by DOM-trained animals. FIGURE 13–1. Structures of some of the examples of hallucinogenic agents listed in Table 13–1.

DET = N,N-diethyltryptamine; DMT = N,N-dimethyltryptamine; DOB = 1-(4-bromo2,5-dimethoxyphenyl)-2-aminopropane; DOET = 1-(2,5-dimethoxy-4-ethylphenyl)-2-aminopropane; DOI = 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; DOM = 1-(2,5-dimethoxy4-methylphenyl)-2-aminopropane; (+)LSD = (+)lysergic acid diethylamide;

-MeT =

3-(2-aminopropyl)indole; -Methylmescaline = 1-(3,4,5-trimethoxyphenyl)-2-aminopropane; 5-OMe DMT = 5-methoxy-N,N-dimethyltryptamine. Because animals trained to discriminate DOM from saline do not recognize (i.e., because substitution does not occur upon administration of), for example, PCP, THC, and amphetamine, it can be assumed that the discriminative stimulus (i.e., cueing) effects produced by these agents are different. Furthermore, drug discrimination studies (i.e., stimulus antagonism studies) with, for example, PCP, THC, and amphetamine, indicate that these agents act via a PCP receptor, cannabinoid receptor, and cholinergic receptor mechanism, respectively (Glennon 2002).

CLASSICAL HALLUCINOGENS: MECHANISM OF ACTION The actions of hallucinogens such as (+)LSD, DOM, mescaline, and many (perhaps hundreds) of other related agents cannot be simply accounted for on the basis of the mechanisms described above. The vast majority of hallucinogenic substances seem to act via a mechanism unique among those already mentioned. Tests of stimulus antagonism have been conducted, using agents such as (+)LSD and DOM as training drugs, with various neurotransmitter antagonists, and serotonin (5-HT) receptor antagonists were found to antagonize their effects. Early on, it was thought to be a curiosity that certain 5-HT

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receptor antagonists but not others were effective in blocking the discriminative stimulus effects of these hallucinogens in tests of stimulus antagonism. However, in retrospect, it is now apparent that there are seven families of 5-HT receptors (5-HT1 –5-HT7 ) and that these receptor types can be further subdivided into more than a dozen different subfamilies (Glennon and Dukat 2002). Initially, ketanserin and pirenperone, and later M 100,907 (formerly MDL 100,907) and other antagonists with an affinity and reasonable selectivity for a particular population of serotonin receptors (i.e., 5-HT2 receptors), were found to be most effective in blocking the stimulus effects of the classical hallucinogens, leading to the concept that certain hallucinogens act as 5-HT2 receptor agonists. Subsequently, the 5-HT2 receptor affinities of various hallucinogens were measured, and a significant correlation was found between any two of the following parameters: 1) drug discrimination–derived potencies using DOM-trained rats, 2) human hallucinogenic potencies, and 3) 5-HT2 receptor affinities. Hallucinogens that bind at 5-HT2 receptors have been termed classical hallucinogens. This theory has become known as the 5-HT2 hypothesis of classical hallucinogen action (Glennon 1994), and this class of agents has been alternatively referred to as serotonergic hallucinogens (Glennon 2003). This hypothesis does not preclude a role for other populations of 5-HT (or nonserotonin) receptors in the actions of hallucinogens. Indeed, individual hallucinogens can display widely varying binding profiles. Nevertheless, 5-HT2 receptor affinity is the one feature that all classical hallucinogens have in common. In the first clinical study of its kind, the actions of the indolealkylamine hallucinogen psilocybin, the phosphate ester of psilocin, was shown to be antagonized in humans by the 5-HT2 antagonist ketanserin (Vollenweider et al. 1998). Three populations of 5-HT2 receptors (5-HT2A, 5-HT2B, and 5-HT2C ) have been identified since the 5-HT2 hypothesis was originally proposed. Although classical hallucinogens typically bind at all three subpopulations (Nelson et al. 1999), work from several laboratories indicates that classical hallucinogens act primarily via a 5-HT2A receptor agonist mechanism (Fiorella et al. 1995; Ismaiel et al. 1993; Schreiber et al. 1994). Hence, it might be more appropriate to refer to the classical hallucinogens as those agents that specifically activate brain 5-HT2A serotonin receptors. Most of the classical hallucinogens are indolealkylamines or phenylalkylamines (see Table 13–1). This is not to imply that all indolealkylamines and phenylalkylamines are hallucinogenic. Nevertheless, a very large number of agents have been described as such. Furthermore, structure-activity relationships have been formulated, and today there is a fairly good understanding of what structural features are necessary for an agent to produce DOM-like effects. Perhaps the best compilations of the pharmacological effects produced by indolealkylamines and phenylalkylamines in human subjects are those by Shulgin and Shulgin (1991), (1997). In many instances, the particular agents were evaluated only in limited subject populations. Notwithstanding this shortcoming, these works are some of the best descriptions of the human actions produced by, literally, hundreds of indolealkylamines and phenylalkylamines. It is also clear from the above-mentioned structure-activity studies that other, previously unreported, substances remain to be synthesized and evaluated. Hence, it is likely that newer agents will continue to appear on the clandestine market in the future.

HALLUCINOGEN-RELATED AND OTHER DESIGNER DRUGS Designer drugs, or controlled-substance analogues, are structural variants of known drugs of abuse. Because they are "new" and are thought to promise a seemingly novel effect, they appear to have appeal to individuals interested in exploring the effects of novel substances. Initially, the term designer drug was reserved for new substances being introduced to the clandestine market to circumvent legal constraints. Today, the term is applied to nearly any substance making an appearance on the street, regardless of whether it is new or was previously reported in the scientific literature. There is no specific type of pharmacological action associated with agents termed designer drugs. For example, the designer drug Nexus (2-CB) is a phenylethylamine or mescaline-like analogue of the phenylisopropylamine (PIA) hallucinogen 1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane (DOB) and is a hallucinogen. The PIAs represent one of the largest categories of hallucinogens. Not all PIA designer drugs are hallucinogenic. Amphetamine (Figure 13–2), a nonhallucinogen central stimulant that

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can produce hallucinations (called amphetamine psychosis) upon chronic administration of high dosages, is also a PIA. Amphetamine and some related PIAs are amphetamine-like central stimulants rather than hallucinogens. Cathinone (Figure 13–2), a constituent of the shrub khat, is also a central stimulant; it is similar in structure to amphetamine and has been shown to produce amphetamine-like pharmacological effects. Methcathinone ("cat") (Figure 13–2), the N-monomethyl analogue of cathinone, shares structural similarity with methamphetamine and is an example of a designer drug with stimulant activity. Other PIAs produce empathogenic effects (i.e., increased empathy, talkativeness, openness, and feelings of well-being). The 3,4-methylenedioxy analogue of amphetamine, 1-(3,4methylenedioxyphenyl)-2-aminopropane (MDA; "love drug") (Figure 13–2) is known to possess hallucinogenic and central stimulant character. MDA is a mixture of optical isomers, and it has been demonstrated that its hallucinogenic properties are associated primarily with its R(–)isomer whereas its stimulant character is attributable to its S(+)isomer. A prototypical example of an empathogenic agent is the N-monomethyl analogue of MDA: 3,4-methylenedioxy-N-methylamphetamine (MDMA; "XTC," "ecstasy," "X," "E") (Nichols and Oberlender 1989). MDMA also produces some amphetamine-like stimulant actions. Although not a new substance, the N-ethyl homologue of MDMA, MDE (or MDEA; "Eve") (Figure 13–2), is gaining in popularity. N-Methyl-1-(3,4-methylenedioxyphenyl)-2-aminobutane (MBDB; "Eden," "methyl-J"), the

-ethyl homologue of MDMA, is an MDMA-like agent that seems to lack

central stimulant character (Nichols and Oberlender 1989). Yet another type of PIA is represented by the designer drug N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA), a nonhallucinogenic nonstimulant N-methyl analogue of 4-methoxyamphetamine (PMA; "white death," "chicken powder") (Figure 13–2). Thus, minor structural alterations of a PIA can result in agents with central stimulant, hallucinogenic, or other actions (see Figure 13–3). In fact, stimulus generalization occurs in the optical isomers of 3,4-DMA among animals trained to discriminate either MDMA or PMMA from saline vehicle, but does not occur in animals trained to discriminate (+)amphetamine or DOM from vehicle. As such, 3,4-DMA might be considered the common denominator for MDMA-like and PMMA-like stimulus actions. A PIA might have more than one such action, depending on its specific chemical structure. Unlike stimulant PIAs, hallucinogenic PIAs are not typically self-administered by animals; however, the multiplicity of effect of certain PIAs might explain why some PIA hallucinogens are self-administered, whereas most are not. FIGURE 13–2. Structures of some central stimulants, designer drugs, and related substances described in the text.

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FIGURE 13–3. Venn diagram representing possible overlapping activities or behavioral similarities among the psychoactive phenylisopropylamines.

The agent 1-(3,4-methylenedioxyphenyl)-2-aminopropane [(±)MDA] seems to represent the common (heavily shaded) intersect in that it produces all three actions. See Glennon et al. (1997) and Glennon and Young (2002) for further discussion. A=central stimulant, typified by (+)amphetamine; H=hallucinogenic, typified by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM); P=other activity, typified by N-methyl-1-(4-methoxyphenyl)-2-aminopropane (PMMA). Hallucinogenic, central stimulant, and empathogenic phenylalkylamines share a common basic chemical structure and their specific action is determined by the particular substituents appended to the molecule. The structurally simplest phenylalkylamine is phenylethylamine; this compound lacks significant central actions because it does not readily penetrate the blood-brain barrier, and what little does get into the

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brain is rapidly metabolized. In contrast, the addition of one more carbon unit, resulting in the simplest phenylisopropylamine or PIA, amphetamine, affords an agent that readily enters the brain and produces central effects (i.e., central stimulation). Further structural changes of this template molecule, depending upon the particular change, can result in retention of central stimulant effects (e.g., methamphetamine) or can shift its actions to those of a hallucinogen (e.g., DOM) or an empathogen (e.g., MBDB). The PIA moiety serves as a malleable skeleton whose pharmacological properties can be altered by the introduction of various other structural features. In general, homologation of the -methyl group of the PIAs to an -ethyl group diminishes their central stimulant or hallucinogenic potency but seems to have little effect on their empathogenic character. As such, it is not uncommon to find an -ethyl group present in the structures of phenylalkylamines (e.g., MDDB) and indolealkylamines (e.g.,

-ET) that retain empathogenic or MDMA-like qualities. Further homologation

of this -ethyl group to a longer homologue (e.g.,

-n-propyl or

-n-butyl homologue) results in a

further decrease in either hallucinogenic, central stimulant, or empathogenic potency, depending on the action of the parent agent; hence, it is fairly uncommon to find the longer-chain functionalities in potent psychoactive agents. Using the PIA template, other designer drugs have appeared that generally conform to established structure-activity considerations. For example, 1-(4-methylthiophenyl)-2-aminopropane (4-MTA; "flatliner") (Figure 13–2) has been shown to produce MDMA-like and PMMA-like, but not amphetamine-like or DOM-like, stimulus effects in animals (Khorana et al. 2004). On the other hand, 2C-T-7 ("blue mystic") (Figure 13–2) has been shown to be a hallucinogenic agent that lacks MDMA-like or amphetamine-like stimulus properties (Fantegrossi et al. 2005; Khorana et al. 2004). Using the PIA—more specifically, 1-phenyl-2-aminopropiophenone—cathinone as a new structural template, researchers have identified several novel agents. For example, the N-monomethyl analogue of MDC (i.e., 3,4-methylenedioxycathinone), 3,4-methylenedioxymethcathinone (i.e., 1-[3,4methylenedioxyphenyl]-2-aminopropiophenone, MDMC), has been shown to be an MDMA-like agent with amphetamine-like character (Dal Cason et al. 1997). MDMC, more recently termed methylone, is known on the street as "explosion" (Bossong et al. 2005; Cozzi et al. 1999). The parent indolealkylamine, tryptamine, has also been used as a template for agents that are receiving some notoriety. Of recent interest is the hallucinogen 5-methoxy-N,N-diisopropyltryptamine (5-OMe DIPT; "foxy methoxy") (Fantegrossi et al. 2006; Glennon et al. 1983; Shulgin and Carter 1980) (Figure 13–2). The

-ethyl homologue of -MeT,

-ethyltryptamine ( -ET; AET, ET) (Figure 13–2), has

been shown to produce a combination of effects (Glennon et al. 2006) (see below). To better characterize the stimulus effects produced by various phenylalkylamine-related designer drugs, such agents were examined in rats trained to discriminate one of three agents from vehicle in tests of stimulus generalization: DOM, (+)amphetamine, and PMMA. Substitution does not occur among these three agents regardless of which is used as a training drug, indicating that their stimulus actions are distinct. Tests of stimulus generalization with other phenylalkylamines showed that they substitute in one or more of these three training groups. The concept is summarized in Figure 13–3. For example, methamphetamine substituted only in the (+)amphetamine-trained animals and can be considered an A-type agent, whereas DOB substituted only in the DOM-trained animals and can be considered an H-like agent. By use of this classification scheme (Figure 13–3), Nexus now can be classified as a DOM-like hallucinogen, and methcathinone as an amphetamine-like stimulant. MDMA is best characterized as an A/P-type agent, in that it produces both amphetamine-like and PMMA-like effects. On the other hand, MBDB, a homologue of MDMA that lacks stimulant character (Nichols and Oberlender 1989), is defined as a PMMA-like agent (Rangisetty et al. 2001). Racemic MDA represents the common intersect because it produces all three actions; however, its individual optical isomers, R(–)MDA and S(+)MDA, are classified as H/P- and A/P-type agents, respectively (Glennon and Young 2002). PMMA and 1-(4-methoxyphenyl)-2-aminopropane (PMA) have been used to adulterate MDMA or have been represented on the street as MDMA-like substances; PMA produces PMMA-like effects. An example of a

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newer PMMA-like agent is 4-MTA. MDMC (methylone) is an A/P-type agent because it substituted both in (+)amphetamine- and PMMA-trained animals. Such a classification scheme also has been extended to indolealkylamine hallucinogens such as -ET. S(–) -ET substituted in (+)amphetamine- and PMMA-trained animals but not in DOM-trained animals, whereas R(+) -ET substituted in DOM- and PMMA-trained animals but not in (+)amphetamine-trained animals (Glennon et al. 2006). The specific mix of actions of certain agents may contribute to their attractiveness as drugs of abuse and may also explain the difficulty of classifying various PIAs and indolealkylamines with respect to their observed clinical effects (Glennon et al. 1997). Various new agents are appearing on the street; little is known about their actions and mechanisms of action. These agents (including their metabolites and synthetic by-products) require further investigation. But a classification of drug action and recognition that certain agents can produce multiple effects could impact treatment modalities for drug overdose. One last and important note regarding designer drugs is that the identity of clandestine substances is not always as advertised. For example, tablets sold as MDMA have been found to include other agents (including MDA, PMA, MBDB, DOB, MDE, methamphetamine, and 5-OMe DIPT) in addition to MDMA, or instead of MDMA (Cheng et al. 2006; Tanner-Smith 2006). When the identity of an ingested substance is unknown, this creates a significant problem not only from a toxicity and treatment standpoint, but it also confounds self-reports of the pharmacological effects and effective dosages of street drugs.

CONCLUSION Hallucinogens/psychotomimetics represent a diverse group of agents that are perhaps best understood by subdividing them into several categories (e.g., PCP-like psychotomimetics, cannabinoids, cholinergic hallucinogens, classical or serotonergic hallucinogens). The agents that generally come to mind when one hears the term hallucinogen, such as LSD and mescaline, are categorized as classical hallucinogens. Even though the agents in this latter class do not necessarily produce identical effects, they do seem to produce a common effect that represents the activation of 5-HT2A receptors in the brain. Structural modification of these agents modulates their potency and action. That is, certain structurally related designer drugs produce hallucinogenic, central stimulant, and/or other actions, depending upon their pendant substituents, and the effects of these phenylalkylamines and indolealkyamines should be considered when addressing or treating hallucinogen abuse.

KEY POINTS Hallucinogens (sometimes referred to as psychotomimetics) represent a very large and (chemically and pharmacologically) heterogeneous class of agents that can produce distinctive, and not necessarily identical, behavioral effects. No animal assay has yet been identified that reliably identifies hallucinogens as a class, but drug discrimination studies have aided the classification of such substances. Hallucinogens/psychotomimetics can, depending upon the particular agent, act via one of several different types of brain mechanisms. One of the largest categories of hallucinogens is the classical hallucinogens. Classical hallucinogens are made up mainly of indolealkylamines and phenylalkylamines. Indolealkylamine hallucinogens include tryptamine derivatives (e.g., N,N-dimethyltryptamine [DMT]) and lysergamides (e.g., lysergic acid diethylamide [LSD]); phenylalkylamine hallucinogens consist of phenylethylamines (e.g., mescaline) and phenylisopropylamines (e.g., 1-[2,5-dimethoxy4-methylphenyl]-2-aminopropane [DOM] and 1-[4-bromo-2,5-dimethoxyphenyl]-2-aminopropane [DOB]). The classical hallucinogens share a common ability to bind at a particular population of serotonin receptors (i.e., serotonin type 2A receptors) and act in an agonist fashion. Structural modification of indolealkylamines and phenylalkylamines can result in substances (i.e., designer drugs or controlled substance analogues) with hallucinogenic, central stimulant, and/or

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empathogenic character. Novel designer drugs include derivatives of indolealkylamines and phenylalkylamines. Designer drugs can produce one or more of several different (e.g., hallucinogenic, central stimulant, empathogenic) pharmacologically relevant effects, and the effect(s) produced by such drugs is highly dependent upon the particular substitution pattern of the agent. That is, indolealkylamines and phenylalkylamines serve as malleable templates, and specific substituents appended to these structures determine what effect(s) the agent produces.

REFERENCES Bossong MG, van Dijk JP, Niesink RJ: Methylone and mCPP, two new drugs of abuse? Addict Biol 10:321–323, 2005 [PubMed] Brimblecombe RW, Pinder RM: Hallucinogenic Agents. Bristol, England, Wright-Scientechnica, 1975 Cheng JY, Chan MF, Chan TW, et al: Impurity profiling of ecstasy tablets seized in Hong Kong by gas chromatography–mass spectrometry. Forensic Sci Int 162:87–94, 2006 [PubMed] Cozzi NV, Slevert MK, Shulgin AT, et al: Inhibition of plasma membrane monoamine transporters by beta-ketoamphetamines. Eur J Pharmacol 381:63–69, 1999 [PubMed] Dal Cason TA, Young R, Glennon RA: Cathinone: an investigation of several N-alkyl and methylenedioxy-substituted analogs. Pharmacol Biochem Behav 58:1109–1116, 1997 Fantegrossi WE, Harrington AW, Eckler JR, et al: Hallucinogen-like actions of 2,5-dimethoxy4-(n)-propylthiophenethylamine (2C-T-7) in mice and rats. Psychopharmacology (Berl) 181:496–503, 2005 [PubMed] Fantegrossi WE, Harrington AW, Kiessel CL, et al: Hallucinogen-like actions of 5-methoxyN,N-diisopropyltryptamine in mice and rats. Pharmacol Biochem Behav 83:122–129, 2006 [PubMed] Fiorella D, Rabin RA, Winter JC: The role of 5-HT2A and 5HT2C receptors in the stimulus effects of hallucinogenic drugs, I: antagonist correlation analysis. Psychopharmacology (Berl) 121:347–356, 1995 [PubMed] Glennon RA: Animal models for assessing classical hallucinogens, in Animal Models for the Assessment of Psychoactive Drugs. Edited by Boulton AA, Baker GB, Wu PH. Clifton, NJ, Humana Press, 1992, pp 345–381 Glennon RA: Classical hallucinogens: an introductory overview. NIDA Res Monogr 146:4–32, 1994 [PubMed] Glennon RA: Classical hallucinogens, in Pharmacological Aspects of Drug Dependence (Handbook of Experimental Pharmacology, Vol 118). Edited by Schuster CR, Kuhar MJ. Berlin, Springer, 1996, pp 343–372 Glennon RA: Arylalkylamine drugs of abuse: an overview of drug discrimination studies. Pharmacol Biochem Behav 64:251–256, 1999 [PubMed] Glennon RA: Hallucinogens, stimulants, and related drugs of abuse, in Foye's Principles of Medicinal Chemistry, 5th Edition. Edited by Williams DA, Lemke TL. Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 434–452 Glennon RA: The pharmacology of serotonergic hallucinogens and "designer drugs," in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith M, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 271–285 Glennon RA, Dukat M: Serotonin receptors and drugs affecting serotonergic neurotransmission, in Foye's Principles of Medicinal Chemistry, 5th Edition. Edited by Williams DA, Lemke TL. Philadelphia, PA,

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Lippincott Williams & Wilkins, 2002, pp 315–337 Glennon RA, Young R: Effect of 1-(3,4-methylenedioxyphenyl)-2-aminopropane and its optical isomers in PMMA-trained rats. Pharmacol Biochem Behav 72:307–311, 2002 [PubMed] Glennon RA, Young R, Jacyno JM, et al: DOM-Stimulus generalization to LSD and other hallucinogenic indolealkylamines. Eur J Pharmacol 86:453–459, 1983 [PubMed] Glennon RA, Young R, Dukat M, et al: Initial characterization of PMMA as a discriminative stimulus. Pharmacol Biochem Behav 57:151–158, 1997 [PubMed] Glennon RA, Bondareva T, Young R:

-Ethyltryptamine ( -ET) as a discriminative stimulus in rats.

Pharmacol Biochem Behav 85:448–453, 2006 [PubMed] Hoffer A, Osmond H: The Hallucinogens. New York, Academic Press, 1967 Hollister LE: Chemical Psychoses. Springfield, IL, Charles C Thomas, 1968 Ismaiel AM, De Los Angeles J, Teitler M, et al: Antagonism of the 1-(2,5-dimethoxy-4-methylphenyl)-2aminopropane stimulus with a newly identified 5-HT2 - versus 5-HT1C -selective antagonist. J Med Chem 36:2519–2525, 1993 [PubMed] Jacob P III, Shulgin AT: Structure-activity relationships of the classical hallucinogens and their analogs, in Hallucinogens: An Update. Edited by Lin GC, Glennon RA. Washington, DC, U.S. Department of Health and Human Services, 1994, pp 74–91 Khorana N, Pullagurla MR, Dukat M, et al: Stimulus effects of three sulfur-containing psychoactive agents. Pharmacol Biochem Behav 78:821–826, 2004 [PubMed] Lin GC, Glennon RA (eds): Hallucinogens: An Update. Washington, DC, U.S. Department of Health and Human Services, 1994 Nelson DL, Lucaites VL, Wainscott DB, et al: Comparisons of hallucinogenic phenylisopropylamine binding affinities at cloned human 5-HT2A, 5-HT2B, and 5-HT2C receptors. Naunyn Schmiedebergs Arch Pharmacol 359:1–6, 1999 [PubMed] Nichols DE, Oberlender R: Structure-activity relationships of MDMA-like substances. NIDA Res Monogr 94:1–29, 1989 [PubMed] Prisinzano TE: Psychopharmacology of the hallucinogenic sage Salvia divinorum. Life Sci 78:527–531, 2005 [PubMed] Rangisetty JB, Bondarev ML, Chang-Fong J, et al: PMMA-stimulus generalization to the optical isomers of MBDB and 3,4-DMA. Pharmacol Biochem Behav 69:261–267, 2001 [PubMed] Riba J, Barbanoj MJ: Bringing ayahuasca to the clinical research laboratory. J Psychoactive Drugs 37:219–230, 2005 [PubMed] Schreiber R, Brocco M, Millan MJ: Blockade of the discriminative stimulus effects of DOI by MDL 100,907, and the 'atypical' antipsychotics clozapine and risperidone. Eur J Pharmacol 264:99–102, 1994 [PubMed] Shulgin AT, Carter MF: N,N-Diisopropyltryptamine (DIPT) and 5-methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT). Two orally active tryptamine analogs with CNS activity. Commun Psychopharmacol 4:363–369, 1980 Shulgin A, Shulgin A: PiHKAL. Berkeley, CA, Transform Press, 1991 Shulgin A, Shulgin A: TiHKAL. Berkeley, CA, Transform Press, 1997 Siva Sankar DV: LSD: A Total Study. Westbury, NY, PJD Publications, 1975 Tanner-Smith EE: Pharmacological content of tablets sold as "ecstasy": results from an online testing

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service. Drug Alcohol Depend 83:247–254, 2006 [PubMed] Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, et al: Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport 9:3897–3902, 1998 [PubMed] Yan F, Roth BL: Salvinorin A: novel and highly selective kappa-opioid receptor agonist. Life Sci 75:2615–2619, 2004 [PubMed]

SUGGESTED READING Glennon RA: Classical hallucinogens: an introductory overview. NIDA Res Monogr 146:4–32, 1994 Glennon RA: Classical hallucinogens, in Pharmacological Aspects of Drug Dependence (Handbook of Experimental Pharmacology, Vol 118). Edited by Schuster CR, Kuhar MJ. Berlin, Springer, 1996, pp 343–372 Glennon RA: Hallucinogens, stimulants, and related drugs of abuse, in Foye's Principles of Medicinal Chemistry, 5th Edition. Edited by Williams DA, Lemke TL. Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 434–452 Nichols DE: Hallucinogens. Pharmacol Ther 101:131–181, 2004. Shulgin A, Shulgin A: PiHKAL. Berkeley, CA, Transform Press, 1991 Shulgin A, Shulgin A: TiHKAL. Berkeley, CA, Transform Press, 1997 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Michael F. Weaver, Sidney H. Schnoll: Chapter 14. Hallucinogens and Club Drugs, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.347400. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Hallucinogens and Club Drugs Michael F. Weaver, M.D. Sidney H. Schnoll, M.D., Ph.D.

HALLUCINOGENS AND CLUB DRUGS: INTRODUCTION Drugs considered hallucinogens are a diverse group of compounds (Table 14–1) including lysergic acid diethylamide (LSD), designer drugs, and many others that produce perceptual distortions (rarely complete hallucinations). Phencyclidine (PCP) and ketamine are dissociative anesthetics that produce perceptual distortions similar to hallucinogens, resulting in their being classified as hallucinogens. Designer drugs are synthetic compounds that are chemically related to stimulants, often with additions to the phenyl ring of amphetamine that cause them to have hallucinogen properties. These ring substitutions, such as are found in methylenedioxymethamphetamine (MDMA; "ecstasy"), can produce perceptual distortions. Club drugs are licit and illicit drugs from different classes that are used primarily by young adults in bars, clubs, concerts, and dance parties or "raves." The National Institute on Drug Abuse (NIDA) has identified six drugs as club drugs (Table 14–2), including some hallucinogens (LSD, MDMA). However, the club drug scene changes rapidly and can include prescription and over-the-counter drugs (Table 14–3). There is wide geographic variation in popularity of different club drugs. These substances are used illicitly in those settings due to the perception that they enhance the sensory experience at dance parties where strobe lights, glow sticks, and techno music (wordless music with a driving beat) are part of the overall event.

HALLUCINOGENS There are many types of hallucinogens, including naturally occurring plant and animal derivatives, synthetic drugs, and designer drugs. The prototypical hallucinogens are LSD, psilocybin, and mescaline; LSD is labeled a club drug by NIDA. Designer drugs are synthetic derivatives of federally controlled substances, created by slight alterations in the molecular structure and produced illegally in clandestine laboratories. Designer drugs have some psychoactive properties and cause visual disturbances but are not true hallucinogens like LSD (Beebe and Walley 1991). Hallucinogens may be taken orally, smoked, or injected. Some hallucinogens are derived from plants and may be consumed in this organic form (Stephens 1999). Very potent hallucinogens, such as LSD, may exert their effects from even a single drop touched to the tongue. Hallucinogen abuse dropped off precipitously in the mid- and late 1970s and remained at low levels during the 1980s. A U.S. study reported in 2006 found that lifetime LSD use (13%) was second only to ecstasy use (14%) by young adults ages 16–23 years (Wu et al. 2006). Use of LSD is associated with frequent heavy alcohol use and high-risk sexual behavior (Rickert et al. 2003) as well as criminal activity (Wu et al. 2006).

Acute Intoxication Recreational users of hallucinogens describe many different experiences from their hallucinogen use. Perceptual distortions are more common than hallucinations (Table 14–4). Some users have described existential experiences such as feelings of oneness with the universe or great understanding.

Signs and symptoms Hallucinogens produce perceptual distortions and cognitive changes with a clear sensorium and without

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impairment in level of consciousness or attention (Abraham et al. 1996). The quality of the hallucinogeninduced psychedelic state, or "trip," is influenced by the mood and environment of the user at the time of induction (set and setting; Zinberg 1980). A bad trip can be caused by fear, anxiety, or anger at the time the drug is taken; most bad trips can be handled without medication by a friend, nurse, or physician. It may be difficult to distinguish between a bad trip and an acute psychotic reaction. Reactions to hallucinogenic drugs are idiosyncratic, with periods of lucidity alternating with periods of intense reaction to the drug. Individual reactions to the hallucinogen vary according to the purity of the drug taken, the dose, and the setting. Generally, reactions are most intense and frequent in the early part of a trip, leading to a peak and then longer periods of lucidity with gradual clearing of the drug. Acute physiological complications of hallucinogen intoxication rarely require medical treatment. However, malignant hyperthermia and seizures may occur. Agitation, dry skin, and increased muscle tension are warning signs for hallucinogen hyperthermia. Clinical features of hallucinogen intoxication are in Table 14–4.

Treatment It is important to make physical contact with the patient (e.g., holding hands) when treating a bad trip; this may be the only means of contact with someone who is having very severe hallucinations. The patient may react suddenly or violently to a touch, and the contact person should be alert for this. The physical space in which treatment takes place should be quiet, softly lit, and away from large groups of people; excessive stimuli may overwhelm the patient. Absence of stimuli, however, may intensify the hallucinations. Deep, slow breathing may be helpful as a distraction. Try to make contact with the patient during lucid intervals and maintain this contact into the intense periods of drug reaction. Efforts to make contact with the patient during an intense period are generally not fruitful. Severe agitation may be treated with a benzodiazepine or haloperidol. As with any drug intoxication or overdose, if verbal contact can be made, ascertain what was taken, how much was taken, and how long ago it was taken. It may be helpful to have parents or friends retrieve a sample from the same batch and to talk to others who took the same dose at the same time.

Long-Term Consequences The long-term consequence most commonly associated with hallucinogen use is flashbacks. A flashback is an episode during which certain aspects of a previous hallucinogenic experience are reexperienced unexpectedly. The content varies widely and may include emotional or somatic components but most often involves reexperience of perceptual effects. This may consist of afterimages, trails behind moving objects, flashes of color, or lights in the peripheral visual fields. These episodes last several seconds to several minutes and are self-limited. Triggers include stress, exercise, use of other drugs (especially marijuana), or entering a situation similar to the original drug experience. Flashbacks may also occur spontaneously and their unpredictability often provokes anxiety when they occur. Flashbacks are fairly rare and tend over time to decrease in frequency, duration, and intensity as long as no additional hallucinogen is taken (Strassman 1984). Flashbacks are unlikely to occur more than 1 year after the original hallucinogen experience. Treatment of flashbacks consists of supportive care, including reassurance that the episode will be brief. Benzodiazepines help reduce anxiety, but haloperidol can worsen flashbacks (Moskowitz 1971). Hallucinogen use may result in long-term psychiatric consequences, such as anxiety, depression, or psychosis. The risk of a prolonged psychiatric reaction depends on the user's underlying predisposition to develop psychopathology, the amount of prior hallucinogen use, the use of other drugs, as well as the dose and purity of the hallucinogen taken (Strassman 1984). Patients may present with apathy, hypomania, paranoia, delusions, hallucinations, formal thought disorder, or dissociative states. Treatment of prolonged anxiety, depression, or psychosis is the same as when these conditions are not associated with hallucinogen use.

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PCP and ketamine are arylcyclohexylamines, which are dissociative anesthetics that produce perceptual distortions similar to hallucinogens, as well as other effects. PCP at various times has achieved popularity as a street drug and is frequently sold in mixtures with other drugs (Schnoll 1980). Its use waxes and wanes because of its unpredictable effects. Ketamine is a derivative of PCP that is less potent and shorter-acting and is still used therapeutically in medical settings as an anesthetic in humans (Chen et al. 1959). Ketamine use has a low prevalence among adolescents in the general population, but use appears to be concentrated among young adults attending clubs or parties, including raves. It is labeled a club drug by NIDA. Ketamine users are older (in their 20s as opposed to teens), employed, and better educated compared with most other club drug users (Dillon et al. 2003). PCP and ketamine can be taken orally or intravenously, smoked, or inhaled. Reasons cited for taking them are to enhance self-exploration as well as to induce relaxation and pleasure (Dalgarno and Shewan 1996). The PCP experience is regarded as pleasant only half the time and as aversive the other half, but some users report that this unpredictability of effects is an attractive feature (Carroll 1985).

Acute Intoxication Signs and symptoms PCP produces brief dissociative psychotic reactions, similar to schizophrenic psychoses. These reactions are characterized by changes in body image (feeling that the body is made of wood, plastic, or rubber) and possible feelings of spiritual separation from the body. At higher doses, users have great difficulty differentiating between themselves and their surroundings. Some users have religious experiences while intoxicated, such as feelings of meeting God or of impending death (Gorelick et al. 1986). Ketamine effects include profound changes in consciousness and psychotomimetic effects similar to those of PCP, including out-of-body experiences. In low-dose intoxication, the patient presents with nystagmus, confusion, ataxia, and sensory impairment. This is the only drug of abuse that causes a characteristic vertical nystagmus (it can also cause horizontal or rotatory nystagmus), which helps to identify it as the cause when a patient presents with intoxication by an unknown drug. Moderate PCP intake may lead to a catatonic-like state, with the patient staring blankly and not responding to stimuli; the eyes remain open, even when the patient is in a comatose state. In high doses, the drug produces seizures and severe hypertension. The hypertension should be treated vigorously because it may cause hypertensive encephalopathy or intracerebral bleeding. PCP can also cause life-threatening hyperthermia, with temperatures above 106˚F, which may occur many hours after use. A dissociative phenomenon occurs occasionally, with PCP abusers exhibiting dangerous or violent behaviors (Marrs-Simon et al. 1988). The patient also may appear psychotic. Previous psychiatric history is associated with a higher likelihood for assaultive behavior from PCP use (McCardle and Fishbein 1989). Levels of consciousness may fluctuate rapidly while the patient is recovering from the intoxication. The effects of PCP can last for several days. Ketamine can induce a state of virtual helplessness and pronounced lack of coordination. This is known to users as "being in a K-hole" and can be problematic if the user is in a public setting (Jansen 1993).

Treatment The most effective treatment of PCP intoxication is to increase its urinary excretion by acidifying the urine with ammonium chloride or ascorbic acid (Weaver and Schnoll 2007). Urine acidification should only be performed after it is determined that the patient does not have myoglobinuria (indicating rhabdomyolysis), to prevent the development of acute renal failure. Some practitioners feel that the benefits of urine acidification are outweighed by the risks, especially in patients with hepatic or renal impairment. If the patient is at low risk for hepatic or renal disease, the urine pH should be monitored

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and kept around 5.5, after which a diuretic can be administered to enhance excretion. The urine should be checked for the presence of PCP to ensure that it is being excreted. PCP can be deposited in adipose tissue and released over time, which may result in a prolonged state of confusion that can last for weeks; urine acidification may be helpful to deplete the reserve drug. In a patient who is hypertensive due to PCP, intravenous antihypertensive medications should be administered to reduce blood pressure. Psychotic behavior can be treated with haloperidol. If the patient is severely agitated and poses a potential threat to self or others, haloperidol or lorazepam is effective to control agitation; barbiturates may be even more efficacious (Olney et al. 1991).

Long-Term Consequences Phencyclidine organic mental disorder is a mental impairment that may result from chronic PCP use (Weaver and Schnoll 2007). Characteristics include memory deficits, confusion or reduced intellectual function, assaultiveness, visual disturbances, and speech difficulty. The most common speech difficulty is blocking, which is the inability to retrieve the proper words. The course is variable.

STIMULANTS Stimulants are drugs that stimulate the central nervous system (CNS) to produce enhanced psychomotor activity. Methamphetamine is a stimulant that is classified as a club drug by NIDA. Ecstasy (MDMA) is a designer drug that is also a stimulant but has some hallucinogen-like effects and is classified as a club drug by NIDA. Methylphenidate is a prescription stimulant that is used primarily for treatment of attention-deficit disorder and is abused at parties and clubs, although it has not been classified as a club drug by NIDA. Pseudoephedrine is an over-the-counter stimulant found in cough and cold preparations that is abused by teenagers. Stimulants are typically taken as tablets when used as club drugs. Methamphetamine can be intranasally insufflated (sniffed, snorted) or smoked as well as taken orally.

Acute Intoxication Signs and symptoms The short-term complications of methamphetamine and other stimulants are due to increased sympathomimetic effects (Table 14–5). Repeated use of low doses of stimulants can result in exaggerated startle reactions, dyskinesias, and postural abnormalities (Weaver and Schnoll 1999). Toxicity may be related to additives to the designer drugs, including ketamine and LSD.

Treatment The acutely intoxicated stimulant user should be approached in a subdued manner; never speak in a loud voice or move quickly, never approach the patient from behind, and try to avoid touching the patient unless absolutely sure it is safe to do so (Weaver et al. 1999). Treatment for acute toxicity includes acute stabilization of airway, breathing, and circulation; activated charcoal; seizure control with benzodiazepines; aggressive management of hypertension with

and

antagonists or vasodilators; management of hyperthermia; and consideration of urine acidification.

Long-Term Consequences High-dose stimulant use over long periods of time causes neurophysiological changes in brain systems; CNS effects can take months to resolve, and occasionally do not resolve, after cessation of stimulant use. As an example, a study in twins found that after at least 1 year of abstinence, the abusing twin had deficits in attention and motor skills as compared with the nonabusing twin (Toomey et al. 2003). Brain imaging of methamphetamine users has shown structural deficits, including gray matter deficits in the cingulate, limbic, and paralimbic cortices and significant reductions in hippocampal volume (Thompson et al. 2004).

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Chronic use of MDMA can lead to a paranoid psychosis that is clinically indistinguishable from schizophrenia; it is usually reversible after a prolonged drug-free state (Buchanan and Brown 1988). Several studies suggest that MDMA use (possibly in conjunction with marijuana) can lead to cognitive decline in otherwise healthy young people (Gouzoulis-Mayfrank et al. 2000). This neurotoxicity has been described to occur with typical recreational doses. An abstinence syndrome can occur with chronic stimulant use. The severity and duration of withdrawal depend on the intensity of the preceding months of chronic abuse and the presence of predisposing psychiatric disorders that amplify withdrawal symptoms. Abrupt discontinuation of stimulants does not cause gross physiological sequelae. If marked depression persists longer than 1 week after withdrawal, the patient should be evaluated carefully to determine if he or she is "self-medicating" an underlying depression, which then should be treated with a specific antidepressant. The clinical features of chronic stimulant use include depression, fatigue, poor concentration, and mild parkinsonian features such as myoclonus (inappropriate, spontaneous muscle contractions), tremor, or bradykinesia (slowing of movements). Patients presenting with these signs should be suspected of stimulant abuse and screened carefully (Weaver and Schnoll 1999). Long-term methamphetamine dependence can cause neurotoxicity even in patients who are no longer users (Ernst et al. 2000).

-HYDROXYBUTYRATE -Hydroxybutyrate (GHB) is a sedative that is both a precursor and a metabolite of -aminobutyric acid (GABA). It has been used as a sleep aid as well as for treatment of narcolepsy (Lammers et al. 1993). It also increases episodic secretion of growth hormone, so some bodybuilders use it to promote muscle growth. It is relatively easy to manufacture from common household products, although improper manufacture may result in unintended toxic by-products. NIDA has labeled GHB a club drug. GHB is ingested orally as a liquid, is rapidly absorbed, and reaches peak plasma concentrations in 20–60 minutes. Desired effects last for around 3 hours and repeated use may prolong its effects. Users report that GHB induces a pleasant state of relaxation and tranquility. Its effects have been likened to those of alcohol, another GABAlike drug (McCabe et al. 1971), with placidity, mild euphoria, mild numbing, pleasant disinhibition, and an enhanced tendency to verbalize.

Acute Intoxication The dose-response curve for GHB is exceedingly steep, so small increases in the amount ingested may lead to significant intensification of effects and onset of CNS depression. GHB has an extremely small therapeutic index, and as little as double the euphorigenic dose may cause serious CNS depression. Furthermore, the drug has synergistic effects with alcohol and other drugs, increasing the chance of overdose.

Signs and symptoms Clinicians should remember to ask about GHB use, especially in younger people. Because GHB is not detectable by routine drug screening, this history is essential. Clinical features of GHB intoxication are in Table 14–6. Death may result from overdose, and increasing numbers of deaths have been linked to GHB (Li et al. 1998).

Treatment In cases of acute GHB intoxication, physicians should provide physiological support and maintain a high index of suspicion for intoxication with other drugs. Most patients who overdose on GHB recover completely if they receive proper medical attention. Management of GHB ingestion in a spontaneously breathing patient includes oxygen supplementation, intravenous access, and comprehensive physiological and cardiac monitoring (Li et al. 1998). Attempt to keep the patient stimulated; use atropine for persistent symptomatic bradycardia. Admit the patient to the hospital if he or she is still intoxicated after 6 hours; discharge the patient (with plans for follow-up) if he or she is clinically well in 6 hours. Patients whose breathing is labored should be managed in the intensive care unit.

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The most dangerous effects of GHB use often occur with the use of other drugs. Concurrent use of sedatives or alcohol may increase the risk of vomiting, aspiration, or cardiopulmonary depression; the use of GHB and stimulants may increase the risk of seizure.

Long-Term Consequences Some individuals develop physiological dependence on GHB, although this requires use multiple times a day. The symptoms of withdrawal include anxiety, tremor, insomnia, and "feelings of doom," which may persist for several weeks after stopping the drug (Galloway et al. 1997). Severe withdrawal involves agitation, delirium, and psychosis (McDaniel and Miotto 2001). GHB withdrawal should be treated with benzodiazepines; very high doses may be required (Dyer et al. 2001). Antipsychotics or pentobarbital (Sivilotti et al. 2001) may have some utility in treatment of severe GHB withdrawal.

PRESCRIPTION DRUGS Flunitrazepam (Rohypnol, roofies) is a short-acting benzodiazepine that is available by prescription in South America and Europe but not in the United States. It is labeled a club drug by NIDA. Some prescription medications, although not officially listed as club drugs by NIDA, are used at parties and clubs (Table 14–3). These include benzodiazepines (alprazolam, diazepam), opioids (hydrocodone, oxycodone), and stimulants (methylphenidate, amphetamine). Over-the-counter preparations containing dextromethorphan (Bobo et al. 2003) or pseudoephedrine may also be used as club drugs. Teenagers may take bottles of medications from their parents' medicine cabinets to parties to distribute to friends for recreational use, a practice known as pharming.

Acute Intoxication Signs and symptoms The clinical features of acute benzodiazepine intoxication include slurred speech, incoordination, unsteady gait, and impaired attention or memory; severe overdose may lead to stupor or coma. Psychiatric manifestations include inappropriate behavior, labile mood, and impaired judgment and social functioning. Physical signs include nystagmus and decreased reflexes. Prescription opioid analgesics may be abused and can lead to intoxication or overdose. OxyContin, an oral controlled-release formulation of oxycodone, has been abused by crushing the tablets and then snorting the powder; when taken in this way by individuals who have no tolerance to the drug, a single 80-mg dose (the highest strength available in a single tablet) can be fatal. Propoxyphene, meperidine, or tramadol can cause seizures. Acute opioid intoxication is characterized by decreased mental status, substantially decreased respiration, miotic pupils, and absent bowel sounds (Sporer 1999).

Treatment Initial management of intoxication and overdose involves general supportive care, including maintenance of an adequate airway, ventilation, and cardiovascular function. Following stabilization of respiratory and cardiac function, activated charcoal should be given to prevent further intestinal absorption of the ingested drug and to prevent active metabolites from being absorbed through enterohepatic recirculation (Jones and Volans 1999). A benzodiazepine antagonist, flumazenil (Romazicon), is available for the treatment of acute benzodiazepine intoxication. However, it may not completely reverse respiratory depression; it can provoke withdrawal seizures in patients with benzodiazepine dependence or, in a mixed overdose with tricyclic antidepressants, may precipitate arrhythmias that were suppressed by the sedative (Lheureux et al. 1992; Weinbroum et al. 1997). Intravenous naloxone is the drug of choice for management of opioid overdose. It is a relatively pure opioid antagonist that is highly lipid soluble, has a rapid onset of action, and is well absorbed intravenously, intramuscularly, or subcutaneously.

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Long-Term Consequences Prescription and over-the-counter club drugs are used primarily by teenagers and young adults opportunistically and intermittently in party settings. Few data are available about long-term physiological and psychological consequences of intermittent use of these drug classes (benzodiazepines, opioids, and stimulants) in the setting of polysubstance abuse. Clinical features of long-term use of benzodiazepines are similar to acute features but may be accompanied by a dementia consisting of recent and remote memory loss (Weaver et al. 1999). Long-term use of benzodiazepines can worsen underlying depression and anxiety (Rickels et al. 1999). Club drug users who abuse prescription benzodiazepines and opioids will often do so in an intermittent or chronic pattern of high doses that are obtained illegally. Chronic use can result in a withdrawal syndrome that often requires detoxification with cross-tolerant medication (clonazepam or phenobarbital for benzodiazepine withdrawal and methadone or buprenorphine for opioid withdrawal).

TREATMENT OF HALLUCINOGEN AND CLUB DRUG ADDICTION Treatment of hallucinogen abuse and dependence is often difficult due to the young age of most users and concurrent polysubstance abuse. Treatment involves similar components to that of other types of substance abuse, including individual counseling, support groups, and 12-step self-help group attendance. Patients who chronically abuse PCP display characteristics such as impulsiveness and poor interpersonal relationships (Weaver and Schnoll 2007). This may make successful treatment more challenging, but a treatment environment with a supportive structure can be helpful. Due to the dissociative effects of PCP, those who abuse it may have a sense of loss of contact with their bodies. Progressive relaxation techniques, yoga, and regular exercise may help patients in treatment to focus and improve their concentration (Weaver and Schnoll 2007). Treatment of club drug abuse and dependence is challenging for several reasons. The club drugs consist of several different classes of substances that vary in their psychological and physiological effects. The pattern of use is usually intermittent in social settings, so this may be perceived as less of a problem. Adolescents and young adults are the primary club drug users, so family members should be part of the treatment program. As with hallucinogens, treatment of club drug abuse and dependence involves modalities typically utilized in other types of substance abuse, including cognitive-behavioral therapy, motivational enhancement therapy, and 12-step self-help group facilitation. Mixing hallucinogen and club drug abusers together in treatment settings makes clinical sense, since the majority of users abuse multiple drugs. There is no pharmacological treatment available for hallucinogen abuse (Abraham et al. 1996). Most pharmacological agents have not proven significantly better than placebo for management of stimulant-dependent men and women (Heinzerling et al. 2006; Schuckit 1994). Treatment settings for hallucinogens and club drugs focus on behavioral components such as individual and group counseling. Contingency management is a strategy for promoting treatment compliance and/or drug abstinence in substance abusers. Individualized positive reinforcement (such as a monetary incentive or reduction in parole time) is contingent on drug abstinence. Patients receive voucher-based incentives for achieving a specified therapeutic goal, such as drug-free urine screenings. As the patient maintains abstinence, the abstinence becomes the primary reinforcer, and the vouchers are no longer necessary. This modality was first developed for treatment of cocaine abuse (Higgins et al. 1991) and has proven effective in increasing the period of continuous abstinence from methamphetamine (Roll et al. 2006) as well as other substances of abuse (Lussier et al. 2006). This may be an effective intervention for those who abuse hallucinogens and club drugs, but more research is required.

KEY POINTS There are many different types of hallucinogens, derived from different sources. Lysergic acid diethylamide (LSD) is the prototypical hallucinogen and is the most commonly abused.

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Hallucinogens cause perceptual distortions more than hallucinations, and "bad trips" do not often require medical treatment. Club drugs identified by the National Institute on Drug Abuse are LSD, ketamine, methamphetamine, methylenedioxymethamphetamine (MDMA), -hydroxybutyrate (GHB), and flunitrazepam. Other club drugs may include prescription opioids, benzodiazepines, and over-the-counter cold preparations. Intoxication or overdose from certain club drugs (GHB, opioids, benzodiazepines), especially in combination, may result in serious medical consequences and death. Treatment of hallucinogen and/or club drug abuse involves components such as individual counseling, support groups, and 12-step self-help group attendance.

REFERENCES Abraham HD, Aldridge AM, Gogia P: The psychopharmacology of hallucinogens. Neuropsychopharmacology 14:285–298, 1996 [PubMed] Beebe DK, Walley E: Substance abuse: the designer drugs. Am Fam Physician 43:1689–1698, 1991 [PubMed] Bobo WC, Miller SC, Jackson JC: Dextromethorphan as a drug of abuse, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 154–155 Buchanan JF, Brown CR: "Designer drugs": a problem in clinical toxicology. Med Toxicol Adverse Drug Exp 3:1–17, 1988 [PubMed] Carroll ME: PCP, the dangerous angel, in Encyclopedia of Psychoactive Drugs, Series 1. Edited by Snyder SH. New York, Chelsea House, 1985 Chen G, Ensor CR, Russell D, et al: The pharmacology of 1-(1-phenylcyclohexyl) piperidine-HCl. J Pharmacol Exp Ther 127:241–250, 1959 [PubMed] Dalgarno PJ, Shewan D: Illicit use of ketamine in Scotland. J Psychoactive Drugs 28:191–199, 1996 [PubMed] Dillon P, Copeland J, Jansen K: Patterns of use and harm associated with non-medical ketamine use. Drug Alcohol Depend 69:23–28, 2003 [PubMed] Dyer J, Roth B, Hyma BA: Gamma-hydroxybutyrate withdrawal syndrome. Ann Emerg Med 37:147–153, 2001 [PubMed] Ernst T, Chang L, Leonido-Yee M, et al: Evidence for long-term neurotoxicity associated with methamphetamine abuse: a 1H MRS study. Neurology 54:1344–1349, 2000 [PubMed] Galloway GP, Frederick SL, Staggers FE, et al: Gamma-hydroxybutyrate: an emerging drug of abuse that causes physical dependence. Addiction 92:89–96, 1997 [PubMed] Gorelick DA, Wilkins JN, Wong C: Diagnosis and treatment of chronic phencyclidine (PCP) abuse. NIDA Res Monogr 64:218–228, 1986 [PubMed] Gouzoulis-Mayfrank E, Daumann J, Tuchtenhagen F, et al: Impaired cognitive performance in drug free users of recreational ecstasy (MDMA). J Neurol Neurosurg Psychiatry 68:719–725, 2000 [PubMed] Heinzerling KG, Shoptaw S, Peck JA, et al: Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence. Drug Alcohol Depend 85:177–184, 2006 [PubMed] Higgins ST, Delaney DD, Budney AJ, et al: A behavioral approach to achieving initial cocaine abstinence. Am J Psychiatry 148:1218–1224, 1991 [PubMed] Jansen KLR: Non-medical use of ketamine. BMJ 306:601–602, 1993 [PubMed]

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Jones AL, Volans G: Management of self poisoning. BMJ 319:1414–1417, 1999 [PubMed] Lammers GJ, Arends J, Declerck AC, et al: Gammahydroxybutyrate and narcolepsy: a double-blind placebo-controlled study. Sleep 16:216–220, 1993 [PubMed] Lheureux P, Vranckx M, Leduc D, et al: Flumazenil in mixed benzodiazepine/tricyclic antidepressant overdose: a placebo-controlled study in the dog. Am J Emerg Med 10:184–188, 1992 [PubMed] Li J, Stokes S, Woeckener A: A tale of novel intoxication: a review of the effects of gammahydroxybutyric acid with recommendations for management. Ann Emerg Med 31:729–736, 1998 [PubMed] Lussier JP, Heil SH, Mongeon JA, et al: A meta-analysis of voucher-based reinforcement therapy for substance use disorders. Addiction 101:192–203, 2006 [PubMed] Marrs-Simon PA, Weiler M, Santangelo MA, et al: Analysis of sexual disparity of violent behavior in PCP intoxication. Vet Hum Toxicol 30:53–55, 1988 [PubMed] McCabe E, Layne E, Sayler D, et al: Synergy of ethanol and a natural soporific: gamma hydroxybutyrate. Science 171:404–406, 1971 [PubMed] McCardle L, Fishbein DH: The self-reported effects of PCP on human aggression. Addict Behav 14:465–472, 1989 [PubMed] McDaniel CH, Miotto KA: Gamma hydroxybutyrate (GHB) and gamma butyrolactone (GBL) withdrawal: five case studies. J Psychoactive Drugs 33:143–149, 2001 [PubMed] Moskowitz D: Use of haloperidol to reduce LSD flashbacks. Mil Med 136:754–756, 1971 [PubMed] Olney JW, Labruyere J, Wang G, et al: NMDA antagonist neurotoxicity: mechanism and prevention. Science 254:1515–1518, 1991 [PubMed] Rickels K, Lucki I, Schweizer E, et al: Psychomotor performance of long-term benzodiazepine users before, during, and after benzodiazepine discontinuation. J Clin Psychopharmacol 19:107–113, 1999 [PubMed] Rickert VI, Siqueira LM, Dale T, et al: Prevalence and risk factors for LSD use among young women. J Pediatr Adolesc Gynecol 16:67–75, 2003 [PubMed] Roll JM, Petry NM, Stitzer ML, et al: Contingency management for the treatment of methamphetamine use disorders. Am J Psychiatry 163:1993–1999, 2006 [Full Text] [PubMed] Schnoll SH: Street PCP scene: issues on synthesis and contamination. J Psychedelic Drugs 12:229–233, 1980 [PubMed] Schuckit MA: The treatment of stimulant dependence. Addiction 89:1559–1563, 1994 [PubMed] Sivilotti ML, Burns MJ, Aaron CK, et al: Pentobarbital for severe gamma-butyrolactone withdrawal. Ann Emerg Med 38:660–665, 2001 [PubMed] Sporer KA: Acute heroin overdose. Ann Intern Med 130:584–590, 1999 [PubMed] Stephens RS: Cannabis and hallucinogens, in Addictions: A Comprehensive Guidebook. Edited by McCrady BS, Epstein EE. New York, Oxford University Press, 1999, pp 121–140 Strassman RJ: Adverse reactions to psychedelic drugs: a review of the literature. J Nerv Ment Dis 172:577–595, 1984 [PubMed] Thompson PM, Hayashi KM, Simon SL, et al: Structural abnormalities in the brains of human subjects who use methamphetamine. J Neurosci 24:6028–6036, 2004 [PubMed] Toomey R, Lyons MJ, Eisen SA, et al: A twin study of the neuropsychological consequences of stimulant abuse. Arch Gen Psychiatry 60:303–310, 2003 [PubMed]

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Weaver MF, Schnoll SH: Stimulants: amphetamines and cocaine, in Addictions: A Comprehensive Guidebook. Edited by McCrady BS, Epstein EE. New York, Oxford University Press, 1999, pp 105–120 Weaver MF, Schnoll SH: Phencyclidine and ketamine, in Treatments of Psychiatric Disorders, 4th Edition. Edited by Gabbard GO. Washington, DC, American Psychiatric Publishing, 2007, pp 271–280 Weaver MF, Jarvis MA, Schnoll SH: Role of the primary care physician in problems of substance abuse. Arch Intern Med 159:913–924, 1999 [PubMed] Weinbroum AA, Flaishon R, Sorkine P, et al: A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose. Drug Saf 17:181–196, 1997 [PubMed] Wu LT, Schlenger WE, Galvin DM: Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths. Drug Alcohol Depend 84:102–113, 2006 [PubMed] Zinberg NE: The social setting as a control mechanism in intoxicant use. NIDA Res Monogr 30:236–244, 1980 [PubMed]

SUGGESTED READING Dance Safe: Available at http://www.dancesafe.org Strassman RJ: Adverse reactions to psychedelic drugs: a review of the literature. J Nerv Ment Dis 172:577–595, 1984 Wu LT, Schlenger WE, Galvin DM: Concurrent use of methamphetamine, MDMA, LSD, ketamine, GHB, and flunitrazepam among American youths. Drug Alcohol Depend 84:102–113, 2006 National Institute on Drug Abuse: Important information and resources on club drugs. Available at http://www.clubdrugs.org U.S. Office of National Drug Control Policy: Available at http://www.whitehousedrugpolicy.gov Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 15. Nicotine and Tobacco

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Tony P. George, Andrea H. Weinberger: Chapter 15. Nicotine and Tobacco, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.34 7930. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Nicotine and Tobacco Tony P. George, M.D., F.R.C.P.C. Andrea H. Weinberger, Ph.D.

NICOTINE AND TOBACCO: INTRODUCTION Although rates of tobacco use and dependence have been reduced substantially since the 1960s, one in five Americans continues to smoke. The prevalence of smoking appears to be substantially higher in persons with psychiatric and substance use disorders, and these individuals also have less success when they attempt smoking cessation. In this chapter we review the epidemiology of tobacco use and dependence and the pharmacological effects of nicotine and tobacco and discuss the clinical assessment of tobacco users. We then review behavioral and pharmacological treatments, including the U.S. Food and Drug Administration (FDA)–approved pharmacotherapies: nicotine replacement therapies (NRTs), sustained-release bupropion, and varenicline. Finally, we discuss the integration of tobacco dependence treatment into mental health settings with the view that tobacco dependence is a chronic medical disorder and that more effective treatment of this comorbidity in psychiatric disorders may require targeted treatments based on a better understanding of the pathophysiology of individual psychiatric disorders.

EPIDEMIOLOGY OF TOBACCO USE Cigarette smoking is the single largest preventable cause of morbidity and mortality in Western countries. In the United States, approximately 22% of the population are tobacco users, compared with a rate of 47% in 1965. Since the release of the Surgeon General's report in 1965, smoking prevalence has been substantially reduced, but this reduction appears to have slowed in recent years. Cigarette smoking is the most common (>90%) method of tobacco use (Centers for Disease Control and Prevention 2002; Giovino 2002), although other forms of tobacco are also commonly used, including pipe tobacco, cigars, and smokeless tobacco. Approximately 440,000 people in the United States die each year as a result of smoking-attributable medical illnesses such as lung cancer, chronic obstructive pulmonary disease, cardiovascular disease, and stroke. Economic and health care costs of tobacco use exceed $400 billion annually (Giovino 2002). Worldwide, it is estimated that approximately 1.1 billion people use tobacco on a regular basis, including approximately 65 million in the United States (Centers for Disease Control and Prevention 2002). Smoking is now increasing rapidly throughout the developing world, and it is estimated that current cigarette smoking will cause about 450 million deaths worldwide in the next 50 years. Reducing current smoking by 50% would prevent 20–30 million premature deaths in the first quarter of this century and 150 million in the second quarter (Centers for Disease Control and Prevention 2002). For most smokers, quitting is the single most important thing that can be done to improve health. The results of a recent epidemiological study in Norway suggest that even with sustained reductions in smoking consumption (>50%), there is little if any reduction in cardiovascular disease or lung or other smoking-related cancer risk (Tverdal and Bjartveit 2006), further substantiating the merits of quitting rather than reducing smoking.

MOLECULAR BIOLOGY AND PHARMACOLOGY OF NICOTINIC RECEPTORS Nicotine is the primary reinforcer in tobacco smoke, with contributions from over 4,000 components to the sensory (nonnicotinic) aspects of cigarette smoking. In tobacco dependence, the primary site of action of nicotine is the

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4 2

nicotinic acetylcholine receptor (nAChR), and the endogenous transmitter

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acting on nAChRs is acetylcholine. nAChRs in the central nervous system (CNS) are pentameric ion channel complexes (Leonard and Bertrand 2001), which are composed of two with the seven

subunits designated 2 – 9 and the three

and three

subunits,

subunits designated 2 – 4 . This produces

considerable diversity in subunit combinations, which may explain some of the region-specific and functional selectivity of nicotinic effects in the CNS. Activation of nAChRs leads to Na+/Ca2+ ion channel fluxes and neuronal firing. nAChRs are located presynaptically on several neurotransmitter-secreting neuron types in the CNS, including mesolimbic dopamine (DA) neurons that project from the ventral tegmental area to the nucleus accumbens (McGehee et al. 2006). In addition, nAChR activation on mesolimbic DA neurons leads to DA secretion in the nucleus accumbens. The regulation of mesolimbic DA neurons is depicted in Figure 15–1. FIGURE 15–1. Mesolimbic dopamine neurons and their regulation by nicotinic, cholinergic, GABAergic, and glutamatergic inputs.

ACh = acetylcholine; DA = dopamine; GABA = γ-aminobutyric acid; Glu = glutamate; NAc = nucleus accumbens; nAChR = nicotinic acetylcholine receptor; VTA = ventral tegmental area. At low concentrations of nicotine,

4 2

nAChR stimulation of afferent -aminobutyric acid (GABA)-ergic

projections onto mesoaccumbal DA neurons predominates, leading to reduced mesolimbic DA neuron firing and DA release. At higher nicotine concentrations,

4 2

nAChRs desensitize, and activation of

7

nAChRs on glutamatergic projections predominates, leading to increased mesolimbic DA neuron firing and DA secretion. Subsequently, within several milliseconds of activation by nicotine, nAChRs desensitize. After overnight abstinence, nAChRs resensitize, which presumably explains why most smokers report that the first cigarette in the morning is the most satisfying. Interestingly, recent positron emission tomography (PET) neuroimaging studies have shown that smoking two to three puffs from a cigarette produces saturation of nAChRs in the brain reward system (Brody et al. 2006), suggesting that although binding to central nAChRs is an important first step in the effects of nicotine, it is not a complete explanation for continued smoking behavior.

CLINICAL EFFECTS OF NICOTINE AND TOBACCO More than 90% of tobacco users are cigarette smokers and, although there is a subset of cigarette smokers who do not smoke every day, most cigarette smokers are daily users and have some degree of physiological dependence on nicotine (Rigotti 2002). degree of physiological dependence on nicotine (Rigotti 2002). Smokers typically describe a "rush" and feelings of alertness and relaxation when smoking, and it is well known that nicotine has both stimulating and anxiolytic effects, depending on

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basal level of arousal (Parrott 1998). Airway stimulation is an important aspect of smoking behavior and additives such as menthol enhance the experience by increasing the taste and reducing the harshness of smoked tobacco. Determination of nicotine dependence is typically accomplished clinically by historical documentation of daily smoking (typically, 10–40 cigarettes/day) for several weeks, evidence of tolerance (e.g., lack of aversive effects of nicotine, such as nausea), and the presence of symptoms of nicotine withdrawal upon smoking cessation. These withdrawal symptoms, which peak within 24 hours of cessation, include dysphoria, anxiety, irritability, decreased heart rate, insomnia (waking in the middle of the night), increased appetite, and craving for cigarettes. In addition, most dependent smokers state that they smoke their first cigarette of the day within 5 minutes of awakening. Timeline follow-back procedures (Sobell et al. 1988) and smoking diaries have been used successfully to monitor smoking consumption over time. Scales such as the Fagerström Test for Nicotine Dependence (Heatherton et al. 1991) allow assessment of the level of nicotine dependence, with scores of 4 or higher on a scale of 0–10 consistent with physiological dependence to nicotine. Nicotine craving and withdrawal can be reliably monitored using validated scales such as the Tiffany Questionnaire for Smoking Urges (Tiffany and Drobes 1991) and the Minnesota Nicotine Withdrawal Scale (Hughes and Hatsukami 1986). These scales also appear to have reasonable test-retest reliability and internal consistency among people with schizophrenia, compared with nonpsychiatric control smokers (Weinberger et al. 2007). Interestingly, the positive effects of cigarette smoking (e.g., taste, satisfaction) appear to be mediated by non-nicotine components of tobacco, such as tar (Dallery et al. 2003). In addition to positive reinforcement, withdrawal, and craving, there are several secondary effects of nicotine and tobacco use that may contribute to both maintenance of smoking and smoking relapse, such as mood modulation (e.g., reduction of negative affect), stress reduction, and weight control. In addition, conditioned cues can elicit the urge to smoke even after prolonged periods of abstinence. Specific effects might be most relevant to individuals focused on dietary restraint (weight reduction), or those with psychiatric disorders (mood modulation, cognitive enhancement, stress reduction). These secondary effects may present additional targets for pharmacological intervention in certain subgroups of smokers (e.g., schizophrenic, depressed, or overweight smokers).

PSYCHOSOCIAL TREATMENTS Behavioral therapies are based on the theory that learning processes operate in the development, maintenance, and cessation of smoking. Behavioral treatments for smoking can facilitate motivation to quit, provide an emphasis on the social and contextual aspects of smoking, and enhance overall success at smoking cessation (Patten and Brockman 2006). In most reviews and meta-analyses, 6-month quit rates with behavior therapies are 20%–25%, and behavior therapy typically increases quit rates up to twofold over control groups (see Lancaster and Stead 2006 for review). The primary goals of behavioral therapies in treatment of tobacco dependence include 1) providing necessary skills to smokers to aid them in quitting smoking; and 2) teaching skills to avoid smoking in high-risk situations. See Table 15–1 for a summary of behavioral treatments for tobacco dependence.

Brief Interventions and Self-Help Materials Brief advice has been found to increase the rate of smoking cessation (Fiore et al. 2000); therefore, it is recommended that doctors use the five As with all patients: ask patients if they smoke, advise patients to quit, assess patients' motivation level for quitting, assist with quit attempts, and arrange follow-up contacts. Providing self-help material is a form of brief intervention used to increase motivation to quit and impart smoking cessation skills. Several recent studies have documented that minimal behavioral interventions such as community support groups (Bakkevig et al. 2000), telephone counseling (Stead et al. 2006), and computer-generated, tailored self-help materials (Etter and Perneger 2001) can augment smoking cessation rates in controlled settings.

Motivational Interventions The goal of motivational interviewing (MI) interventions is to elicit change by addressing ambivalence,

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increasing intrinsic motivation for change, and creating an atmosphere of acceptance in which patients take responsibility for making changes happen. Brief MI interventions have been developed for smoking cessation (Rollnick et al. 1997), and there is some evidence for increased smoking cessation using MI techniques (Carpenter et al. 2004). Rollnick et al. (1997) reported that clinicians found MI interventions to be feasible and acceptable due to the brief nature of the intervention and the focus on patient responsibility and enhancement of the clinician–patient relationship.

Cognitive-Behavioral Therapies In cognitive-behavioral therapies, patients learn to anticipate situations in which they are likely to smoke and then enact a plan to cope with these situations using behavioral (e.g., substitution of behavior) and cognitive (e.g., challenging thoughts) techniques. Some degree of efficacy of cognitivebehavioral therapies in smokers with and without psychiatric and substance use disorders has been observed for both individual (Lancaster and Stead 2006) and group (Stead and Lancaster 2005) counseling formats.

Relapse Prevention A large number of smokers relapse within 6 months of quitting. Focusing on relapse prevention skills, including recognizing high-risk situations and coping with lapses can be included in initial smoking cessation treatment or following a quit attempt. Recent studies (Lancaster et al. 2006) have not found an overall benefit for including relapse prevention with smokers after a quit attempt and indicate that more work is needed in this area of treatment research.

PHARMACOLOGICAL TREATMENTS There are three FDA-approved classes of smoking cessation pharmacotherapies—nicotine replacement therapies (NRTs), sustained-release bupropion, and varenicline. Several other off-label and novel medications are also discussed in this section. See Table 15–1 for a summary of pharmacological treatments for tobacco dependence.

Nicotine Replacement Therapies The goal of NRT is to relieve tobacco withdrawal, which allows smokers to focus on habit and conditioning factors when attempting cessation. After the acute withdrawal period, NRT is gradually reduced so that patients experience fewer withdrawal symptoms. NRTs rely on systemic venous absorption and therefore do not produce the rapid, high levels of arterial nicotine achieved when cigarette smoke is inhaled. Thus, individuals are unlikely to become addicted to NRTs. NRTs should be discontinued if the individual resumes smoking, although safety concerns regarding smoking while using a patch appear to be less serious than previously thought. All commercially available forms of NRT are effective and increase quit rates by approximately 1.5- to 2.5-fold compared with placebo (Silagy et al. 2004). The transdermal patch, gum, and lozenge are available over the counter (OTC), whereas the nasal spray and inhaler are only available by prescription.

Nicotine gum Nicotine ingested orally is extensively metabolized on first pass through the liver. Nicotine polacrilex gum avoids this problem via buccal absorption. Nicotine gum was approved as an OTC medication in the United States in 1996, and contains 2 mg or 4 mg of nicotine that can be released from a resin by chewing. Nicotine gum should be administered by scheduled dosing (e.g., one piece of 2-mg gum/hour). The original recommended duration of treatment was 3 months, although many experts believe longer treatment is more effective. Nicotine absorption from the gum peaks 30 minutes after start of gum chewing . Venous nicotine levels from 2-mg and 4-mg gum are about one-third and two-thirds, respectively, of the steady-state (i.e., between cigarettes) levels of nicotine achieved with cigarette smoking. Nicotine via cigarettes is absorbed directly into the arterial circulation; thus, arterial levels from smoking are 5–10 times higher than those from the 2-mg and 4-mg gums. Absorption of nicotine in the buccal mucosa is decreased by an acidic environment, and patients should not use beverages

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(e.g., coffee, soda, juice) immediately before, during, or after nicotine gum use. Several placebo-controlled trials established the safety and efficacy of nicotine gum for smoking cessation (reviewed in Silagy et al. 2004). There appears to be some evidence to support using higher doses of nicotine gum (4-mg pieces) in more highly dependent cigarette smokers (25 cigarettes/day), which supports the idea of matching nicotine gum dose to dependence level of the smoker. Side effects from nicotine gum are rare and include those of mechanical origin (e.g., difficulty chewing, sore jaw) or local pharmacological origin (e.g., burning in mouth, throat irritation). Tolerance develops to most side effects over the first week, and education about proper use of the gum (e.g., do not chew too vigorously) decreases side effects.

Nicotine polacrilex lozenges Nicotine lozenges that deliver nicotine (2-mg and 4-mg preparations) by buccal absorption were approved for OTC use in the United States in 2002. Lozenges offer further flexibility for nicotine replacement options for smokers and are known to allow greater absorption of nicotine compared with nicotine gum. Mild throat and mouth irritation have been reported in preliminary trials (Shiffman et al. 2002). A 6-week, double-blind, placebo-controlled, randomized, controlled trial of 2-mg and 4-mg nicotine lozenges has shown their superiority to placebo lozenges (Shiffman et al. 2002), with significant reduction in nicotine craving and withdrawal. Furthermore, high doses of lozenges may be more efficacious in more highly dependent smokers, suggesting that lozenge dose can be matched with dependence level.

Nicotine transdermal patch The four available transdermal formulations take advantage of ready absorption of nicotine across the skin. Three of the patches are for 24-hour use and one is for 16-hour use. Starting doses are 21- to 22-mg/24-hour patch and 15-mg/16-hour patch. Patches are applied every morning. Nicotine via patches is slowly absorbed, such that on the first day venous nicotine levels peak 6–10 hours after administration. Thereafter, nicotine levels remain fairly steady, with a decline from peak to trough of 25%–40% with 24-hour patches. Nicotine levels obtained with the use of patches are typically half of those obtained by smoking. After 4–6 weeks on a high-dose patch (21 mg or 22 mg/24 hour, and 15 mg/16 hour), smokers are tapered to a middle dose (e.g., 14 mg/24 hours or 10 mg/16 hours), and then to the lowest dose after 2–4 more weeks (7 mg/24 hours or 5 mg/16 hours). Results of most studies indicate that abrupt cessation of the use of patches often causes no significant withdrawal; thus, tapering does not appear to be necessary (Silagy et al. 2004). The recommended total duration of treatment is usually 6–12 weeks. The overall efficacy of the nicotine transdermal patch (NTP) for smoking cessation has been well documented (Silagy et al. 2004). A meta-analysis of 17 randomized controlled trials in 1994 (Fiore et al. 2000) reported end-of-treatment abstinence rates for NTP of 27% versus 13% for placebo patch (odds ratio [OR] = 2.6) and 22% versus 9% at 6-month follow-up (OR = 3.0). The effects of active NTP were independent of patch type, treatment duration, tapering procedures, and behavioral therapy format or intensity, although it should be noted that behavioral treatment with patch enhanced outcomes, compared with patch alone. Significant adverse events with nicotine patches have not been found; the most common minor side effects have been skin reactions (50%), insomnia and increased or vivid dreams (15% with 24-hour patches), and nausea (5%–10%). Tolerance to these side effects usually develops within a week. Rotation of patch sites decreases skin irritation. Insomnia reported in the first week postcessation appears to be mostly due to nicotine withdrawal rather than the nicotine patch itself. A 24-hour patch can be removed before bedtime to determine if the insomnia is due to the nicotine patch. Without treatment, insomnia usually abates after 4–7 days. There appears to be little dependence liability associated with patch use, given that only 2% of patch users continue to use this product for an extended period after a cessation trial (West et al. 2001).

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Nicotine nasal spray Nicotine nasal spray is a nicotine solution in a nasal spray bottle similar to those used with saline sprays. This NRT was approved for treatment of nicotine dependence in the United States in 1996. Nasal spray delivers droplets that average about 1 mg of nicotine per administration, and the patient administers the spray (10 mg/mL) to each nostril every 4–6 hours. This formulation produces a more rapid rise in nicotine levels than does nicotine gum, and the rise in nicotine levels produced by nicotine spray falls between the levels produced by nicotine gum and cigarettes. Peak nicotine levels occur within 10 minutes, and venous nicotine levels are about two-thirds those of between-cigarette levels. Smokers may use the nasal spray ad lib up to 30 times/day for 12 weeks, including a tapering period. Randomized, double-blind, placebo-controlled trials of nasal spray compared with placebo spray (Silagy et al. 2004) have established the safety and efficacy of the nasal spray for smoking cessation. Both trials employed treatment for 3–6 months, and active nasal spray led to a doubling of quit rates during active use. Differences were reduced or absent with extended follow-up, suggesting the need for maintenance use of this agent. However, to date, such long-term studies have not been published. The major side effects from nicotine nasal spray are nasal and throat irritation, rhinitis, sneezing, coughing, and watering eyes. Nicotine nasal spray may have some dependence liability. In a controlled study by West et al. (2001), this prolonged use of nasal spray was determined to be nicotine dependence among 10% of smokers using the nasal spray; therefore, follow-up of smokers using nasal spray is recommended.

Nicotine vapor inhalers Nicotine vapor inhalers are cartridges (plugs) of nicotine (containing about 1 mg of nicotine each) placed inside hollow cigarette-like plastic rods. The cartridges produce a nicotine vapor when warm air is passed through them. Absorption from the nicotine inhaler is primarily buccal rather than respiratory. More recent versions of inhalers produce a rise in venous nicotine levels more rapidly than with nicotine gum but less rapidly than with nicotine nasal spray, with nicotine blood levels of about one-third that of between-cigarette levels. Smokers are instructed to puff continuously on the inhaler (0.013 mg/puff) during the day, and recommended dosing is 6–16 cartridges daily. The inhaler is to be used ad lib for about 12 weeks. No serious medical side effects have been reported with nicotine inhalers; 50% of subjects report throat irritation or coughing. Double-blind, placebo-controlled, randomized, controlled trials have demonstrated the superiority of nicotine vapor inhaler to placebo inhalers for smoking cessation (Silagy et al. 2004). Results revealed a two- to threefold increase in quit rates (17%–26%) at trial endpoint compared with placebo inhalers, but smaller differences at follow-up periods of 1 year or longer. These data support the short-term efficacy of nicotine vapor inhalers in cigarette smokers, but longer-term trials with the inhaler are needed. There is some modest concern about abuse liability based on long-term use of the product in fewer than 10% of smokers (West et al. 2001).

Sustained-release bupropion The phenylaminoketone, atypical antidepressant agent bupropion in the sustained-release (SR) formulation (Zyban) is a non-nicotine, first-line pharmacological treatment for nicotine-dependent smokers who want to quit smoking. The exact mechanism of action of this antidepressant agent in the treatment of nicotine dependence is unclear, but it is likely to involve dopamine and norepinephrine reuptake blockade (Ascher et al. 1995), as well as antagonism of high-affinity nAChRs (Slemmer et al. 2000). The goals of bupropion therapy are 1) smoking cessation, 2) reduction of nicotine craving and withdrawal symptoms, and 3) prevention of cessation-induced weight gain. The target dose of this agent in nicotine dependence is 300 mg/day (150 mg, two times a day). It is typically started 7 days prior to the target quit date at 150 mg/day, and then increased to 150 mg two times a day after 3–4 days. Unlike the NRTs, there is no absolute requirement that smokers completely

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cease smoking by the target quit date, though many smokers report a significant reduction in urges to smoke and craving, which facilitates cessation at the time of the target quit date when drug levels reach steady-state plasma levels. Some smokers gradually reduce their cigarette smoking over several weeks prior to quitting. There presently is little data about the subgroups of smokers for whom bupropion may have the most utility. A pivotal multicenter study by Hurt et al. (1997) established the efficacy and safety of bupropion SR for treatment of nicotine dependence, which led to its FDA approval in the United States in 1998. In a 7-week double-blind, placebo-controlled, multicenter trial, three doses of bupropion SR (100, 150, and 300 mg/day in two divided doses) in combination with weekly, individual cessation counseling were given to 615 cigarette smokers using at least 15 cigarettes per day. The end-of–trial, 7-day, pointprevalence cessation rates were 19.0%, 28.8%, 38.6%, and 44.2%, respectively, for placebo and 100 mg/day, 150 mg/day, and 300 mg/day bupropion dosages, respectively. At 1-year follow-up, cessation rates were 12.4%, 19.6%, 22.9%, and 23.1%, respectively. Bupropion treatment dose-dependently reduced weight gain associated with smoking cessation and significantly reduced nicotine withdrawal symptoms at the 150 mg/day and 300 mg/day dosages. The primary side effects reported with bupropion administration in cigarette smokers are headache, nausea and vomiting, dry mouth, insomnia, and agitation, most of which occur during the first week of treatment. The main contraindication for the use of bupropion is a past history of seizures of any etiology. The rates of de novo seizures are low with this agent (<0.5%), at doses of 300 mg/day or less, and have been observed when daily dosing exceeds 450 mg. The combination of bupropion SR with an NTP was evaluated in a double-blind, double placebocontrolled, randomized, multicenter trial (Jorenby et al. 1999). A total of 893 cigarette smokers, using at least 15 cigarettes/day, were randomly selected to one of four experimental groups: 1) placebo bupropion (0 mg/day) plus placebo patch; 2) bupropion (300 mg/day) plus placebo patch; 3) placebo bupropion plus nicotine patch (21 mg/day for 4 weeks, with 2 weeks of 14 mg/day and 2 weeks of 7 mg/day); and 4) bupropion plus patch. Bupropion was administered 1 week prior to the target quit date (day 15), at which time patch treatment was initiated for a total of 8 weeks. All subjects received weekly, individual, smoking-cessation counseling. Cessation rates at the 1-year follow-up assessment were 15.6% for placebo; 16.4% for active NTP alone; 30.3% for bupropion alone; and 35.5% for the combination of patch and bupropion. Both bupropion-plus-patch and bupropion-alone groups fared significantly better than the placebo and patch-alone conditions, but the group receiving combination did not fare significantly better than the group receiving bupropion alone. Weight suppression after cessation was most robust in the combination therapy group. Side effects were consistent with the profiles of patch and bupropion, and the combination was well tolerated. However, a higherthan-expected rate of treatment-emergent hypertension (4%–5%) was noted among those in the group receiving the combination of bupropion and patch (Jorenby et al. 1999). Hays et al. (2001) examined the effects of bupropion compared with placebo on the prevention of smoking relapse in 784 cigarette smokers who achieved smoking abstinence after a 7-week, open-label trial of bupropion (300 mg/day). Abstinent smokers were then randomly assigned to receive bupropion (300 mg/day) or placebo for a total of 45 weeks. Fifty-nine percent of smokers enrolled in the open-label phase of the trial quit smoking. Significantly more smokers were abstinent at the end of the 52-week treatment period in bupropion versus placebo groups (55.1% vs. 42.3%, P <0.01), but not at the 1-year follow-up assessment. In addition, days-to-smoking relapse was higher in the bupropion group than the placebo group (156 vs. 65 days, P <0.05). Weight gain was significantly less in the bupropion group at both the end of treatment and at 1-year follow-up. The results of this study indicate the efficacy of bupropion in preventing smoking relapse. Data regarding the optimal duration of bupropion therapy for maintenance treatment indicate further study is needed.

Varenicline Varenicline tartarate (Chantix in the United States, Champix in Europe), a

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was approved as a first-line smoking cessation agent by the FDA in 2006. The results of two independent but identical 12-week, Phase III trials comparing varenicline (1 mg, two times a day) with bupropion SR (150 mg, two times a day) and placebo have recently been published (Gonzales et al. 2006; Jorenby et al. 2006). The quit rates for both studies were similar for continuous abstinence over the last 4 weeks (weeks 9–12) of the study: in the Jorenby et al. (2006) study (study 1), the quit rates were 43.9% for varenicline, 29.8% for bupropion SR, and 17.6% for placebo; in the Gonzales et al. (2006) study (study 2) the quit rates were 44.0% for varenicline, 29.5% for bupropion SR, and 17.7% for placebo. Quit rates were significantly higher for participants taking varenicline as compared with those taking bupropion SR (P <0.0001) and both drugs resulted in significantly higher quit rates than placebo. Continuous abstinence over the follow-up period (weeks 9–52) were lower and participants taking varenicline continued to show a higher rate of abstinence (study 1: 22.1%, study 2: 23.0%) than participants taking bupropion (study 1: 16.4%, P <0.001 compared with varenicline; study 2: 15.0%, P = 0.064 compared with varenicline) and placebo (study 1: 8.4%, study 2: 10.3%). A third study examining the efficacy of the drug on smoking relapse prevention used a 12-week, open-label varenicline phase followed by randomization to 12 weeks of varenicline or placebo (Tonstad et al. 2006). These investigators found that participants taking varenicline were more likely to be continuously abstinent during weeks 13–24 (70.5% vs. 49.6%, P <0.001) and weeks 13–52 (43.6% vs. 36.9%, P = 0.02) than those taking placebo. Varenicline was found to reduce cravings and smoking satisfaction and to be safe and well tolerated. There were similar discontinuation rates for varenicline and bupropion, and the most common adverse event reported by the varenicline group was nausea (study 1: 28.1%, study 2: 29.4%).

Off-Label Medications Nortriptyline Nortriptyline is a tricyclic antidepressant that has been shown in several double-blind, placebo-controlled trials to be superior to placebo (Hall et al. 1998; Prochazka et al. 1998) and to have comparable efficacy to bupropion (Hall et al. 2002). Its efficacy may be improved with higher- rather than lower-intensity behavioral therapies. Its mechanism of action is thought to relate to norepinephrine and serotonin reuptake blockade. Side effects include dry mouth, blurred vision, constipation, and orthostatic hypotension. Nortriptyline appears to have some utility for smokers with past histories of major depression, but its potential for fatal overdose has likely limited its utilization. Nonetheless, it can be recommended as a second-line agent after nicotine replacement therapies and bupropion, though more study of this agent is necessary.

Clonidine Clonidine is a presynaptic 2 receptor agonist that dampens sympathetic activity originating at the locus ceruleus. It appears to have efficacy for treating opioid withdrawal; thus, it was tested as a nicotine withdrawal treatment during smoking cessation trials. The most common side effects of clonidine are dry mouth, sedation, and constipation. Postural hypotension, rebound hypertension, and depression are rare with clonidine in smoking cessation treatment. Several clinical trials tested oral or transdermal clonidine in dosages of 0.1–0.4 mg/day for 2–6 weeks with and without behavior therapy. Results have revealed that clonidine is more effective in women than in men (Covey and Glassman 1991); however, other studies have failed to find this association (Gourlay and Benowitz 1995). In general, the effects of clonidine have not proven to be as robust as those of NRTs. An initial study of heavy smokers (N = 71) showed that at dosages of up to 0.4 mg/day, cessation rates were doubled in comparison with placebo (Glassman et al. 1988), and in a follow-up study by the same researchers (N = 300) this initial finding was replicated (Glassman et al. 1993). In fact, a meta-analysis of 9 placebocontrolled studies and 813 patients found short-term quit rates of 39% by those receiving clonidine versus 21% for those receiving placebo (OR = 2.4, 1.7–32.8) (Covey and Glassman 1991). These findings suggest that clonidine was effective in the transdermal preparation and more helpful to female

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smokers. A meta-analysis by Gourlay and Benowitz (1995) of four subsequent studies found long-term follow-up quit rates in 31% by those receiving clonidine and 17% by those receiving placebo (OR = 2.0, 1.3–3.0). Clonidine appears to be useful in reducing acute nicotine withdrawal symptoms and may play a role for smokers who have high levels of anxiety during early cessation (Niaura et al. 1996). Recent trials of the transdermal clonidine preparation (Niaura et al. 1996) and oral clonidine (Nana 1998) have found less impressive support for clonidine's efficacy for smoking cessation, but this agent should be considered as a second-line therapy for smokers failing initial treatment with NRTs or bupropion.

Mecamylamine Mecamylamine (MEC) is a noncompetitive blocker at the ion channel site of both high-affinity CNS and peripheral nAChRs (Young et al. 2001). When MEC is given to smokers who are not trying to stop smoking, they initially increase their smoking in an attempt to overcome the blockade produced by this drug. MEC does not precipitate withdrawal in humans, perhaps because it is a noncompetitive nAChR antagonist. Common side effects include abdominal cramps, constipation, dry mouth, and headaches. Based on a theory that combined blockade and agonist therapy at the nAChR might be beneficial, similar to the nAChR partial-agonist profile of varenicline, two randomized trials were conducted comparing MEC and nicotine patch with placebo and nicotine patch. The rationale for this theory was that MEC would reduce the rewarding effects of nicotine, and the patch would reduce nicotine withdrawal symptoms (Rose et al. 1994, 1998). In the first trial (Rose et al. 1994), MEC (up to 10 mg/day; 5 mg two times a day for 5 weeks) or placebo was given in combination with a nicotine patch (21 mg/day) for up to 8 weeks, and cessation rates were significantly higher in the combination group than the patch-alone group (12/24 [50.0%] versus 4/24 [16.7%], P <0.05). MEC was reported to reduce cigarette craving, negative affect, and appetite increases associated with tobacco withdrawal. In a subsequent study of 80 cigarette smokers (Rose et al. 1998), MEC at dosages of up to 10 mg/day was given as a pretreatment for 4 weeks prior to nicotine patch initiation at the target quit date, and the combination of MEC and patch was continued for 6 weeks. As in the first study, the combination of MEC with NTP increased continuous abstinence rates after the target quit date compared with NTP alone (19/40 [47.5%] vs. 11/40 [27.5%], P <0.05). These data indicate the efficacy of the combination of MEC with NTP, and this combination should be considered a second-line therapy.

Naltrexone Naltrexone is a long-acting congener of the

opioid receptor antagonist naloxone. The rationale for

using naltrexone for smoking cessation is that the performance-enhancing and other positive effects of nicotine may be opioid mediated (Krishnan-Sarin et al. 1999; Pomerleau 1998). Early studies revealed that naltrexone monotherapy increases smoking, presumably as an attempt to overcome blockade; however, a study of naltrexone in heavy-smoking alcoholic individuals showed that cigarette smoking was decreased modestly (Rosenhow et al. 2003). Adverse events included elevated liver enzymes, nausea, and vomiting. A trial by Covey et al. (1999) of 68 cigarette smokers who were highly motivated to quit and were using at least 20 cigarettes/day compared naltrexone (up to 75 mg/day, initiated 3 days prior to the target quit date) with placebo for a total of 4 weeks. Cessation rates in the naltrexone group were nonsignificantly higher than in the placebo group (46.7% vs. 26.3%, P <0.10), and at 6-month follow-up there were no group differences. More promising data with naltrexone come from its use in combination with NRT. An initial study compared the combination of naltrexone (50 mg/day) and NTP (21 mg/day) with naltrexone alone, NTP alone, and placebo (there being no placebo patch condition) in 100 cigarette smokers for a total of 12 weeks (Wong et al. 1999). Cessation rates for placebo alone and naltrexone alone groups were 19% and 22%, and for NTP alone and NTP plus naltrexone, 48% and 46%, respectively, suggesting only a main effect of NTP treatment and no effects of naltrexone on smoking cessation, either alone or in combination. In addition, there was no effect of naltrexone on amount smoked or cigarette craving. However, a preliminary study by Krishnan-Sarin et al. (2003) revealed that the combination of naltrexone and NTP is superior to NTP alone, if NTP administration precedes that of naltrexone

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(presumably to decrease naltrexone-related withdrawal). In a larger trial of the combination of nicotine patch (21 mg/day) with four active doses of naltrexone (0, 25, 50, and 100 mg/day), it was shown that the highest dosage of naltrexone-plus-patch significantly improves continuous smoking abstinence rates compared with placebo (O'Malley et al. 2006), but these effects appeared to be confined to the first weeks of treatment. Further studies of naltrexone either alone or in combination with the patch are needed, including studies of patients with concurrent alcohol misuse.

Monoamine oxidase inhibitors The use of monoamine oxidase (MAO) inhibitors is a potentially useful strategy for smoking cessation, given that blockade of the metabolism of neurotransmitters such as DA (MAO B), and serotonin and norepinephrine (MAO A) leads to increased synaptic levels of these transmitters, which are reduced during acute withdrawal. A trial of the MAO A inhibitor moclobemide (Berlin et al. 1995) was conducted that indicated short-term increases in smoking cessation in smokers (N = 88). Furthermore, the results of a small trial by George et al. (2003) involving 40 smokers suggested the short-term efficacy of the MAO B inhibitor selegiline hydrochloride (10 mg/day), for smoking cessation. Moreover, results of a trial of the combination of selegiline and nicotine patch compared with the patch alone suggested the superiority of this combination in smokers (N = 109), but this difference was not significant (Biberman et al. 2003). Finally, a trial with the reversible MAO B inhibitor lazabemide showed promising effects for smoking cessation compared with placebo, but this agent demonstrated liver toxicity in other trials and was thus withdrawn from subsequent development (Berlin et al. 2002). Larger controlled trials of these agents are warranted before firm recommendations for the use of these agents for smoking cessation can be made.

Rimonabant and nicotine vaccine Two important novel pharmacological strategies that are not yet approved in the United States may offer some additional strategies for smoking cessation and smoking relapse prevention. The cannabinoid receptor (CB1 ) antagonist, rimonabant (Accomplia), demonstrated promising results in clinical trials in the United States and Europe, and at 20 mg/day doubled the chance of quitting compared with placebo. Most notably, it potently suppresses smoking cessation–related weight gain (Gelfand et al. 2006). Side effects include nausea, vomiting, and tremors, which are dose dependent. Although the drug is likely to be approved for the treatment of obesity, it was not approved specifically for the indication of smoking cessation, but may have a particular role in the treatment of weight-concerned smokers. The nicotine vaccine (Hatsukami et al. 2005) is being developed by several companies. It appears to be well tolerated and enhances smoking abstinence rates; higher abstinence rates are observed as a function of higher serum antibody titres. The nicotine vaccine may also hold promise for the prevention of smoking relapse or initiation of smoking and will likely be tested for these indications. Side effects include soreness at the injection site and hypersensitivity reactions to vaccine components.

INTEGRATION OF TOBACCO DEPENDENCE TREATMENT IN MENTAL HEALTH CARE SETTINGS As the high rates of tobacco use and dependence and low rates of smoking cessation are becoming increasingly appreciated in psychiatric and addicted populations (Grant et al. 2004; Kalman et al. 2005; Lasser et al. 2000), it is increasingly emphasized that mental health and addiction clinics have done little to address the tobacco culture that permeates institutional environments. However, smoking bans are becoming increasingly common in psychiatric hospitals and addiction treatment programs, and the bans appear to be successfully implemented in the majority of reported cases (Lawn and Pols 2005). The utilization of standard tobacco dependence treatments such as behavioral therapies, NRT, and bupropion has been increasingly reported in psychiatric and substance-abusing smokers. For example, various formulations of NRT, including NTP (Addington et al. 1998; Chou et al. 2004; George et al. 2000), nasal spray (Williams et al. 2004), and bupropion SR (Evins et al. 2001, 2005; George et al. 2002) have been reported to be well tolerated and efficacious in increasing rates of both smoking

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reduction and cessation in patients with schizophrenia when combined with CBT and motivational enhancement therapy. Both NRTs and bupropion have also been studied in smokers with major depression (Chengappa et al. 2001; Hayford et al. 1999; Kinnunen et al. 1996), posttraumatic stress disorder (Hertzberg et al. 2001; McFall et al. 2005), and alcohol (Hughes et al. 2003; Hurt et al. 1995; Kalman et al. 2004) and opioid (Shoptaw et al. 2002) dependence and found to be well tolerated and effective. Moreover, a recent study that compared integration of behavioral and pharmacological treatments in a mental health setting for smokers with posttraumatic stress disorder found enhanced quit rates compared to nonintegrated smoking cessation therapies (McFall et al. 2005, 2006), which suggests that provision of integrated mental health and tobacco treatment produces enhanced cessation outcomes. Finally, a better understanding of the pathophysiology of mental disorders may lead to improved treatments for this population. For example, schizophrenia is associated with a broad range of cognitive deficits, particularly those related to prefrontal lobe dysfunction; atypical antipsychotic drugs (e.g., clozapine, olanzapine) that improve certain cognitive deficits associated with schizophrenia may facilitate reduction of smoking (George et al. 1995; McEvoy et al. 1995; Procyshyn et al. 2002) or smoking cessation with standard pharmacotherapies such as the nicotine patch or bupropion SR (George et al. 2000). The development of novel medications that target the underlying pathophysiology of psychiatric or substance use disorders may well lead to important advances in the management of tobacco dependence in these special populations of smokers.

CONCLUSION Tobacco dependence remains one of the leading preventable causes of morbidity and mortality in the Western world. Nonetheless, smoking cessation therapies are among the most cost-effective and proven therapies in psychiatry and medicine, yet most health care providers do not identify tobacco use in their patients. In fact, a survey of psychiatric practices found that only 9.1% of smokers under the care of psychiatrists received treatment for nicotine dependence (Montoya et al. 2005). Nonetheless, the American Psychiatric Association has recently published an update of its Clinical Practice Guidelines for Nicotine Dependence (Kleber et al. 2006), which should provide standards for the field of psychiatry in the assessment and treatment of tobacco dependence. Furthermore, although medication and behavioral treatments have documented efficacy in treating tobacco dependence, it is important that these therapies be used in combination to achieve the best overall results and to ensure adequate skill acquisition and treatment adherence. Future challenges include developing safer and more effective smoking cessation therapies and making these therapies available to all individuals who want to quit smoking.

KEY POINTS Tobacco dependence rates have decreased substantially, but many people who smoke appear to have comorbidities, such as psychiatric and substance use disorders, that reduce their chance of quitting. Identification of smokers in clinical settings is of critical importance to the treatment of tobacco dependence. There are effective pharmacological and behavioral therapies for tobacco dependence, which work best when used in combination. A better understanding of the pathophysiology of mental health and addictive disorders may lead to improved treatment approaches for tobacco dependence in these smoking populations. Smokers with psychiatric and substance use comorbidity may best be treated in settings that integrate smoking cessation treatments with mental health and addiction treatment.

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SUGGESTED READING George TP (ed): Medication Treatments for Nicotine Dependence. Boca Raton, FL, Taylor & Francis, 2006 Hurt RD, Sachs DPL, Glover ED, et al: A comparison of sustained-release bupropion and placebo for smoking cessation. N Engl J Med 337:1195–1202, 1997 Jorenby DE, Hays JT, Rigotti NA, et al: Efficacy of varenicline, an alpha4 beta2 nicotinic acetylcholine receptor partial agonist, vs. placebo or sustained release bupropion for smoking cessation. J Am Med Assoc 296:56–63, 2006 Rigotti N: Treatment of tobacco use and dependence. N Engl J Med 346:506–512, 2002 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 16. Benzodiazepines and Other Sedatives and Hypnotics

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Adam Bisaga: Chapter 16. Benzodiazepines and Other Sedatives and Hypnotics, in The A merican Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.350267. Printed 10/7/2011 from www.psychi atryonline.com Textbook of Substance Abuse Treatment >

Benzodiazepines and Other Sedatives and Hypnotics Adam Bisaga, M.D.

BENZODIAZEPINES AND OTHER SEDATIVES AND HYPNOTICS: INTRODUCTION In this chapter I will discuss treatment strategies for individuals who abuse or are dependent on benzodiazepines and other medications that have sedative-hypnotic properties; that is, individuals who meet DSM-IV-TR criteria for sedative, hypnotic, or anxiolytic use disorders (American Psychiatric Association 2000). Benzodiazepines are the most frequently prescribed class of psychotropic agents. About 100 million prescriptions are written annually for benzodiazepines, and 3%–4% of adults in the United States and Canada are taking them at any one time (Neutel 2005; Paulose-Ram et al. 2004). Medications included in this class are used in a wide range of psychiatric and medical conditions, including anxiety disorders, sleep disorders, seizure disorders, movement disorders, and muscle spasticity. Sedative and anxiolytic properties of these medications are used in the symptomatic treatment of anxiety and agitation associated with other psychiatric and neurological disorders, including psychotic, mood, and cognitive (dementia, delirium) disorders (Hollister et al. 1993). Sedative and hypnotic properties of these medications have a variety of uses in anesthesiology and emergency medicine. These medications are also used for the symptomatic treatment of syndromes related to abuse of other drugs, such as agitation secondary to intoxication with stimulants, as well as signs and symptoms associated with withdrawal from alcohol, sedative-hypnotics, or opiates. Sedative-hypnotic medications represent a variety of chemically distinct groups of compounds including barbiturates, benzodiazepines, and selective nonbenzodiazepine hypnotics (Table 16–1). These medications share a general sedative profile of clinical effects, but they differ in other pharmacological properties, including their therapeutic profile, safety, and potential to produce adverse behavioral effects, such as abuse or dependence. Newer agents, such as benzodiazepines and selective hypnotics, have a more favorable efficacy and safety profile, and their safety profile has led to a decrease in the prescription and clinical issues associated with the use of older agents, such as barbiturates or meprobamate. In this chapter I will discuss older agents where it is relevant, but I will mostly concentrate on issues that are specific to benzodiazepines. The author would like to thank Drs. John Mariani, Edward Nunes, and James Woods for their comments on this manuscript; Ms. Aaisha Mirza for her assistance with manuscript preparation; and Ms. Eve Vagg for help in drawing figures.

HISTORY Medications that have sedative, hypnotic, or anxiolytic properties have been widely used in the era of modern pharmacology; this is mainly attributable to their usefulness in the management of a variety of disorders and positive subjective effects. Unfortunately, all of these medications have potential to produce adverse effects, and because their use has often been widespread, the number of individuals affected with adverse effects has been substantial. This has stimulated discovery of new compounds with better safety profiles and has resulted in new generations of sedative-hypnotic medications becoming available for clinical use. Newer medications have more selective pharmacological effects and a better therapeutic index, separating sedative-hypnotic from toxic behavioral (confusion, lethargy) and respiratory effects. However, each newer class of medications has the potential to produce physiological dependence, as well as excessive use, abuse, and dependence. Chloral hydrate was the first medication in this class; it was synthesized in 1832 and is still in clinical use today. Chloral hydrate quickly became a widely popular hypnotic medication, but it has been associated with adverse gastrointestinal and behavioral effects, delirium, and risk of death. Bromide salts were introduced in the late nineteenth century; they were used initially to treat epilepsy, but later used as a sedative and anxiolytic agent. Bromides have a very narrow therapeutic index and chronic use has been associated with a particular set of neurotoxic symptoms known as bromism that include symptoms of somnolence, delirium, psychosis, and seizures. Its use has been discontinued in the United States, but it is still in use in other countries and in veterinary medicine. Phenobarbital, a derivative of barbituric acid, was introduced as a sedative and hypnotic in 1912 and continues to be in clinical use today. Barbiturates produce alcohol-like intoxication and were widely used and abused in the first half of the twentieth century. Reports of their propensity to produce behavioral disturbances and physiological dependence began to appear in the 1950s. The search for safer alternatives to barbiturates resulted in the synthesis of meprobamate in 1950, which seemed to have fewer sedative effects and more antianxiety effects than its predecessors. However, it also has a significant euphoric effect and was soon widely prescribed and abused; it was later scheduled as a controlled substance by the U.S. Food and Drug Administration. Meprobamate is still available, but its clinical use and related abuse problems have greatly decreased. Problems with abuse and physical dependence are seen currently in individuals using carisoprodol, which is an unscheduled muscle relaxant that is metabolized to

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meprobamate (Reeves et al. 1999). Benzodiazepines were discovered in the late 1950s, with chlordiazepoxide and diazepam becoming widely available for clinical use in the early 1960s. Compared with older sedative-hypnotics, benzodiazepines have a more favorable safety profile, and have gradually displaced them from clinical use. A popular benzodiazepine, diazepam was the most prescribed medication in the United States during the 1970s. In that time, there were growing concerns about the adverse effects (sedation and falls) of longer-acting agents that were related to accumulation of active drug and its metabolites. This led to a decrease in prescription of longer-acting agents and an increase in the use of shorter-acting agents (alprazolam, lorazepam, triazolam). As a result, alprazolam became one of the most prescribed medications of the 1990s. With increasing use of short-acting agents, concerns about their potential to produce serious adverse effects such as amnesia, psychosis, and depression emerged and, although none of these concerns were actually supported by evidence (Bunney et al. 1999), apprehension led to a significant reduction in the use of triazolam. More recently, with the expanding knowledge of the pharmacology of sedative-hypnotics, medications with even greater specificity have been developed, most notably nonbenzodiazepine hypnotic agents that have preferential binding to the

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subunit of the -aminobutyric acid (GABA)A

receptor (e.g., zolpidem). These agents have a better safety profile and a lesser tendency to produce a wide range of adverse effects than traditional benzodiazepines; however, they continue to have the potential to produce physical dependence and abuse. It was hoped that agents that are partial agonists at the GABAA receptor (e.g., abecarnil) might have improved therapeutic profiles. Although these agents have less potential to produce physiological dependence and lower abuse liability, they also have less clinical efficacy and were never developed clinically. Extensive clinical experience obtained with benzodiazepines since the 1960s confirms that these medications have a very favorable safety profile, and the range of available agents allows flexibility in their clinical use. However, similar to earlier sedative-hypnotics, all of these medications have the potential to produce physical dependence and a substance use disorder. Some of the dangers associated with widespread and unsupervised use of these benzodiazepines have been mitigated by regulatory oversight, and physician education has resulted in more rational and safer prescribing practices. Recognition that safety concerns and efficacy are coupled with and inherent in the use of GABAA agonists has prompted expanding use of agents that enhance GABAergic neurotransmission indirectly, such as gabapentin, pregabalin, tiagabine, or other newer anticonvulsants. Effectiveness of these medications as sedatives, anxiolytics, or hypnotics may be limited and differ among individuals; however, they have better behavioral safety profiles than traditional sedative-hypnotics.

BEHAVIORAL PHARMACOLOGY GABAA Receptors Advances in the understanding of the pharmacological mechanisms mediating effects of sedative, hypnotic, and anxiolytic medications began with the discovery of the GABAA benzodiazepine receptor complex (Squires and Brastrup 1977), the predominant inhibitory receptor in the central nervous system. It is a ligand-gated ion channel, which is activated by the neurotransmitter GABA. Activation leads to increase in Cl– ion influx into the neuron and hyperpolarization of the neuronal membrane. As a result, the threshold required for the excitatory neurotransmitter to depolarize the membrane and produce an action potential is increased (i.e., GABA inhibits "excitability" of neuronal membranes). The GABAA receptor has binding sites for GABA, as well as regulatory sites for benzodiazepines, barbiturates, neurosteroids, anesthetics, anticonvulsants, and ethanol (Mohler et al. 2002) (Figure 16–1). There is considerable evidence that all sedative-hypnotics and alcohol interact with the GABAA receptor and that inhalants that are subject to abuse (various volatile organic compounds present in fuels, solvents, and cleaning products) may have similar mechanisms (Whiting 2003). The exact neural mechanism of each class of sedative-hypnotics is not well understood, but considering the similarities in behavioral and physiological effects of these drugs, it is reasonable to assume that physiological dependence and abuse liability associated with these agents is related to the changes occurring in the GABAergic receptor system. FIGURE 16–1. Schematic representation of the GABAA receptor complex.

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(A) Each GABAA receptor contains five transmembrane subunits arranged in a circle around the channel. Many different subunits have been identified to date, which are grouped into several classes. Most receptors include two subunits, and a ,

, , , or

subunits, two

subunit (Mohler et al. 2002). (B) View from the extracellular space of the most

commonly encountered receptor subtype with the location of the benzodiazepine and low-affinity GABA sites. This receptor has high affinity for benzodiazepines, mediating its sedative, amnestic, anticonvulsant, and reinforcing effects. It also has a high affinity site for flumazenil and zolpidem. BZ = benzodiazepine; Cl – = chloride ion; GABA = -aminobutyric acid. At least 20 different GABAA receptors have been identified, each with a distinct pharmacological profile. Sensitivity of individual receptors for a particular sedative-hypnotic drug is determined by the receptor's subunit composition, the concentration of GABA, and the brain localization of the receptor. For example: 1) barbiturates activate receptors that are insensitive to benzodiazepines; 2) benzodiazepines require the presence of GABA to activate receptors, which is not the case with barbiturates; and 3) flumazenil blocks effects of benzodiazepines and zolpidem but not effects of barbiturates (Macdonald and Olsen 1994). Greater selectivity of benzodiazepines' effects results in greater safety and lower abuse liability of benzodiazepines as compared with older sedative-hypnotics. The heterogeneity in the expression of GABAA receptors results in receptors selectively mediating specific behavioral effects of sedative-hypnotics, such as sedation and sleep, anxiolysis, learning and memory, anesthetic effects, and sensorimotor processing. In addition, each class of sedative-hypnotic agents preferentially binds to receptors with a different subunit composition (Table 16–2). This opens exciting possibilities for discovery of medications that may be more selective in their psychoactive profile and devoid of the adverse effects associated with benzodiazepines and older sedative-hypnotics (Mohler et al. 2002; Whiting 2003). For example, newer selective hypnotics (zolpidem, zaleplon) that have preferential affinity for

1

subunits of GABAA receptors

have fewer anxiolytic or muscle relaxant properties and therefore have a better safety profile. However, binding to an

1

subunit may also be associated with reinforcing effects (Rowlett et al. 2005). Therefore, it is not yet clear if hypnotic effects can be completely separated from the abuse potential of these medications. Another layer of the pharmacological heterogeneity of the GABAA receptor system that may be useful therapeutically involves synthesis of agents that bind to the receptor but that may have differential pharmacodynamic effect. Agents may have a full or partial agonist effect, inverse agonist effect (opposite effect as agonist; e.g., anxiogenic and proconvulsant), or neutral antagonist effect (without effect on its own, but blocking action of both agonists and inverse agonists). Flumazenil

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is a benzodiazepine compound that functions as an antagonist and is used to reverse effects of benzodiazepines, such as in cases of benzodiazepine overdose. However, it may induce seizures when given to physically dependent individuals (Seger 2004). Newer medications, particularly medications with partial agonist effects at selected subtypes of GABAA receptors, may be selective in their behavioral profile, with less propensity to produce physical dependence and abuse.

Behavioral Effects Benzodiazepines produce a wide range of behavioral effects, some that are beneficial therapeutically (e.g., anxiolysis), some that may be desired primarily by substance abusers (euphoria), and some that are generally considered adverse (e.g., amnesia). Most benzodiazepines have a comparable profile of anxiolytic, sedative, and hypnotic effects, which are difficult to distinguish when medications are given in comparable doses (considering their relative potency) under controlled conditions. The main differences among acute effects of different benzodiazepines are related to their pharmacokinetics and route of administration, rates of absorption, and elimination, which determine onset and duration of pharmacological effect.

Abuse liability Benzodiazepines produce sedative and anxiolytic therapeutic effects, which are seen as positive and desirable by individuals experiencing anxiety, insomnia, or agitation in a treatment setting. However, healthy subjects rate these effects mostly as unpleasant, and, when given a choice, they prefer placebo to benzodiazepines (de Wit et al. 1989). Such a lack of preference suggests the absence of reinforcing effects and indicates low abuse liability in a great majority of individuals. However, a subpopulation of sedative abusers or alcohol drinkers with histories of drug use shows greater liking and preference for barbiturates and, to a smaller extent, benzodiazepines over placebo (Chutuape and de Wit 1994). Evidence obtained in well-controlled human laboratory studies generally suggests that all clinically effective benzodiazepines and

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selective hypnotics, when given in comparable doses, have comparable subjective and reinforcing effects. For example, effects from high doses of zopiclone or zolpidem cannot be readily distinguished from effects of typical benzodiazepines (Rush et al. 1999). However, medications with a faster onset of action may be more reinforcing than medications with a slower onset of action (Griffiths et al. 1984). Interestingly, benzodiazepines are reinforcing only in a particular behavioral context (e.g., when self-titrated or taken as needed), but not when experimenter-administered; or before a relaxation period, but not before a work task (c.f. Griffiths and Weerts 1997). Consistent with these human laboratory studies, it has generally been difficult, compared with other classical drugs of abuse, to show that sedative-hypnotics can be self-administered (serve as reinforcers) in established animal models. Generally, sedative-hypnotics are reinforcing when administered intravenously, but not orally. Barbiturates and meprobamate produce greater reinforcing effects than benzodiazepines. However, all sedative-hypnotics have less reinforcing efficacy compared with other drugs of abuse or alcohol (Griffiths and Weerts 1997). Laboratory studies are generally consistent with clinical observations. A great majority of individuals treated with benzodiazepines do not find them reinforcing, and these people are at very low risk of developing a substance use disorder. Abuse potential of sedative-hypnotics depends not only on the intrinsic properties of the drug (receptor selectivity and pharmacokinetics) but also on the characteristics of the individual and environmental circumstances. Barbiturates and meprobamate are more likely to produce abuse or dependence than are benzodiazepines and

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selective hypnotics

(Uhlenhuth et al. 1999). Medications with slower onset and longer offset of action may be safer than fast-acting agents (Table 16–1); however, any medication that acts as an agonist at the GABAA receptor has some abuse potential. Individuals who have a history of sedative-hypnotic, alcohol, or any other substance use disorders are at higher risk of developing abuse or dependence. A family history of drug or alcohol dependence should also be considered in evaluating dependence potential for a given individual, given that some of the risk may be hereditary (Kendler et al. 2000).

Other adverse effects Even at therapeutic doses, benzodiazepines adversely affect attention and psychomotor performance and produce amnestic effects (Woods et al. 1992). As with subjective effects, these adverse cognitive and performance effects are generally comparable across currently available agents, and differences among various medications are related to the dose and pharmacokinetics. For example, the effects of zolpidem on performance and memory are comparable to the effect of traditional benzodiazepines, but its duration is shorter, consistent with their shorter duration of action (Wesensten et al. 1995). Most available data support the notion that sedative, hypnotic, and amnestic effects of currently available benzodiazepine agonists are functionally coupled (Wesensten et al. 2005). Most adverse effects induced by benzodiazepines are dose-dependent and related to excessive sedation and intoxication produced by these drugs. This includes sleepiness and lethargy, weakness, dizziness, ataxia, confusion, and disorientation. Benzodiazepines may also contribute to the risk of falls among elderly patients (Leipzig et al. 1999). Individuals receiving maintanence therapy of stable doses of benzodiazepines usually develop tolerance to their sedative effects. However, there is no comparable development of tolerance for the memory-impairing effects of these medications, which can persist even after several years of daily administration (Lister 1985). Benzodiazepines are generally very safe in physically healthy individuals, even if taken in overdose, which is a marked improvement over barbiturates and other older sedativehypnotics. Overdoses on benzodiazepines are almost never fatal, unless they occur in combination with sedative agents with a different pharmacological mechanism, such as opiates or alcohol.

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NEUROBIOLOGY OF SEDATIVE-HYPNOTIC USE DISORDERS Physiological Dependence A proportion of individuals treated long-term with benzodiazepines, even at therapeutic doses, develop physiological dependence and present signs of withdrawal upon abrupt discontinuation of the medication. This process, which represents a neuroadaptation of the organism in response to the continuous presence of the benzodiazepines, is not unique to drugs of abuse, and can occur with other psychotropic medications (Warner et al. 2006). Chronic exposure to sedative-hypnotics, as well as to alcohol, alters the function of the GABAA receptor, generally producing down-regulation of the receptor level and function (Klein and Harris 1996). A variety of mechanisms are responsible for the functional alteration of the GABAA receptor, including changes in the receptor subunit composition and the emergence of atypical receptors (Krystal et al. 2006; Raol et al. 2005). These changes in the GABAergic neurotransmission are most likely responsible for the development of physiological dependence in individuals using sedative-hypnotics, and recent data point to the

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subunit of the GABAA

receptor as a site mediating physiological dependence for alcohol and other sedative-hypnotics (Hood et al. 2006). Sedative-hypnotics differ in their potential to produce physiological dependence, with barbiturates and meprobamate producing the greatest levels of dependence, followed by benzodiazepines and partial or selective GABAA agonists (Griffiths and Johnson 2005). Human laboratory studies suggest that physiological dependence develops and reaches ceiling level rather quickly (within a few weeks), at which time there is no further increase in intensity of withdrawal (Rosenberg and Chiu 1985). In the clinical setting, development of physiological dependence is positively correlated with the dose and duration of exposure to the drug. Physiological dependence is almost never seen in patients treated for less than 2 weeks, and it occurs in approximately 50% of patients treated daily for more than 4 months. All patients prescribed benzodiazepines for longer periods of time should be warned of this and instructed not to discontinue the medications abruptly, because withdrawal symptoms, seizures, or delirium may occur. The level of physiological dependence does not depend on the duration of medication effect, with short- and long-acting benzodiazepines producing comparable severity of withdrawal. The development of physiological dependence is reduced with intermittent, as opposed to a continuous, exposure to benzodiazepines, which may explain clinical observations showing that many individuals who are treated with benzodiazepines—even for extended periods of time—do not experience withdrawal, similar to many individuals' experience with chronic alcohol use (Rickels et al. 1999a).

Compulsive Substance Use Among individuals exposed to sedative-hypnotic medication, a small subset will gradually escalate use of these medications and will develop compulsive drug-seeking and -taking behavior, with loss of control and an inability to stop this behavior (DSM-IV-TR syndrome of substance dependence, also referred to as addiction). Such patients often relapse and resume compulsive substance use even after detoxification and extended periods of abstinence. Intense research efforts have focused on understanding neurobiological mechanisms responsible for the transition from occasional or controlled substance use to compulsive use with loss of control over drug taking, and on mechanisms responsible for the relapsing course of the illness. Selected aspects of addiction can be modeled in animals and human volunteers, which permits study into mechanisms and advances in development of new treatment strategies. Much focus to date has been on biochemical changes associated with chronic exposure to drugs and on pharmacological mechanisms of drug self-administration. Research into mechanisms of physiological dependence on sedatives can help improve detoxification strategies; however, it is generally believed that physiological dependence is not a significant factor determining development of compulsive drug use (Woods and Winger 1995). Even though physiological dependence is often seen in patients with the DSM-IV-TR syndrome of sedative-hypnotic dependence, the majority of patients treated chronically with benzodiazepines, who presumably may have physiological dependence, do not develop compulsive substance use (Soumerai et al. 2003), and some patients present with compulsive substance use without physiological dependence (de las Cuevas et al. 2003). Benzodiazepines have lower abuse potential when compared with other drugs of abuse (Rickels et al. 1999a), which is likely related to the differences in neurochemical and behavioral effects among benzodiazepines and other drugs of abuse. Interestingly, benzodiazepines are the only major class of drugs with abuse liability that decrease dopamine levels in the mesolimbic system (Finlay et al. 1992); all other drugs of abuse increase dopamine levels (Di Chiara and Imperato 1988). The pathophysiology of benzodiazepine use disorders has not been studied thoroughly, mostly because of difficulties encountered in developing a laboratory model of benzodiazepine dependence. Neuroadaptive changes in the GABA and possibly opioid receptor systems may be responsible for the development and maintenance of benzodiazepine dependence in vulnerable individuals. Similar changes may be responsible for behavioral aberrations that persist in early abstinence (e.g., anxiety, insomnia, vulnerability to stress) and may contribute to relapse. Recent data indicate that binding to an

1

subtype of a GABAA receptor plays a prominent role in regulating reinforcing

effects of sedative-hypnotics (Rowlett et al. 2005). Reinforcing effects of benzodiazepines may also be mediated via an opioid mechanism. The anxiolytic effect of benzodiazepines is blocked by

opioid receptor antagonists (Agmo et al. 1995;

Berridge and Pecina 1995; Richardson et al. 2005). In humans, diazepam can substitute for heroin (Spiga et al. 2001), and naltrexone attenuates anxiolytic and positive subjective effects of benzodiazepines (Duka et al. 1982). This overlap in the pharmacological and behavioral effects of benzodiazepines and opioids may explain the overlap between opioids and

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sedatives seen in the clinical setting, including the high level of co-occurrence of sedative and opioid dependence, the usefulness of benzodiazepines in the treatment of opioid withdrawal, and the potential for naltrexone to reduce benzodiazepine use in opioid-dependent individuals receiving naltrexone maintenance therapy (Kosten 1994). Understanding of the neurobiology of sedative-hypnotic use disorders is further complicated by their frequent co-occurrence with other addictive and psychiatric disorders. It appears that the presence of another disorder increases the risk and may facilitate the development of sedative-hypnotic use disorders. However, the nature of this interaction is unknown. Presence of pharmacological and clinical overlaps between use of benzodiazepines and alcohol or opiate dependence suggests that the neurobiological mechanism involved in compulsive drug taking may be shared across several drugs of abuse. Recent data obtained in studies of other drugs of abuse suggest a compromised reward system may be involved in the maintenance of drug taking, and overactive brain stress–response systems and compromised orbitofrontal/prefrontal cortex function may be involved in relapse (Koob 2006). Future studies examining effects of benzodiazepines and other drugs of abuse will inform development of new strategies to manage dependence on sedatives.

EPIDEMIOLOGY Clinical use of benzodiazepines had gradually increased since their introduction in the 1960s, and by the late 1970s they replaced older sedative-hypnotic agents. Since the 1980s, the clinical use of benzodiazepines in the U.S. general population has fluctuated but has remained fairly stable overall. During that time, prescription benzodiazepines represented a constant fraction of all drug sales, with 5%–8% of individuals receiving benzodiazepine treatment in any given month (Woods and Winger 1995). Two main groups of patients who are prescribed benzodiazepines can be identified: the first group consists of individuals who take them only for a short period of time (days or weeks); the second group is smaller and includes individuals who are treated with benzodiazepines chronically, often for several years (Neutel 2005). More recent benzodiazepine prescribing trends include 1) a decrease in the use of longer-acting agents and an increase in the use of shorter-acting agents, 2) a decrease in the use of benzodiazepines as anxiolytics, and 3) an increase in the use of selective 1

subunit agonists as hypnotics. Relatively high but fairly constant rates of benzodiazepine prescribing confirm their

widespread efficacy and acceptance in the medical community. At the same time that benzodiazepines were being extensively prescribed and used, a small proportion, but still a significant number, of individuals presented with problematic use of these medications. In the United States, rates of nonmedical use of benzodiazepines have fluctuated, but have remained fairly constant overall since the 1980s, with 1%–2% of individuals using medications without medical supervision. Among unsupervised users of sedatives and tranquilizers, about 15% meet DSM-IV-TR criteria for abuse or dependence (SAMHSA 2007a). The most commonly misused benzodiazepine is alprazolam, which is also the most often prescribed sedative-hypnotic medication. In the recent National Epidemiologic Survey on Alcohol and Related Conditions conducted in the United States, lifetime prevalence rates of nonmedical use of sedatives or tranquilizers were 4.1% and 3.4%, respectively, with a respective prevalence of related substance use disorders of 1.1 and 1.0 (Huang et al. 2006). In this sample, individuals with sedative or tranquilizer use disorder were more likely to have alcohol use disorder (odds ratios [ORs]= 13.4–14.2) or any additional mood, anxiety, or personality disorder (ORs = 3.7–6.6). Benzodiazepines are rarely a primary substance of abuse in individuals admitted for addiction treatment, making up less than 1% of all admissions, with the majority of these individuals reporting abuse of alcohol or opioids in addition to benzodiazepines. The population of primary benzodiazepine abusers in treatment is particularly compromised psychiatrically; almost half of these individuals have another psychiatric disorder, which is twice as often as admissions for other drugs of abuse. This suggests that benzodiazepine use, abuse, or dependence is a useful clinical sign, indicating that other co-occurring psychiatric disorders (mood, anxiety, personality, etc.) may be present. Benzodiazepines are often reported as secondary drugs of abuse among individuals admitted to treatment for opiates or alcohol as a primary drug of abuse (Darke et al. 2003; SAMHSA 2007b). Benzodiazepine abuse is particularly common in opioid-dependent patients receiving methadone maintenance treatment, 40%–50% of which at any one time use benzodiazepines (Gelkopf et al. 1999; Iguchi et al. 1993). These rates are generally higher than rates of use in the general population. However, it is not clear how many of these individuals require benzodiazepines as a treatment for coexisting psychiatric disorders and how many have benzodiazepine abuse or dependence. Indeed, benzodiazepine-using patients receiving methadone maintenance treatment are generally more psychiatrically compromised, with higher rates of polysubstance abuse and intravenous drug use, higher levels of psychopathology, and more social dysfunction (Bleich et al. 1999; Ross and Darke 2000). During treatment, rates of benzodiazepine use in these patients generally remain constant or decrease only slightly (Fairbank et al. 1993).

TREATMENT Initial evaluation of patients presenting with problematic use of sedative-hypnotics must aim to clarify the relationships among the medication use, adverse behavioral effects that may result from it, and the presence of other psychiatric or substance use disorders. Generally, such patients can be categorized in one of four diagnostic groups: patients with a primary psychiatric disorder, with or without concurrent sedative-hypnotic use disorder; and patients with a primary substance use disorder, with or without another psychiatric disorder. Each of these groups presents with unique clinical characteristics that will guide appropriate diagnosis and treatment (Table 16–3).

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Therapeutic intervention for these patients can be implemented at three separate stages. The first stage, prevention, would involve identification and treatment of individuals who are using sedative-hypnotic medication and are at high risk of developing abuse or dependence. The second stage, cessation of use, would focus on creation of strategies designed to decrease use and related adverse effects on and induction of initial abstinence in dependent patients. The third stage, relapse prevention, would entail implementation of treatment aimed at maintaining continuous abstinence and minimizing risk of relapse.

Prevention Identifying and targeting high-risk individuals Due to widespread popularity, sedative-hypnotic medications are present in many households and are easily available for illicit use and diversion. Screening for sedative-hypnotic use, including a history obtained using nonthreatening questioning and possibly through a urine toxicology, should be part of an evaluation for each individual during regular medical checkups. This might allow early detection of use of medications among individuals obtaining and taking medications without supervision. Many individuals who might be abusing sedative-hypnotic medications, particularly those with comorbid psychiatric disorders, are already in some form of treatment, which creates opportunity for a treating physician to prevent the potential problem or initiate treatment relatively early in the course of the disease. All patients who are receiving sedative-hypnotic medication maintenance treatment should be assessed at each visit for the signs of abuse or dependence (see Table 16–3 to guide clinical assessment). However, taking medication, even for a long time, and evidence of physical dependence are not by themselves an indication of a substance use disorder. Positive screening should be pursued further with clinical evaluation, which should include a detailed history, and current use of alcohol or other drugs should be verified by the collateral information as well as psychiatric evaluation and toxicology. A history of drug or alcohol abuse in these patients should raise concerns but it is not an absolute contraindication to therapeutic benzodiazepine use (Posternak and Mueller 2001). Finally, all patients entering treatment for alcohol or drug dependence should be screened for the use of sedative-hypnotics. In these patients, positive toxicology for sedativehypnotic medications should raise a strong suspicion of use disorder and require close monitoring and treatment. Because of the high incidence of other psychiatric disorders in the population of sedative-hypnotic users, a thorough psychiatric evaluation is warranted. Subsequently, a detailed management plan can be developed for high-risk individuals that may involve close monitoring of medication taking, implementation of strategies to prevent development of tolerance and physical dependence, initiation of therapeutic intervention to prevent or decrease adverse behavioral effects, and the treatment of co-occurring psychiatric disorders.

Prescribing in high-risk groups It is often believed that prescribing medications with abuse liability is contraindicated in patients with a history of substance use disorders. Many clinicians are reluctant to prescribe a sedative-hypnotic medication to patients with substance abuse history who would otherwise be good candidates for treatment with these medications. The decision to use sedativehypnotics in such a patient requires an individualized risk-benefit assessment and may involve placing into a subgroups based on the level of risk the patient shows to developing problematic use of these medications (Mariani and Levin 2006), which in turn can guide treatment decisions (Table 16–4). Even patients who have a recent history of alcohol use disorders can be safely and effectively treated with benzodiazepines (Kosten et al. 2000), although caution is certainly warranted here, given that these individuals may be particularly vulnerable to development of use disorders.

Managing physiological dependence Since physiological dependence can complicate discontinuation of a short-term treatment, attempts should be made to minimize the risk of physical dependence development, although it is not known whether prevention of physiological dependence alters the risk of developing compulsive drug use. Strategies to prevent physiological dependence may include 1) aggressive, short-term treatment (e.g., use of high doses over a few weeks); 2) short-term treatment using medications on an as-needed rather than continuous basis; or 3) implementing drug holidays (i.e., intermittent use of medications only during "high-demand" situations). It is suggested that more than half of patients with generalized anxiety disorder may be treated using such intermittent treatment strategies (Rickels et al. 1999a). One recent, and still experimental, strategy to prevent development of tolerance and physiological dependence involves intermittent administration of a benzodiazepine antagonist (flumazenil) to "reset" receptors and block neuroadaptive changes while preserving the therapeutic effects of benzodiazepines (Gerra et al. 1993). Many individuals who are chronically prescribed benzodiazepines for the treatment of anxiety disorders will develop physiological dependence. This is often seen as a serious adverse effect that warrants discontinuation of medication, because otherwise it will lead to the development of iatrogenic addiction, with detrimental medical consequences for the patient and possibly legal implications for the prescriber (e.g., Lader 1998). These concerns have been quite common in the past, particularly among physicians without expertise in addictions. Trepidation among physicians was based on the general lack of awareness that physiological dependence may occur even with therapeutic doses, and the confusion in differentiating physical dependence from addiction (O'Brien 2006). As a result, benzodiazepines are often prescribed in subtherapeutic

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doses and for an inadequate period. However, considerable data accumulated since the late 1980s do not support the validity of such concerns (Rickels et al. 1999a; Woods and Winger 1995). Patients with primary anxiety disorder treated with benzodiazepines will rarely develop substance use disorder, similar to patients treated with opioids for pain, and the likelihood of its development does not correlate with the duration of treatment (Soumerai et al. 2003). The presence of physiological dependence, even for many years, is not particularly harmful, apart from the discomfort associated with withdrawal, which can, for the most part, be greatly minimized by 1) using sufficient doses of medication, 2) sufficient dosing frequently for short-acting agents to prevent interdose withdrawal, or 3) conversion to the long-acting agent. Similar confusion and concerns about risks of long-term agonist maintenance treatment led to criticism of opioid replacement therapy. This might have been an obstacle for many patients who would have benefited from treatment but were concerned about methadone addiction. There is also evidence suggesting that, in some patients, abrupt discontinuation of chronically prescribed benzodiazepines may increase their reinforcing effects (Cappell et al. 1987). In the clinical setting, this may lead to relapse to inappropriate use and emergence of compulsive drug use after abrupt discontinuation of maintenance treatment with benzodiazepines, similar to what is widely observed in the population of opioid-dependent individuals who abruptly discontinue agonist replacement treatment. Ongoing monitoring and treatment of residual anxiety symptoms using additional antianxiety agents such as antidepressants, buspirone, or anticonvulsants would also serve to reduce reinforcing effects of benzodiazepines and prevent the development of use disorder.

Cessation of Use Patients with primary psychiatric comorbidity and sedative-hypnotic use disorders Patients who present with adverse effects secondary to sedative-hypnotic medications require a thorough evaluation, including an appraisal of whether adverse effects outweigh benefits of continuing treatment. Adverse effects include the development of excessive sedation or memory problems that interfere with functioning or increase risk of falls in the elderly, potential for adverse interaction with alcohol or other sedative medications, and compulsive/uncontrollable side effects involved in maintenance therapy with alternative antianxiety medications such as antidepressants, mood stabilizers, or neuroleptics. In the instances when adequate symptom control cannot be achieved without adverse effects, the alternative treatment strategy is warranted. This might include 1) conversion to and stabilization on the equivalent dose of an alternative benzodiazepine with a slower onset and a longer duration of effect (e.g., conversion from alprazolam to clonazepam); 2) conversion to and stabilization on the lower dose of the alternative benzodiazepine; 3) complete discontinuation of benzodiazepines and stabilization on an alternative GABAergic agent with a more favorable safety profile (e.g., carbamazepine or valproate); or 4) discontinuation of medication and implementation of behavioral treatment strategies (see Figure 16–2 for the suggested treatment strategies). FIGURE 16–2. Suggested sequenced treatment strategies for individuals with a primary psychiatric disorder who developed sedative-hypnotic use disorder.

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Discontinuation of benzodiazepines or other sedative-hypnotics in patients with comorbid anxiety or mood disorders using a rapid taper of medication, such as is often done in detoxification from alcohol or opiates, is generally not very effective. Even when detoxification is extended over several weeks, a substantial number of patients are not able to successfully complete discontinuation (Rickels et al. 1993; Schweizer et al. 1990). A very gradual and staged approach, extending detoxification to several months, has permitted a greater number of patients to complete detoxification (Rickels et al. 1999a). One of the main problems that complicate the attempt at discontinuation of benzodiazepines in these patients is that the withdrawal syndrome can be very similar to the syndrome of anxiety that was originally treated with benzodiazepines. In this case, the emergence of withdrawal may be confused with the recurrence of the anxiety symptoms, signifying the need for continuing treatment rather than stopping it. Furthermore, underlying mood or anxiety problems are likely to recur if the benzodiazepine is indeed successfully treating the symptoms, making it difficult for patients not to resume the medication. Therefore, discontinuation of benzodiazepines is not recommended if anxiety symptoms persist despite treatment. During discontinuation, a very slow lowering of medication dose should be combined with pharmacotherapy to target residual withdrawal and anxiety symptoms, and intensive behavioral treatment should be provided in order to improve tolerability of medication change. In patients with comorbid psychiatric disorders, discontinuation of short-acting agents, such as alprazolam, is usually more problematic than the discontinuation of a long-acting agent, because it results in a faster onset of withdrawal symptoms and greater likelihood of the emergence of rebound anxiety (Schweizer et al. 1990). Therefore, the first stage of detoxification may involve transitioning to and stabilizing on a medication with a more favorable pharmacokinetics (slower onset and longer duration of action), such as clonazepam, chlordiazepoxide, or oxazepam. Most benzodiazepines have comparable profiles of receptor activity, but their tolerability may be related to pharmacokinetic properties. Therefore, change to an equivalent dose of another benzodiazepine may result in better tolerability without change in efficacy. This can be usually accomplished by a fairly rapid (1–2 weeks) cross-taper to equivalent doses of a new agent and a stabilization on a new medication (see Table 16–1 for a guideline on the dose equivalency). Often, the potential benefits of medications are outweighed by the significant adverse effects of high doses, and the second step might involve a significant dose decrease (e.g., to 20%–30% of the original dose). Such a dose decrease can be usually accomplished over a 6- to 8-week period without significant discomfort. At the lower dose, medication may have a less adverse effect and, therefore, a better overall therapeutic profile, and the decreased dose may be clinically indicated to continue maintenance treatment. In patients who cannot be stabilized on the alternative regimen of benzodiazepines, discontinuation of medication may be warranted. The most efficient approach to achieving complete cessation of benzodiazepine use involves a very (6–12 months) gradual taper (Ashton 2005) or a staged discontinuation in which patients receive the reduced dose for several months before proceeding with a further taper (Rickels et al. 1999a). Because a very slow discontinuation plan is often not feasible, it can be argued that an addition of adjunct medication may facilitate discontinuation and improve success rates. Strategies of

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pharmacological management of benzodiazepine withdrawal include targeting withdrawal symptoms and treatment of anxiety and mood or sleep disturbances that emerge during benzodiazepine discontinuation. A variety of medications that could potentially improve success rates of benzodiazepine discontinuation have been tested, but few well-controlled studies are available to confirm the efficacy of this strategy. The most promising approach involves addition of medications that enhance GABAergic activity through mechanisms other than that of a stimulation of GABAA, such as carbamazepine, valproate, gabapentin, topiramate, or lamotrigine. These medications are most commonly used as anticonvulsants, though their use in psychiatry in the treatment of anxiety or mood disorders (van Ameringen et al. 2004) as well as addictions (Johnson 2005) has been expanding. Some of these medications have been found to facilitate discontinuation of benzodiazepines. For example, adding valproate or carbamazepine has improved success rates of benzodiazepine discontinuation (Rickels et al. 1999b; Schweizer et al. 1991). Moreover, adding antidepressant medications such as imipramine (Rickels et al. 2000) or trazodone (Rickels et al. 1999b) during discontinuation and for several weeks afterward has also improved discontinuation success rates. Finally, targeting sleep disturbances by adding melatonin has improved sleep quality and facilitated discontinuation of benzodiazepines, compared with placebo treatment (Garfinkel et al. 1999). Other medications aimed at symptomatic treatment of withdrawal syndrome have included propranolol, clonidine, hydroxyzine, buspirone, and paroxetine, but none of these medication shows effectiveness when tested in controlled trials (Roy-Byrne et al. 1993; Voshaar 2006; Zitman and Couvée 2001). Most recently, a strategy aimed at underlying changes at the GABAA receptor has been proposed. Treatment with the benzodiazepine antagonist flumazenil was found to reduce craving and improve 1-month posttreatment abstinence rates compared with placebo or a rapid oxazepam taper (Gerra et al. 2002). Tolerability of benzodiazepine discontinuation can be greatly improved by addition of psychological therapy. Such therapy usually includes cognitive and behavioral components to help patients recognize and manage symptoms of withdrawal and rebound anxiety. Additionally, therapy can help patients transition from relying on medications to control anxiety toward promoting self-efficacy and developing behavioral strategies aimed at symptom control (Spiegel 1999). Treatment with adjunctive medications and behavioral therapy should continue during benzodiazepine discontinuation and for several weeks or months during the postdiscontinuation period, or until most residual symptoms are stabilized. At that point, a gradual discontinuation of adjunctive treatment may be initiated, if clinically warranted.

Patients with primary substance use comorbidity Use of sedative-hypnotics is very common in the population of substance abusers, and such use should certainly raise concern and warrants careful evaluation. However, there is no adequate evidence to suggest that use of these medications in individuals with other substance use disorders is equivalent to abuse or dependence and warrants immediate discontinuation. The general approach to dealing with these patients involves a traditional alcoholism treatment model and includes inpatient admission with a rapid (2- to 3-week) detoxification, followed by an abstinence-based outpatient treatment (Ashton 2005). However, treatment experience and research evidence in addiction psychiatry accumulated since the late 1990s suggest that a more individualized approach may benefit greater numbers of these patients (Watkins et al. 2005). The first step should include clarification of the primary reasons for taking medication, the presence of concurrent psychiatric problems, the presence of adverse physical and behavioral effects that may result from it, and the relationship between the use of sedative-hypnotics and alcohol or other drugs. Based on this assessment, an individualized treatment plan can be developed that may include psychosocial as well as pharmacological treatments (see Figure 16–3 for the suggested medication treatment strategies). FIGURE 16–3. Suggested sequenced treatment strategies for individuals with a primary substance use disorder who developed sedative-hypnotic use disorder.

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GABA = -aminobutyric acid.

Patients with abuse of or dependence on multiple drugs or alcohol Many patients who abuse sedative-hypnotics and alcohol or other drugs have relatively little additional psychiatric comorbidity. In these individuals, any use of sedative-hypnotics, even if it does not meet criteria of abuse or dependence, may escalate and further disrupt functioning. Treatment directed at discontinuation of all drugs of abuse is warranted in this case, and may include inpatient admission for detoxification and stabilization or an outpatient treatment approach. Admission to an inpatient unit for detoxification is indicated for all individuals who may be physically dependent on several substances (sedatives, anxiolytics, opiates, or alcohol); an outpatient approach is less likely to be successful in these patients. Because of the more complicated nature of withdrawal from multiple drugs, a more gradual detoxification process may be indicated. In these patients, detoxification from sedative-hypnotics and alcohol is best accomplished using a traditional benzodiazepine substitution and rapid discontinuation method (Harrison et al. 1984). Patients are stabilized on a long-acting benzodiazepine (such as chlordiazepoxide or clonazepam), which is then gradually reduced (e.g., at a rate of 10% per day). The initial dose can be established by calculating dose equivalency based on patient self-reports (see Table 16–1). However, in the case of dependence on various medications and alcohol, when calculation of equivalent dose is difficult, a loading technique may be preferable. In this case, increasing doses of medication (e.g., clonazepam in 1-mg dose increments) are given every 1–2 hours until mild signs of intoxication are evident. The initial 24-hour dose requirement can then be given in two divided doses for the next 2 days, after which the dose can be reduced by 10% until the patient is completely withdrawn, or the dose can be adjusted as indicated by the clinical condition (presence of intoxication or a significant withdrawal). Detoxification in patients who are elderly or have impaired liver function may be better accomplished by an agent with a shorter half-life and no active metabolites, such as lorazepam. Patients who were abusing barbiturates, meprobamate, or chloral hydrate may benefit from detoxification using a phenobarbital substitution technique (Smith and Wesson 1971). If patients have concurrent physical dependence on opiates, a stable, low dose of methadone (e.g., 20–30 mg/day) can be maintained during sedative-hypnotic detoxification to prevent most opiate withdrawal symptoms. After the benzodiazepine is discontinued, a decision regarding treatment of opioid dependence should be made. This might include stabilization on an agonist (methadone or buprenorphine) or transitioning to naltrexone. In patients who are dependent on several drugs, taking naltrexone as maintenance treatment might result in the best clinical outcome; rates of concurrent benzodiazepine use are lowest when patients are receiving naltrexone, as compared with buprenorphine or methadone maintenance treatment (Kosten 1994). In addition, naltrexone may be effective in preventing relapse to alcohol, which is commonly used by these patients. Opioid detoxification to complete abstinence without naltrexone maintenance is generally not indicated in this population, unless a very intensive and long-term residential treatment program can follow detoxification, given that the rate of relapse and risk for overdose in these patients is very high. Naltrexone is a viable alternative for

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patients with strong external incentives to remain abstinent (O'Brien and Cornish 2006), and this medication may become a more broadly applicable alternative with the advent of injectable, long-acting naltrexone (Comer et al. 2006). Cessation of drug use may also be attempted on an outpatient basis, and may include a slow-taper procedure, similar to procedures used in patients without polysubstance abuse (e.g., McDuff et al. 1993). However, detoxification completion rates for these patients are much lower than for patients who have a primary psychiatric disorder. In addition, a polydrug user may continue to abuse medications prescribed for the purposes of detoxification. An alternative outpatient strategy to decrease use and induce abstinence involves a behavioral therapy approach, such as a contingency management therapy. This can be particularly useful in patients participating in a structured outpatient treatment program. This therapy produced significant reduction of benzodiazepine use in a population receiving methadone maintenance treatment who was provided methadone take-home doses or vouchers in return for benzodiazepine-negative toxicology (Stitzer et al. 1992).

Patients with coexisting psychiatric disorders Patients who have a substance abuse disorder with a coexisting psychiatric disorder may still benefit from benzodiazepine treatment. This is particularly relevant for patients whose psychiatric symptoms are well controlled with medication and who have few or no treatment-related adverse effects. Close monitoring is warranted in these patients because the risk of developing sedative-hypnotic use disorders is increased in patients with comorbid psychiatric disorders (see Table 16–4). Maintenance treatment with benzodiazepines has also been suggested, particularly for patients with substantial psychiatric comorbidity who are usually doing poorly during and following complete discontinuation of sedative-hypnotics (Joughin et al. 1991). This approach may involve transitioning and maintenance treatment with a long-acting agent, such as clonazepam, with a close monitoring of effectiveness and safety. Maintenance treatment as a general course is supported by extensive successful experience with the treatment of opioid dependence using methadone or buprenorphine. However, experimental evidence to support its safety and efficacy in the treatment of sedative-hypnotic dependence is still scarce and relies mostly on uncontrolled trials and anecdotal reports (Weizman et al. 2003). In this population, treatment with benzodiazepines may stabilize psychiatric symptoms, decreasing general distress and removing triggers for use of alcohol or other drugs. Despite concerns that using benzodiazepines in patients with drug and alcohol abuse will lead to worsening of their clinical condition, such patients showed no differences from untreated patients during the follow-up (Barlow 1997) and might even have incurred some benefits (Kosten et al. 2000).

Relapse Prevention The goal of relapse prevention treatment is to maintain gains achieved during detoxification and attain a sustained, long-term abstinence. Neurobiological abnormalities resulting from chronic drug use can persist for weeks or months following detoxification and may be expressed as emotional disturbances, altered hedonic state, or increased vulnerability to stress and stimuli previously associated with drug use (O'Brien et al. 1998). These changes, which may result from overactive brain stress systems and compromised orbitofrontal/prefrontal cortex function, can contribute to relapse in the first months following cessation of drug use (Koob 2006). Pharmacological interventions may be necessary to target relapse. Recent studies have shown that the neurobiological mechanisms responsible for the maintenance of drug taking are different from the mechanisms that underlie relapse (Shaham et al. 2003). Therefore, treatments targeting specific pathological processes at different stages of the disease process may be necessary to optimize long-term clinical management of addicted individuals, and will most likely involve a combination of behavioral therapy and medications. Pathophysiology of relapse might involve altered functioning of GABAA receptors. Consistent with that, preliminary clinical evidence supports the use of indirect GABAergic agonists, such as carbamazepine or valproate, in early abstinence. These medications can be used not only to facilitate discontinuation of benzodiazepines but also afterward to prevent relapse. This plan would be functionally parallel to partial agonist–based treatment that has been found to be effective in the long-term treatment of opioid (Ling et al. 1996) and nicotine (Jorenby et al. 2006) dependence. Indeed, studies that used valproate or carbamazepine to assist in detoxification have revealed that beneficial effects on abstinence persisted only in patients maintained on medication following detoxification (Rickels et al. 1999b; Schweizer et al. 1991). Another related medication, topiramate, has been found to be effective in some patients with alcohol dependence (Johnson et al. 2003). As pharmacological and behavioral effects of alcohol substantially overlap with effects of benzodiazepines, it is conceivable that topiramate and related compounds may be effective in the long-term treatment of sedative-hypnotic dependence. Another approach that remains investigative at this stage involves treatment with the benzodiazepine antagonist flumazenil. Patients who received flumazenil infusions during detoxification had significantly lower relapse rates during the first month after detoxification than did patients who were treated with oxazepam or placebo (Gerra et al. 2002). It is proposed that a course of flumazenil may reverse neuroadaptations that persist in early abstinence and may contribute to relapse. However, safety of this approach requires further studies, given that flumazenil may precipitate withdrawal and induce seizures in physically dependent patients (Seger 2004). Until more is known about the neurobiology of relapse and more medications become available, psychosocial approaches will remain a mainstay of treatment. Numerous approaches are available, and implementation of behavioral therapy following discontinuation of medication taper can be very effective in preventing relapse. Abstinence rates have been maintained in over 75% of patients with panic disorder who discontinued alprazolam pharmacotherapy (Bruce et al. 1999).

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Combining psychological treatments with medications that target mechanisms underlying relapse may further enhance efficacy of available treatments.

KEY POINTS Benzodiazepines and other sedative-hypnotics with a common mode of action at -aminobutyric acid (GABA)A receptors are highly useful medications for treatment of anxiety and insomnia as well as other disorders in psychiatry, neurology, and anesthesiology. The abuse liability of benzodiazepines and the risk of developing DSM-IV-TR sedative-hypnotic use disorders are generally low. This also pertains to patients who are treated with sedative-hypnotics for an extended period of time and develop physical dependence. Patients who are chronically prescribed benzodiazepines or other sedative-hypnotics should always be monitored both for the development of adverse side effects and the behavioral changes suggestive of a substance use disorder. Signs of emerging abuse or dependence include 1) the development of excessive tolerance to the primary effect, with frequent requests for dose escalation; 2) continued and escalating use despite the presence of impairing adverse effects (e.g., excessive sedation); 3) use of medication to obtain euphoric effects; 4) preoccupation with medication and reported inability to function without it; and 5) additional use of illicit drugs and excessive use of alcohol. Patients who meet DSM-IV-TR criteria for sedative-hypnotic use disorder often have other drug or alcohol use disorders, which are frequently the presenting problem. Thus, patients presenting with any substance use disorder should always be screened for sedative-hypnotic use, abuse, or dependence. It is preferable not to prescribe benzodiazepines or other sedative hypnotics as a first choice to treat psychiatric disorders in patients with a history of current alcohol or drug use disorders. These patients are at greater risk of developing benzodiazepine use disorder, and, often, other medications with lower abuse liability can be used. History of substance use disorder is not an absolute contraindication to treatment with sedative-hypnotics. Benzodiazepines are useful for detoxification from alcohol and opioids. Patients with anxiety disorder or insomnia who show resistance to other treatments can often be treated safely, along with careful monitoring for the emergence of signs of abuse or dependence. The presence of benzodiazepine or other sedative-hypnotic use in patients with alcohol or drug use disorders should prompt a careful history to look for co-occurring mood, anxiety, or sleep disorders, given that appropriate treatment for these conditions may reduce or eliminate the need for benzodiazepines. Patients who may no longer benefit from sedative-hypnotic medications, those who cannot be stabilized on the alternative dosing regimen, and those who primarily abuse the medication to achieve euphoria require medication discontinuation and treatment to prevent relapse. Detoxification from benzodiazepines in individuals who were maintained on them for a long time can be best accomplished by substituting an agent with slow absorption and a long half-life (e.g., clonazepam, chlordiazepoxide), followed by a very slow (i.e., several months), gradual taper. Inpatient detoxification may be indicated in individuals with substance use disorders who are physically dependent on several substances (sedatives, anxiolytics, opiates, or alcohol). In the last phase of detoxification, stabilization on a very low dose of tapered medication may be warranted. Furthermore, during the final stage of detoxification, intensive behavioral therapy and adjunctive medication (e.g., carbamazepine, valproate, or imipramine) may be added to facilitate transition to complete abstinence. This treatment should be maintained for several weeks or months afterward to prevent early relapse and solidify extended abstinence.

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SUGGESTED READING Griffiths RR, Weerts EM: Benzodiazepine self-administration in humans and laboratory animals—implications for problems of long-term use and abuse. Psychopharmacology (Berl) 134:1–37, 1997 Mohler H, Fritschy JM, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 300:2–8, 2002 Rickels K, DeMartinis N, Rynn M, et al: Pharmacologic strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol 19:12S–16S, 1999a Spiegel DA: Psychological strategies for discontinuing benzodiazepine treatment. J Clin Psychopharmacol 19:17S–22S, 1999 Watkins KE, Hunter SB, Burnam MA, et al: Review of treatment recommendations for persons with a co-occurring affective or anxiety and substance use disorder. Psychiatr Serv 56:913–926, 2005 Woods JH, Winger G: Current benzodiazepine issues. Psychopharmacology (Berl) 118:107–115; discussion 120–121, 1995 Copyright © 2011 American Psychiatr c Associat on. All Rights Reserved.

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Chapter 17. Treatment of Anabolic-Androgenic Steroid-Relat...

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Harrison G. Pope, Kirk J. Brower: Chapter 17. Treatment of Anabolic-Androgenic Steroid–Related Disorders, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.348286. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Treatment of Anabolic-Androgenic Steroid–Related Disorders Harrison G. Pope Jr., M.D. Kirk J. Brower, M.D.

TREATMENT OF ANABOLIC-ANDROGENIC STEROID–RELATED DISORDERS: INTRODUCTION The anabolic-androgenic steroids (AAS) are a family of hormones that includes the natural male hormone testosterone and more than 100 other synthetic relatives of testosterone (Pope and Brower 2004). All AAS possess both anabolic (muscle-building) and androgenic (masculinizing) properties. Data from the National Household Survey on Drug Abuse (1994) suggest that about 1 million American men have used these drugs at some time. Although AAS use was once confined largely to elite athletes, increasing numbers of young men have now begun to use these drugs to gain muscle and lose fat, often simply for the sake of personal appearance (Kanayama et al. 2001). The majority of these men are in their 20s or 30s, with a minority starting AAS use as teenagers (Kanayama et al. 2007). Girls and women rarely use AAS because they are less likely to want to be muscular and because AAS use makes women subject to their masculinizing effects, such as beard growth, deepening voice, and masculinizing of sexual characteristics (Gruber and Pope 2000). Although some recent anonymous surveys have suggested that substantial numbers of females have used AAS (CDC, U.S. Department of Health and Human Services 2005), these surveys have likely produced inflated estimates as a result of false positive responses on questionnaires; the true number of female AAS users is likely very small (Kanayama et al. 2007). For these reasons, the following discussion will focus primarily on treatment of male AAS users, although the general principles expressed would presumably apply to the rare cases of female users as well (Gruber and Pope 2000). Although AAS pose important medical and psychiatric risks (described later in this chapter), AAS users almost never seek treatment. Indeed, one recent study reported that 56% of illicit users had never disclosed their AAS use to any physician at any time in their lives (Pope et al. 2004). There are several reasons for this phenomenon. First, many users perceive their use of AAS to be a positive and healthy activity when it is combined with intensive exercise and optimal diet as part of a bodybuilding lifestyle. Commercial and societal forces are partly responsible for this misperception of AAS (Kanayama et al. 2001): muscular male bodies are portrayed as an ideal in advertising, magazines, television, and movies. Even children's action toys, such as G.I. Joe, have grown from ordinary-looking men in the 1960s and 1970s to muscle-bound specimens in the 1990s (Pope et al. 1999). Makers of cars, electronics, and other products may promote their products as "on steroids," but they would never claim that their products were "on marijuana" or "on cocaine." Given this societal climate, it is not surprising that AAS users rarely perceive their drug use as a psychiatric disorder requiring treatment. Second, AAS are very different from conventional drugs of abuse. Most drugs of abuse described in this volume deliver an immediate reward in the form of intoxication within minutes or hours of ingestion. However, with body image drugs such as AAS, the immediate reward is negligible (except perhaps in Stage 2 AAS dependence; see the section "AAS Dependence" later in this chapter), and the user is seeking a long-term reward in the form of a more muscular body, athletic success, or admiration from peers or potential sexual partners. Thus, conventional methods of treating substance abuse are usually inappropriate unless modified specifically for AAS users (Brower 2000; Kanayama et al. 2001).

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Third, some AAS users have little respect for doctors. Underground guides and Internet sites for illicit AAS users are replete with derogatory remarks about health professionals (Duchaine 1989); AAS users may regard physicians as "geeks" or "pencil-necks" who have no understanding of the bodybuilding world. For example, in one recent study, AAS users gave high marks to doctors on knowledge of tobacco, alcohol, and ordinary drugs of abuse, but much lower marks on knowledge of AAS. In the same study, 40% of AAS users reported that they trusted information about AAS from their drug dealers at least as much as information from any physician that they had seen (Pope et al. 2004). There is some basis for this distrust: for decades, many medical professionals asserted that AAS were ineffective for gaining muscle mass. This claim, based on two decades of seriously flawed studies, caused doctors to lose their credibility among many athletes (Pope and Brower 2004). Now, most professionals finally concede that AAS are effective for gaining muscle mass, but they still remain largely uninformed about the extent and nature of the AAS-using subculture. Several recent papers have stressed that clinicians should attempt to become more familiar with AAS and AAS-associated syndromes (Brown 2005; Dawson 2001; Kutscher et al. 2002; Pope and Kanayama 2005). Given the above considerations, it is understandable that AAS users almost never voluntarily request treatment to stop using these drugs. Nevertheless, there are a number of specific situations that bring AAS users to the attention of clinicians, at which point some attempt at treatment may be initiated. These include 1) AAS dependence syndromes; 2) hypomanic and manic syndromes during AAS exposure; 3) syndromes of depression and anxiety associated with AAS withdrawal; 4) co-occurring substance use disorders, including progression from AAS use to opioid abuse and dependence; 5) body image disorders associated with AAS use; and 6) forensic situations, such as cases of AAS-induced violence or criminality. In the sections below, we begin with a general discussion of the initial identification and assessment of AAS users and continue with each of the six clinical issues enumerated above.

IDENTIFICATION AND ASSESSMENT Identification AAS use is one of the few types of substance use where a diagnosis is often suggested simply by looking at the patient as he walks through the door (Pope and Kanayama 2005). As we have described elsewhere (Kouri et al. 1995), there is a fairly sharp upper limit of muscularity that can be achieved by a lean individual without the help of drugs. We have published a formula to calculate muscularity, expressed as the fat-free mass index (FFMI), which clinicians can apply if they know the height, weight, and approximate percentage of body fat of the patient (Kouri et al. 1995). Men who have low body fat and display an FFMI of greater than approximately 26 kg/m 2 are almost certainly using drugs that help them to achieve their size. We have published photographs comparing bodybuilders who have used AAS with those who have not to aid the clinician in making this distinction (Pope and Brower 2004). Clinicians who suspect AAS use in any patient should follow several guidelines, described in the following section, to take a specific history.

History The clinician may lead into the topic of AAS by asking about athletic or fitness-related activities. Young men who lift weights regularly are at greatest risk to use AAS (Brower et al. 1994). Other lead-in topics include the use of over-the-counter and mail-order dietary supplements such as vitamins, minerals, amino acids, creatine, and dehydroepiandrosterone (DHEA), because the use of such legal substances is commonly associated with AAS use. The clinician might also ask whether the patient knows other people who use AAS—potential users often learn about AAS from other users. Finally, the clinician could directly ask whether the patient has ever tried AAS or thought about using them, and if so, why the patient is interested in using and what has prevented the patient from using to date. Patients thinking about AAS use are good candidates for prevention. In addressing these questions, it is particularly critical for the clinician to be nonjudgmental, while still discouraging use. For patients who admit to having tried AAS, both the perceived benefits and any adverse consequences

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of use are important to determine. The dates of first and last use, the names and doses of AAS used, sources of drugs, and routes of administration should be ascertained. Patients who inject AAS should be asked about needle sharing. Sources of drugs include prescriptions, diversion from the legal market (including the veterinary market), and the illicit market. Unlike many other drugs of abuse such as heroin and cocaine, AAS are legally available without a prescription in many countries outside of the United States. Thus, potential AAS users can easily travel to nearby countries and also find Internet sites offering to sell AAS from overseas. Drugs purchased through these sites and received through the mail are often not intercepted. Patients and clinicians should remember that drugs obtained from the illicit domestic market and from overseas sources are frequently adulterated, falsely labeled, and sometimes nonsterile. In short, the user does not necessarily know what and how much he is taking. Inquiry into the patterns of use is also important. Illicit AAS users typically combine, or "stack," multiple AAS, including both oral and injected intramuscular forms, in order to achieve doses that are 10–100 times the amounts ordinarily prescribed for therapeutic indications (Perry et al. 2005; Pope and Brower 2004). AAS are usually taken in courses, or "cycles," of 4–16 weeks or more, often characterized by taking small doses at the beginning, building to large doses and combinations in the middle, and tapering doses at the end—a pattern referred to as a pyramid. The clinician gains useful information when exploring the role of cycling with an individual AAS user. Does the patient cycle off AAS to avoid testing positive on drug screening? Does the patient cycle off AAS to give his body a rest, allowing his endogenous hormonal system a chance to regain normal functioning? Does the patient experience depression or other withdrawal symptoms during off periods? Dependent users may eliminate cycling altogether in favor of prolonged, continuous use in order to avoid withdrawal symptoms. Finally, a history of other drug abuse should be obtained. Users often combine other drugs with AAS to augment their effects (e.g., human growth hormone, human chorionic gonadotropin, clenbuterol), to reduce unpleasant side effects (e.g., clomiphene, tamoxifen), and to mask urine testing (e.g., probenicid, diuretics). Also, in contradiction to the image of the healthy bodybuilding lifestyle, a large portion of AAS users display a history of other forms of substance abuse or dependence. For example, in one study, 25% of men hospitalized for opioid dependence were found to report a history of AAS use (Kanayma et al. 2003a); in another study, 88% of AAS users reported past use of other illicit drugs, and 44% met the DSM-IV-TR criteria for a history of abuse of or dependence on alcohol and/or an illicit drug (American Psychiatric Association 2000; Kanayama et al. 2003b).

Physical Examination The physical examination is essential to detect the somatic consequences of using AAS. Generalized muscle hypertrophy with a disproportionately large upper torso (neck, shoulders, arms, and chest) is readily apparent. The skin is examined for acne (on the face, shoulders, and back) and needle marks in large muscles (especially the gluteals, but sometimes the thigh and deltoids). Gynecomastia, caused by metabolic conversion of excess testosterone to estrogen, may be detectable by palpation or even simple observation in some men. Gynecomastia may occasionally be sufficiently marked to require surgical intervention (Babigian and Silverman 2001). By contrast, the testicles become atrophic as they shut down testosterone production when exogenous AAS are administered in high doses; this may lead to azoospermia and sterility (Torres-Calleja et al. 2001). Male pattern baldness, hirsutism, hypertension, hepatomegaly, right upper quadrant tenderness, jaundice, and prostatic hypertrophy are also possible but are not reliably associated with AAS use. In women, hirsutism, deepening of the voice, and clitoral hypertrophy may be detected.

Mental Status Examination The clinician should assess the patient's appearance for excessive muscularity as described above, sometimes disguised by oversized clothes, especially in patients with muscle dysmorphia who become preoccupied that they do not look big enough (Pope et al. 1997). The patient's cooperation may vary depending on his defensiveness or denial of AAS use. Speech and sensorium are generally normal. However, if the patient is experiencing hypomanic or manic symptoms from current AAS use, he may

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display irritability, agitation, and possibly grandiose beliefs. Patients experiencing depression from AAS withdrawal may exhibit depressed mood, dysphoria, anxiety, psychomotor retardation, and possible suicidal ideation.

Laboratory Examination Laboratory abnormalities reported in AAS users are summarized in Table 17–1. Standard urine screens for drugs of abuse do not include AAS, so urine testing for AAS must be performed at a reference laboratory. Such testing can detect only recent AAS use; orally active AAS disappear from the urine within weeks, and most intramuscular preparations disappear within a few months. However, given the association between AAS use and other illicit drug use, standard urine screens for illicit drugs should also be ordered. Important blood chemistries include skeletal muscle enzymes, but these can be elevated even in non-AAS users after intensive weight training. AAS users may occasionally display extreme elevations of creatine kinase from rhabdomyolysis (Braseth et al. 2001; Pertusi et al. 2001). Standard liver function tests, such as transaminases and lactic dehydrogenase, are nonspecific, because these enzymes are also present in muscle and may be elevated from weight training. Elevation of chemistries specific to the liver, such as bilirubin and -glutamyltransferase, may suggest true hepatic abnormalities, whereas elevated creatine kinase (an enzyme largely specific to muscle) may suggest muscle damage (Braseth et al. 2001). Blood testosterone concentrations may be grossly elevated in patients who are administering exogenous testosterone, or they may be grossly depressed in patients who are administering other types of AAS and thereby inhibiting their own endogenous testosterone production. Testosterone levels may also remain depressed for weeks and sometimes months during AAS withdrawal.

General Considerations Although many health consequences of using AAS are readily detectable by performing a comprehensive history, physical examination, and laboratory tests, the long-term health consequences are poorly studied (Parssinen and Seppala 2002) despite the fact that evidence of premature mortality among AAS users continues to accumulate (Parssinen et al. 2000; Petersson et al. 2006; Thiblin et al. 2000). Therefore, the clinician should be alert to heretofore undocumented sequelae of AAS use as the first generation of users advance in age. In the meantime, the following syndromes resulting from long-term use are most likely to bring AAS users to the attention of psychiatrists.

AAS dependence Although the "anabolic steroid addiction hypothesis" (Kashkin and Kleber 1989) remains subject to debate (Bahrke and Yesalis 1994; Midgley et al. 1999), AAS are included and discussed in DSM-IV-TR under the category of "Other (or Unknown) Substance-Related Disorders," and a recent review of the medical literature has documented at least 165 AAS users who met DSM-III-R or DSM-IV criteria (American Psychiatric Association 1987, 1994) for AAS dependence (Brower 2002). We have hypothesized a two-stage model of dependence on AAS (Brower 2002; Pope and Brower 2004). During stage 1, users are primarily interested in developing muscle size and power to improve their body image or athletic performance. Training and diet at this stage have a compulsive quality to them that extends to using AAS. The AAS user may appear to meet DSM-IV-TR criteria for substance dependence at this stage because of the compulsive nature of drug taking. This stage of dependence, however, can be explained without invoking any psychoactive properties of AAS because AAS are strongly "myoactive" and they do help users to achieve their muscle-related goals when combined with proper training and diet. Addiction-specialized treatment is not likely to be needed at this stage, although treatment for a body image disorder, such as muscle dysmorphia, may be (Pope et al. 1997). According to the model, some AAS users will eventually develop stage 2 dependence, perhaps due in part to genetic vulnerability and in part to cumulative, high-dose exposure to AAS. Chronically

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consumed high doses of AAS are postulated to stimulate brain reward systems in humans, as suggested by the animal literature (Kindlundh et al. 2004; Peters and Wood 2005; Wood 2004), and to result in neuroadaptations in other brain systems that manifest as withdrawal symptoms upon discontinuation. Thus, users take AAS for both their psychoactive and myoactive effects at this stage. Clinically, stage 2 dependence resembles dependence on traditional drugs of abuse, and it meets formal DSM-IV-TR criteria for substance dependence. In addition, stage 2 dependent users may have co-occurring dependence on other drugs of abuse, such as opioids, alcohol, and stimulants. Stage 2 users have difficulty stopping drug use on their own and are likely to require addictionspecialized treatment. The first step in such treatment is to initiate and motivate the patient for abstinence. As with other drugs of abuse, motivational techniques include providing empathic feedback and encouraging self-efficacy as well as involving family and friends (Brower and Rootenberg 1999). Feedback, given in a nonjudgmental manner, about findings from the physical examination and laboratory abnormalities allows for engagement around bodily concerns. Encouraging self-efficacy takes advantage of the patient's need to see oneself as big, powerful, and strong. Initiating abstinence also involves the treatment of withdrawal symptoms, which are discussed in detail in the section "AAS Withdrawal Depression" later in this chapter. After initiating abstinence, the principles of relapse prevention may be applied as with other addicted individuals, but there are also unique therapeutic issues to address in AAS users. One is the overreliance on physical attributes for self-esteem that resembles the dynamics of patients with eating disorders and body dysmorphic disorder (Pope et al. 1997). Therefore, the diagnosis of comorbid mental disorders not ordinarily observed in patients with substance dependence is important. Another therapeutic issue concerns the psychological response to giving up AAS, which have likely served the patient to achieve some measure of competitive success. The patient will likely feel smaller and weaker, both literally and figuratively, without AAS. In helping the patient to accept the loss of AAS, the clinician appreciates that 1) the patient's goals were culturally congruent (the bigger, better, stronger, winner) and 2) AAS are potently myoactive and really can facilitate those goals.

AAS hypomania and mania A substantial portion of the literature since the mid-1990s has demonstrated that AAS produce hypomanic or manic syndromes in some individuals, which are sometimes accompanied by aggressive or violent behavior and, very rarely, psychotic symptoms (Pope and Katz 2003). These effects are rare in individuals taking the equivalent of 300 mg/week or less of testosterone, but they appear to become progressively more common with higher dosages, especially above 1,000 mg/week (Pope and Katz 1994). These syndromes were initially noted in field studies of illicit AAS users, and some investigators questioned whether the effects were actually due to AAS themselves, as opposed to expectational factors, personality variables, or subcultural influences (Bahrke and Yesalis 1994; Riem and Hursey 1995). Recently, however, several studies have demonstrated that such syndromes can develop even in psychiatrically healthy volunteers taking supraphysiological doses of AAS under placebo-controlled, double-blind laboratory conditions (Pope et al. 2000; Su et al. 1993; Yates et al. 1999). Therefore, the mood-altering effects of AAS almost certainly have a biological basis, even though they can undoubtedly be modified by contextual factors (Rubinow and Schmidt 1996). Little has been written about the treatment of manic or hypomanic episodes beyond anecdotal reports (Pope and Katz 1988; Stanley 1994). Thus, the best treatment recommendations would seem to include removal of the offending agent and temporary treatment, if necessary, with neuroleptics or other anti-manic drugs. In general, it appears that manic or hypomanic episodes will remit quickly when AAS are stopped and that clinicians should be alert for the onset of depressive symptoms associated with abrupt AAS withdrawal. If a patient reports a history of mood disorder prior to AAS use or continues to exhibit manic or psychotic symptoms for more than a week or two after AAS are stopped, it would seem important to consider the possibility of an underlying major mood disorder independent of AAS.

AAS withdrawal depression

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The withdrawal syndrome from AAS is primarily depressive in nature and includes symptoms of fatigue, restlessness, anorexia, insomnia, decreased libido, and a desire to take more AAS (craving) in addition to depressed mood (Brower 2000). The syndrome typically lasts for several weeks and usually does not require specific pharmacological treatment. However, some individuals may develop severe or persistent depressive symptoms, sometimes accompanied by suicidal ideation. In one study, 4% of AAS users reported that they had actually made a suicide attempt during AAS withdrawal (Malone et al. 1995). Depression accompanying AAS withdrawal appears to respond well to selective serotonin reuptake inhibitors such as fluoxetine (Malone and Dimeff 1992). These drugs are also the agents of choice for treating muscle dysmorphia and other forms of body dysmorphic disorder that may accompany AAS use (Phillips 2000). The hypothalamic-pituitary-gonadal (HPG) axis can be depressed for many months during the withdrawal period, resulting in sterility in some cases and contributing to depressive symptoms in others. In men who continue to exhibit impaired sexual function or persistent depressive symptoms despite pharmacotherapy, consultation with an endocrinologist should be considered. Endocrine pharmacotherapy, including injected testosterone esters, human chorionic gonadotropin, and anti-estrogens, may be indicated to restore functioning of the HPG axis in such cases (Brower 2000; Menon 2003).

Syndromes associated with AAS use Recent years have seen the appearance of two important syndromes that appear associated with AAS use. The first, termed muscle dysmorphia or reverse anorexia nervosa, is a form of body dysmorphic disorder in which the individual perceives himself to be small and frail, even though he is actually large and muscular (Cole et al. 2003; Kanayama et al. 2006; Olivardia et al. 2000; Pope et al. 1997). Men with muscle dysmorphia will often engage in compulsive weightlifting and bodybuilding, even to the exclusion of other activities that they enjoy. They frequently will avoid situations in which their body will be seen by others, such as going to the beach or changing in a locker room, for fear that they look too small. Not surprisingly, such individuals may use AAS to "treat" their preoccupation, but paradoxically, many describe even more severe symptoms of muscle dysmorphia following initiation of AAS use. There are no systematic studies of treatment of muscle dysmorphia per se, but it seems reasonable to follow general principles of treatment of other forms of body dysmorphic disorder, relying on cognitivebehavioral and pharmacological interventions (Neziroglu ad Khemlani-Patel 2002; Phillips 2000; Phillips et al. 1997). Another ominous syndrome associated with AAS use has been progression from AAS to opioid abuse and dependence. Specifically, many AAS users learn about opioids from fellow bodybuilders and often first purchase opioids from the same individual who sold them AAS (Arvary and Pope 2000; Kanayama et al. 2003a; McBride et al. 1996; Wines et al. 1999). AAS users often start by experimenting with the opioid agonist-antagonist nalbuphine, followed by progression to pure opioid agonists, including heroin. The authors are personally aware of many deaths among AAS users who developed opioid abuse or dependence and then inadvertently overdosed on intravenous opioids. Needless to say, opioid abuse or dependence in current or former AAS users should be aggressively treated (see Chapters 18, 19, and 20 in this volume regarding opioid use and treatment).

AAS IN FORENSIC SITUATIONS AAS users may occasionally come to clinical attention through the courts as the result of violent or criminal behavior. Specifically, numerous works have described individuals, often with no history of psychiatric disorder, violence, or criminal behavior, who became uncharacteristically violent, and sometimes committed murder, while intoxicated with AAS (see Pope and Katz 2003). In some such cases, the relationship to AAS use may be missed because the possibility is never considered. However, AAS use should be suspected in any unusually muscular man apprehended for violent behavior, especially if it appears that this violence is not characteristic of his usual personality. The clinician's index of suspicion should be particularly raised when such a man rapidly develops vegetative symptoms

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of depression after being incarcerated, but then improves a few weeks or months later. This pattern may indicate AAS withdrawal, precipitated by the abrupt discontinuation of AAS following incarceration, with a gradual remission of depressive symptoms as suppressed HPG function gradually returns to normal. Of course, this pattern of biological depression must be distinguished from the situational depression associated with incarceration itself. In cases where AAS use is openly acknowledged by the defendant and appears to have been a clear precipitant of criminal behavior, forensic clinicians may be asked to offer an opinion that the defendant exhibited "involuntary intoxication" or "diminished capacity" from AAS. (The legal aspects of this defense have been discussed in detail elsewhere [Bidwell and Katz 1989].) If an individual is released and placed on probation after a crime believed to be associated with AAS, it may be wise to require random, unannounced, observed urine tests for AAS to ensure that he does not resume these drugs.

CONCLUSION Of the various forms of substance abuse and dependence described in this volume, AAS abuse and dependence may be the least likely to come to the attention of the average clinician. However, the frequency of surreptitious AAS abuse and dependence, together with the various psychiatric syndromes associated with it, is very likely underestimated, and many cases doubtless go unrecognized. Greater awareness of this problem among clinicians may lead to the detection of many more cases as well as a better understanding of how best to treat them.

KEY POINTS The use of anabolic-androgenic steroid (AAS) must be approached differently from other forms of substance abuse because AAS do not produce an immediate reward or "high" in the manner of conventional drugs of abuse and are linked to body dysmorphic disorder. AAS users rarely see their drug use as pathological, rarely seek treatment, and may have contempt for physicians. AAS users often display a history of abuse of or dependence upon other drugs, especially opioids. Some individuals experience hypomanic or manic symptoms during AAS exposure and depressive symptoms during AAS withdrawal. AAS may produce a well-documented dependence syndrome for which an animal model exists.

REFERENCES American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 3rd Edition, Revised. Washington, DC, American Psychiatric Association, 1987 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Arvary D, Pope HG Jr: Anabolic steroids as a gateway to opioid dependence. N Engl J Med 342:1532, 2000 [PubMed] Babigian A, Silverman RT: Management of gynecomastia due to use of anabolic steroids in bodybuilders. Plast Reconstr Surg 107:240–242, 2001 [PubMed] Bahrke MS, Yesalis CE: Weight training. A potential confounding factor in examining the psychological and behavioural effects of anabolic-androgenic steroids. Sports Med 18:309–318, 1994 [PubMed] Bidwell M, Katz DL: Injecting new life into an old defense: anabolic steroid-induced psychosis as a paradigm of involuntary intoxication. University of Miami Entertainment Sports Law Review 7:1–63, 1989

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Braseth NR, Allison EJ Jr, Gough JE: Exertional rhabdomyolysis in a body builder abusing anabolic androgenic steroids. Eur J Emerg Med 8:155–157, 2001 [PubMed] Brower KJ: Assessment and treatment of anabolic steroid abuse, dependence, and withdrawal, in Anabolic Steroids in Sport and Exercise, 2nd Edition. Edited by Yesalis CE. Champaign, IL, Human Kinetics, 2000, pp 305–332 Brower KJ: Anabolic steroid abuse and dependence. Curr Psychiatry Rep 4:377–387, 2002 [PubMed] Brower KJ, Rootenberg JH: Counseling for substance abuse problems, in Counseling in Sports Medicine. Edited by Ray R, Wiese-Bjornstal D. Champaign, IL, Human Kinetics, 1999, pp 179–204 Brower KJ, Blow FC, Hill EM: Risk factors for anabolic-androgenic steroid use in men. J Psychiatr Res 28:369–380, 1994 [PubMed] Brown JT: Anabolic steroids: what should the emergency physician know? Emerg Med Clin North Am 23:815–826, 2005 [PubMed] Centers for Disease Control and Prevention (CDC), U.S. Department of Health and Human Services: Youth risk behavior surveillance—United States, 2005. MMWR Morb Mortal Wkly Rep 55:SS–5, 2006. Data available online at: http://www.cdc.gov/HealthyYouth/yrbs/data/index.htm. Accessed November 22, 2007. Cole JC, Smith R, Halford JC, et al: A preliminary investigation into the relationship between anabolicandrogenic steroid use and the symptoms of reverse anorexia in both current and ex-users. Psychopharmacology (Berl) 166:424–429, 2003 [PubMed] Dawson RT: Drugs in sport—the role of the physician. J Endocrinol 170:55–61, 2001 [PubMed] Duchaine D: Underground Steroid Handbook II. Venice, CA, HLR Technical Books, 1989 Gruber AJ, Pope HG Jr: Psychiatric and medical effects of anabolic-androgenic steroid use in women. Psychother Psychosom 69:19–26, 2000 [PubMed] Kanayama G, Pope HG Jr, Hudson JI: "Body image" drugs: a growing psychosomatic problem. Psychother Psychosom 70:61–65, 2001 [PubMed] Kanayama G, Cohane G, Weiss RD, et al: Past anabolic-androgenic steroid use among men admitted for substance abuse treatment: an underrecognized problem? J Clin Psychiatry 64:156–160, 2003a Kanayama G, Pope HG Jr, Cohane G, et al: Risk factors for anabolic-androgenic steroid use among weightlifters: a case-control study. Drug Alcohol Depend 71:77–86, 2003b Kanayama G, Barry S, Hudson JI, et al: Body image, self-esteem, and attitudes towards male roles in anabolic-androgenic steroid users. Am J Psychiatry 163:697–703, 2006 [Full Text] [PubMed] Kanayama G, Boynes M, Hudson JI, et al: Anabolic steroid abuse among teenage girls: an illusory problem? Drug Alcohol Dep 88:156–162, 2007 [PubMed] Kashkin KB, Kleber HD: Hooked on hormones? An anabolic steroid addiction hypothesis. JAMA 262:3166–3170, 1989 [PubMed] Kindlundh AM, Rahman S, Lindblom J, et al: Increased dopamine transporter density in the male rat brain following chronic nandrolone decanoate administration. Neurosci Lett 356:131–134, 2004 [PubMed] Kouri E, Pope HG, Katz DL, et al: Fat-free mass index in users and non-users of anabolic-androgenic steroids. Clin J Sport Med 5:223–228, 1995 [PubMed] Kutscher EC, Lund BC, Perry PJ: Anabolic steroids: a review for the clinician. Sports Med 32:285–296, 2002 [PubMed]

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Malone DA Jr, Dimeff RJ: The use of fluoxetine in depression associated with anabolic steroid withdrawal: a case series. J Clin Psychiatry 53:130–132, 1992 [PubMed] Malone DA Jr, Dimeff R, Lombardo JA, et al: Psychiatric effects and psychoactive substance use in anabolic-androgenic steroid users. Clin J Sports Med 5:25–31, 1995 [PubMed] McBride AJ, Williamson K, Petersen T: Three cases of nalbuphine hydrochloride dependence associated with anabolic steroid abuse. Br J Sports Med 30:69–70, 1996 [PubMed] Menon DK: Successful treatment of anabolic steroid-induced azoospermia with human chorionic gonadotropin and human menopausal gonadotropin. Fertil Steril 79 (suppl 3):1659–1661, 2003 Midgley SJ, Heather N, Davies JB: Dependence producing potential of anabolic-androgenic steroids. Addiction Research 7:539–550, 1999 National Household Survey on Drug Abuse, 1994. Available at: http://www.icpsr.umich.edu/cocoon /ICPSR/DAS/06949.xml. Accessed November 22, 2007. Neziroglu F, Khemlani-Patel S: A review of cognitive and behavioral treatment for body dysmorphic disorder. CNS Spectrums 7:464–471, 2002 [PubMed] Olivardia R, Pope HG Jr, Hudson JI: Muscle dysmorphia in male weightlifters: a case-control study. Am J Psychiatry 157:1291–1296, 2000 [Full Text] [PubMed] Parssinen M, Seppala T: Steroid use and long-term health risks in former athletes. Sports Med 32:83–94, 2002 [PubMed] Parssinen M, Kujala U, Vartiainen E: Increased premature mortality of competitive powerlifters suspected to have used anabolic agents. Int J Sports Med 21:225–227, 2000 [PubMed] Perry PJ, Lund BC, Deninger MJ, et al: Anabolic steroid use in weightlifters and bodybuilders: an internet survey of drug utilization. Clin J Sport Med 15:326–330, 2005 [PubMed] Pertusi R, Dickerman RD, McConathy WJ: Evaluation of aminotransferase elevations in a bodybuilder using anabolic steroids: hepatitis or rhabdomyolysis? J Am Osteopath Assoc 101:391–394, 2001 [PubMed] Peters KD, Wood RI: Androgen dependence in hamsters: overdose, tolerance, and potential opioidergic mechanisms. Neuroscience 130:971–981, 2005 [PubMed] Petersson A, Garle M, Granath F, et al: Morbidity and mortality in patients testing positively for the presence of anabolic androgenic steroids in connection with receiving medical care. A controlled retrospective cohort study. Drug Alcohol Depend 81:215–220, 2006 [PubMed] Phillips KA: Pharmacologic treatment of body dysmorphic disorder: a review of empirical data and a proposed treatment algorithm. Psychiatr Clin North Am 7:59–82, 2000 Phillips KA, O'Sullivan RL, Pope HG Jr: Muscle dysmorphia. J Clin Psychiatry 58:361, 1997 [PubMed] Pope HG, Katz DL: Affective and psychotic symptoms associated with anabolic steroid use. Am J Psychiatry 145:487–490, 1988 [PubMed] Pope HG, Katz DL: Psychiatric and medical effects of anabolic-androgenic steroid use. A controlled study of 160 athletes. Arch Gen Psychiatry 51:375–382, 1994 [PubMed] Pope HG Jr, Katz DL: Psychiatric effects of exogenous anabolic-androgenic steroids, in Psychoneuroendocrinology: The Scientific Basis of Clinical Practice. Edited by Wolkowitz OM, Rothschild AJ. Washington, DC, American Psychiatric Publishing, 2003, pp 331–358 Pope HG Jr, Brower KJ: Anabolic-androgenic steroid abuse, in Kaplan and Sadock's Comprehensive Textbook of Psychiatry, 8th Edition. Edited by Sadock BJ, Sadock VA. Philadelphia, PA, Lippincott Williams and Wilkins, 2004, pp 1318–1328

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Pope HG Jr, Kanayama G: Can you tell if your patient is using anabolic steroids? Current Psychiatry in Primary Care 2:28–34, 2005 Pope HG, Gruber AJ, Choi P: Muscle dysmorphia. An underrecognized form of body dysmorphic disorder. Psychosomatics 38:548–557, 1997 [Full Text] [PubMed] Pope HG, Olivardia R, Gruber A, et al: Evolving ideals of male body image as seen through action toys. Int J Eat Disord 26:65–72, 1999 [PubMed] Pope HG Jr, Kouri EM, Hudson JI: Effects of supraphysiologic doses of testosterone on mood and aggression in normal men: a randomized controlled trial. Arch Gen Psychiatry 57:133–140, 2000 [PubMed] Pope HG, Kanayama G, Ionescu-Pioggia M, et al: Anabolic steroid users' attitudes towards physicians. Addiction 99:1189–1194, 2004 [PubMed] Riem KE, Hursey KG: Using anabolic-androgenic steroids to enhance physique and performance: effects on moods and behavior. Clin Psychol Rev 15:235–256, 1995 Rubinow DR, Schmidt PJ: Androgens, brain, and behavior. Am J Psychiatry 153:974–984, 1996 [Full Text] [PubMed] Stanley A: Anabolic steroids—the drugs that give and take away manhood. A case with an unusual physical sign. Med Sci Law 34:82–83, 1994 [PubMed] Su TP, Pagliaro M, Schmidt PJ, et al: Neuropsychiatric effects of anabolic steroid in male normal volunteers. JAMA 269:2760–2764, 1993 [PubMed] Thiblin I, Lindquist O, Rajs J: Cause and manner of death among users of anabolic androgenic steroids. J Forensic Sci 45:16–23, 2000 [PubMed] Torres-Calleja J, Gonzalez-Unzaga M, DeCelis-Carrillo R, et al: Effect of androgenic anabolic steroids on sperm quality and serum hormone levels in adult male bodybuilders. Life Sci 68:1769–1774, 2001 [PubMed] Wines JD, Gruber AJ, Pope HG, et al: Nalbuphine hydrochloride dependence in anabolic steroid users. Am J Addictions 8:161–164, 1999 [PubMed] Wood RI: Reinforcing aspects of androgens. Physiol Behav 83: 279–289, 2004 [PubMed] Yates WR, Perry P, MacIndoe J, et al: Psychosexual effects of three doses of testosterone in cycling and normal men. Biol Psychiatry 45:254–260, 1999 [PubMed]

SUGGESTED READING Brower KJ: Anabolic steroid abuse and dependence. Curr Psychiatry Rep 4:377–387, 2002 Pope HG Jr, Brower KJ: Anabolic-androgenic steroid abuse, in Comprehensive Textbook of Psychiatry, 9th Edition. Edited by Sadock BJ, Sadock VA. Philadelphia, PA, Lippincott Williams and Wilkins (in press) Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 18. Neurobiology of Opiates and Opioids

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Mary Jeanne Kreek: Chapter 18. Neurobiology of Opiates and Opioids, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.350941. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Neurobiology of Opiates and Opioids Mary Jeanne Kreek, M.D.

ENDOGENOUS OPIOID SYSTEM The neurobiology of the endogenous opioid system, as well as related neurobiology of opiate addiction, the treatment of addiction, and the management of pain, covers an area of scientific research that has been unfolding over the past 40 years, with increased clinical and laboratory-based information. Between 1992 and 1994, researchers had clearly defined three types of opioid receptors ( ,

, and )

using selective chemical ligands. The challenge to clone the receptor genes was not met until late 1992, at which time two groups working independently in Los Angeles, California, and Strasbourg, France (respectively, the groups of Evans and Kieffer), first cloned an opioid receptor from a neuronal cell line known to have

opioid receptor activity. Soon thereafter, the genes were cloned for the specific

and

opioid receptors, first in rodents, then in humans. Especially rapid advances have been made since the first successful cloning of the genes of the endogenous opioid receptors in late 1992 (e.g., Chen et al. 1993a, 1993b; Evans et al. 1992; Kieffer et al. 1992; J. B. Wang et al. 1993) and many laboratories have written extensive scientific papers on both the early and more recent advances, along with pertinent review articles (Kreek 1986, 1987, 1992, 1996a, 1996b, 1996c, 1996d, 2000a, 2000b, 2001, 2002, 2003, 2005; Kreek and Koob 1998; Kreek et al. 2002, 2004a, 2004b, 2005a, 2005b; LaForge et al. 2000; Novick et al. 1991). There are also many exciting review articles from 2001 onward that may be used to identify more specific scientific papers on the neurobiology of the opioids (Borgland 2001; Contet et al. 2004; Corbett et al. 2006; Cox and Crowder 2004; Evans 2004; Johnson et al. 2005; Kieffer and Evans 2002; Kieffer and Gaveriaux-Ruff 2002; Law et al. 2004; Maher et al. 2005; Nestler 2004, 2005; Ossipov et al. 2005; Pan 2005; Pasternak 2001; Qui et al. 2003; Raehal and Bohn 2005; Snyder 2004; Williams et al. 2001; Zadina 2002).

Opioid Peptides and Receptors In the mid-1960s, a few research groups, including my own, were already postulating the existence of specific opioid receptors and discussing these in the context of various pharmacological perturbations and treatments. These early hypotheses were of seminal importance for the conceptualization and targeting of an appropriate and specific pharmacotherapy for heroin addiction using a presumed (and later proven) long-acting synthetic opioid, methadone (for extensive reviews, see Kreek 1996c, 1996d, 2000a). Using the experimental approach first proposed and reported by Ingoglia and Dole in 1970, and then by Goldstein in 1971 (i.e., the study of specific stereoselective binding of a presumed opioid receptor agonist or antagonist), the groups of Snyder, Simon, and Terenius conclusively identified the specific opiate receptors in 1973 (Dole 1970; Goldstein et al. 1971; Ingoglia and Dole 1970; Pert and Snyder 1973; Simon et al. 1973; Terenius 1973). Then the aggressive search began for the specific endogenous ligands that would bind to these receptors, with the first ligand identified, by the group of Kosterlitz with Hughes, in 1975 (reviewed in many articles, including Kreek 1996d, 2000a). From 1973 to 1992, three different types of opioid receptors ( ,

, and ) were defined by use of

specific chemicals or pharmacological agents. Further work also revealed the existence of three types of endogenous opioids:

-endorphin, enkephalins, and dynorphins. The generic term endorphin was coined

to describe the whole class of endogenous opioid ligands (e.g., Kreek 1996d). The term opioid is correctly used to refer to the entire class of compounds, peptides, and natural heterocyclic compounds and other synthetic chemicals that bind to one or more types of specific opioid receptors. The word

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opiate is correctly used only to refer to compounds directly derived from or synthesized from the natural product thebaine and its derivatives isolated from the poppy plant, with or without further synthetic modification (e.g., morphine and codeine). Heroin is one of the best-known opiates and is a man-made diacetylated derivative of morphine, which was first produced by the Bayer company in Germany in the mid-1800s. Synthetic compounds, such as methadone and the various fentanyl congeners, are technically opioids because they are not derived directly or indirectly from a natural poppy plant product. The genes encoding each of the three endogenous opioid peptide families were cloned and characterized by the end of the 1980s. Of these genes, the pro-opiomelanocortin gene yields a single peptide that in turn is further processed to yield many very important biologically active peptides, including , melanocyte-stimulating hormone, adrenocorticotropic hormone (ACTH),

-lipoprotein, and

, and

-endorphin.

The enkephalin gene yields one peptide that is further processed to yield met-enkephalin, leu-enkephalin, and two other biologically active enkephalin species. The prodynorphin gene yields one peptide that is processed to dynorphin A and dynorphin B, as well as other neuropeptides. One additional class of possible endogenous opioids has been identified: the endomorphins. These include two 4–amino acid residues that have been isolated and characterized and shown to bind to the

opioid

receptor (Zadina 2002). However, the parent peptide from which these are derived has never been identified, nor has any gene of which they might be the product. Therefore, it is unclear whether these are specific natural endogenous opioids or by-products of peptide processing of some larger peptide that bears little to no direct relationship to the endogenous opioid system. A fourth receptor, the orphanin/nociceptin receptor, has been identified, along with an endogenous neuropeptide ligand that binds to that receptor, orphanin/nociceptin. The orphanin/nociceptin receptor has a structure and some functions similar to those of the endogenous opioid receptors, but it does not bind to the classical endogenous opioids, and it is not affected by specific opioid antagonists, such as naloxone. This ligand and receptor are usually referred to as "orphan opioid–like" but are not considered to be technically part of the endogenous opioid system (see Table 18–1). A variety of other putative opioid receptors were proposed early on, but no gene was cloned for any of these and very little research has been done recently evoking their presence. However, extensive research, primarily from the groups of Pasternak and Pan, has defined the presence of numerous "splice variants," especially of the

opioid receptor, in rodents as well as in humans (Pan 2005; Pasternak

2001). It has been suggested that these splice variants may play a major role in the subtle pharmacological differences of various opiate and opioid compounds and may be present and active in specific and different brain regions, thus contributing to diversity of the opioid system. Since 1997, it has also been documented that the opioid and opioid-like receptors form homomeric dimers, as well as heteromeric dimers (e.g., George et al. 2000; Gomes et al. 2000, 2004; Gupta et al. 2006, 2007; Jordan and Devi 1999; Law et al. 2005; Waldhoer et al. 2005). Furthermore, the heterodimers may be formed with non-opioid receptors, such as the cannabinoid receptors (Rios et al. 2006). The extent of dimerization in natural situations in vivo remains only modestly defined, although some novel pharmacological probes aimed at binding at two similar or different receptor types simultaneously (with appropriate spacing between the binding sites) suggest that such in vivo dimerization does occur, possibly in specific regions of the nervous system (Waldhoer et al. 2005). Beginning with the work of Evans, extensive studies have been conducted on the trafficking of opioid receptors, with initial emphasis on the

opioid receptors and later with all three opioid receptor types

(e.g., Alvarez et al. 2002; Haberstock-Debic et al. 2003, 2005; He and Whistler 2005; He et al. 2002; Keith et al. 1998; von Zastrow 2004; von Zastrow et al. 2003; Whistler et al. 1999, 2002). Many findings have been made that have provided elaborate details of the intracellular peptides and pathways involved in binding and the specificity and differences among the three receptor types with respect to their fate after binding to different types of ligands. It has been shown by many groups that the endogenous opioids that bind primarily at the

opioid receptor, such as met-enkephalin and

-endorphin, undergo rapid internalization by endocytosis into clathrin-coated pits once they have bound

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to the receptor on the cell surface. In the acidic milieu of the clathrin-coated pit, dissociation of the ligand and receptor occurs. More recent research has shown that the

opioid receptors are then

promptly represented at the cell surface on the plasma membrane for further biological activity. Subsequent work showed that most exogenous opiates and opioids behave very differently after binding to the

opioid receptor—for example, morphine and related compounds do not rapidly internalize after

binding to

receptors. In sharp contrast, the synthetic opioid methadone undergoes rapid endocytosis

following binding at the

opioid receptor, as do a few other synthetic opioids, including a limited

number of the fentanyl series and etorphine. Binding of an exogenous ligand to the (and especially a prototypic

opioid receptor

agonist such as the opiate morphine) has been shown in in vitro systems

to lead to both rapid and more slowly developing desensitization, accompanied or preceded by receptor phosphorylation. The phenomenon of development of tolerance (see "Tolerance" later in this chapter) has been attributed to receptor desensitization and phosphorylation. More recently, it has been suggested that the failure of

opioid receptor–bound morphine (and most other opiates and opioids) to

undergo rapid endocytosis, with prompt receptor representation on the cell surface membranes, increases desensitization and, thus, increases the rate of development of tolerance. In sharp contrast, rapid internalization, as occurs with methadone, has been suggested to contribute to the well-documented clinical observations of very slow development of tolerance to this synthetic (and in humans, also pharmacokinetically long-acting) opioid.

Signal Transduction Mechanisms All opioid receptors and the orphan opioid–like receptor are classical seven transmembrane domain, G protein–coupled receptors. The three classical opioid receptors have been shown to have very high homology with each other (see Figure 18–1). Most of the differences in amino acids exist in the N-terminus and in the extracellular loops outside the plasma membrane, and also in parts of the carboxy terminus, located within the cytoplasm. The

opioid receptor is the longest of the three opioid

receptors. All three opioid receptors are coupled primarily with inhibitory G I/O pathways. Most actions of the opioid receptor are ultimately inhibitory in type. The coupling of the opioid receptors through the GI/O proteins has a direct impact on the adenylyl cyclase system and an indirect impact on a variety of ion channels, which modulate the influx and efflux of potassium and calcium (see reviews cited above and Akil et al. 1998; Law and Loh 1999; Nestler and Aghajanian 1997; Nestler et al. 1999; Smith et al. 1999). FIGURE 18–1.

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and

opioid receptors in stress-related normal physiology.

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Note. ACTH = adrenocorticotropic hormone; CRF = corticotropin-releasing factor; POMC = pro-opiomelanocortin. Source. Adapted from Kreek et al. 2002. As an endogenous or exogenous

opioid receptor ligand binds to the receptor and the first steps of

signal transduction are mediated through the G protein coupling, phosphorylation of the receptors may occur at specific sites in each receptor, which leads to uncoupling of the receptors from their G protein– coupled single transduction mechanisms. Phosphorylation may or may not be a mandatory step for subsequent binding to the other proteins, which, in turn, may facilitate (or may be necessary for) endocytosis and trafficking. Receptor binding of a ligand, without prompt endocytosis and representation on cell membranes, and/or decreases in new receptor synthesis, could contribute to receptor down-regulation. Also, G protein uncoupling of the opioid receptors could lead to an apparent reduction in effective cell surface receptors, or desensitization. Opioid antagonists bind to

opioid receptors but do

not activate GI/O protein–coupled signal transduction mechanisms; rather, the antagonists prevent action of the endogenous opioid peptides and of most (or all) exogenous opioids and opiates. It has been shown that even the different endogenous, primarily

opioid receptor–directed opioid peptides, such as

-endorphin, and the possibly natural neuropeptide endomorphin may have different mechanisms for and extent of G protein–coupled activation (Mizoguchi et al. 2002). The activation of

opioid receptors coupled with GI/O inhibits adenylyl cyclase and the cyclic adenosine monophosphate (cAMP)–mediated cascade that follows. Decreasing cAMP levels effectively inhibits transmitter release by several different mechanisms, which include effects on vesicular transporters, especially for release of -aminobutyric acid (GABA), glycine, and glutamine. In addition to GI/O coupling, which leads to an inhibition of cyclase cascade, some studies have shown a very small contribution by

opioid receptor coupling with Gs, that is, a cAMP excitatory system. It has been suggested that such a modest stimulatory effect may blunt full effectiveness of opioid agonists (Crain and Shen 1990, 1996; Cruciani et al. 1993; Olmstead and Burns 2005; H. Y. Wang and Burns 2006; H. Y. Wang et al. 2005). Several studies have determined that specific opioid antagonists in extremely small amounts may actually enhance opioid agonist activity and, alternatively, that different

opioid

receptor agonists may differentially affect basal activity (Crain and Shen 1996; Olmstead and Burns 2005; Sadee et al. 2004; D. Wang et al. 2001, 2004; H. Y. Wang and Burns 2006; H. Y. Wang et al. 2005).

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During chronic exposure to opiates, there is cumulative up-regulation of adenylyl cyclase, which results in cyclase supersensitization in the setting of opiate withdrawal and increases neurotransmitter release by activation of protein kinase A (PKA), part of the downstream cascade from increased cAMP levels. With a subsequent reexposure to morphine or other

opioid agonists, cAMP is again inhibited. Related

increases in adenosine may enhance presynaptic inhibitory effects mediated by A1 adenosine receptors. (Further details of each of these findings are found in many reviews, such as Corbett et al. 2006; Kreek 2002; Law et al. 2004; Williams et al. 2001.) Much of the

opioid ligand–induced inhibition of neuronal

excitability is due to the activation of potassium channels in plasma membranes, including the G protein–coupled inwardly rectifying potassium channels (GIRKs), and also both activation and inhibition of diverse types of calcium-activated channels. Furthermore, by inhibition of GABA release, by way of direct inhibition of that neurotransmitter release from the intracellular presynaptic vesicles, overall activation or excitatory actions may ensue. The most important of these effects for opiate addiction is the inhibition of GABAergic neurons in the ventral tegmental area (VTA) of the brain by exogenous opiates or opioids, such as morphine, and thus inhibition of GABAergic release. GABA normally tonically inhibits the dopaminergic neurons in the VTA, thus modulating (increasing) the amounts of dopamine released at the dopaminergic terminals throughout the mesolimbic-mesocortical dopaminergic fields. Potential for activation of G proteins by binding of an opioid ligand at the

opioid receptor can be

assessed by directly measuring agonist-induced stimulation of guanosine 5-[ -thio]triphosphate [35 S]-GTP S. That technique has been extensively used by many investigators, and thus will be mentioned briefly later in this chapter in the discussion of the effects of chronic morphine or heroin on the

opioid receptor systems in rodent models (e.g., Bernstein and Welch 1998; Kruzich et al. 2003;

Selley et al. 1997; Sim-Selley et al. 2000).

Endogenous Opioid System Functions A full discussion of all of the actions of the endogenous opioid system in normal mammalian physiology is beyond the scope of this brief review (see Table 18–2). All of the precise and different physiological effects of the ,

, and

systems have not yet been fully elucidated. The availability now of cloned

human receptors, as well as cloned rat and mouse receptors, has been of considerable help in revealing the relative affinity of different natural and synthetic chemical ligands for each receptor type. Also, the specific signal transduction mechanisms affected by each compound can now be elucidated in in vitro systems to complement in vivo studies. The use of increasingly selective agonists, partial agonists, and antagonists, as well as the ability to compare selective versus specifically defined but nonselective ligands is allowing researchers to further clarify the role of each part of the endogenous opioid system in normal physiology. Early hypotheses and studies on the role of the endogenous opioid system were based, in part, on the careful early studies on the effects of the long-acting opioid methadone versus the short-acting morphine or heroin in humans (Dole et al. 1966; Kling et al. 2000; Kosten et al. 1987, 1992; Kreek 1973, 1978; Kreek et al. 1983, 1984). The findings from these early studies allowed us to address the question of the possible role of the endogenous opioid system and specific components thereof in many different specific physiological functions. Physiological functions have clearly been demonstrated to involve the related endorphin systems, especially action of

opioid receptor system and

-endorphin, the longest of the endogenous opioids (31

amino acid residues), which has preference at the

opioid receptor, as well as met-enkephalin and

some of the other enkephalin species. These functions include importantly the endogenous response to pain, including especially acute pain and the acute and chronic placebo response; specific neuroendocrine functions that are critical for survival, including the stress-responsive hypothalamicpituitary-adrenal (HPA) axis (also shown by our group and others to be extremely important for the acquisition of, persistence of, and relapse to specific addictive diseases) and the reproductive function of the hypothalamic-pituitary-gonadal axis, specifically the modulation of pulsatile luteinizing hormone; specific indices of immunological function, including numbers and activity of natural killer cells as well as numbers and function of many other types of immune cells and compounds, such as B cells, T cells, cytokines, and chemokines; gastrointestinal function, including motility, but also to a lesser extent

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absorption; cardiovascular function, including an increasingly well-documented cardioprotective effect of opioids; pulmonary function; and possibly mood, affect, cognition, memory, and the normal emotions, such as pleasure or reward resulting from any natural substance or event (e.g., a liked food or activity). I would like to acknowledge Kitt Lavoie and Susan Russo for help in the preparation of the manuscript for this chapter. Funding support was received from the National Institutes of Health–National Institute on Drug Abuse Research Scientific Award Grant K05-DA00049, the National Institutes of Health–National Institute on Drug Abuse Research Center Grant P60-DA05130, and the New York State Office of Alcoholism and Substance Abuse Services Grant C003189.

NEUROBIOLOGY OF TOLERANCE, DEPENDENCE, AND ADDICTION: SEPARATE PHENOMENA Tolerance is defined as the need for increasing amounts of compound to achieve a specific physiological or pharmacological effect caused by that compound when acting at a specific site, such as a receptor. Thus, tolerance to opiates and opioids is the need for increasing amounts of opiates or opioids to be administered or used to achieve whatever is the desired effect of that compound when it acts at specific opioid receptors. Dependence upon opioids is a predictable event defined by the appearance of specific physiological signs and symptoms following abrupt cessation of chronic administration of either long- or short-acting opioids in human or animal models. Because of both pharmacokinetic differences among opioid compounds and the receptor affinity differences of each, as well as modest or dramatic differences in specific opiate receptor targeting and the relative degree of agonism, partial agonism, mixed agonism-antagonism, or antagonism, one cannot automatically extrapolate from a mouse to a rat to a nonhuman primate to humans. Dependence is not directly related to tolerance. It has been shown in several very well-conducted studies that there are perturbations and specific types of compounds that clearly may attenuate or prevent the development to tolerance to an opioid—that is, that reverse the need for increasing amounts of compound necessary to achieve a desired effect or an objectively measured response—and yet following chronic administration of that opioid, all the signs and symptoms of physical dependence may be observed and measured. Thus, tolerance and dependence are dissociable phenomena. In studies with

-arrestin knockout mice, Bohn and colleagues showed that

there is a marked attenuation of development of tolerance, yet after chronic administration of morphine and cessation thereof, signs and symptoms of opiate dependence are present (Raehal and Bohn 2005).

Tolerance Tolerance is a phenomenon that is extraordinarily well established in the laboratory and observed and appreciated by all clinicians. Since the discovery of poppy-derived opiates for the management of pain, it was observed that increasing amounts of that compound were essential in order to repeatedly achieve the same level of analgesia or pain relief. Similarly, this phenomenon is very well known to the heroin addict, who finds that increasing amounts of heroin must be self-administered (when financially possible), and sometimes also more frequently during the day, in order to achieve the same high as on previous occasions, because tolerance develops to the short-acting opiate (a phenomenon also seen with morphine and other short-acting opiate drugs of abuse). Despite innumerable advances, the precise molecular, biochemical, and cell biological mechanisms of opioid tolerance are not yet fully understood. However, increasingly it has been accepted that both opioid receptor desensitization and trafficking play major roles in the development of tolerance, as do each of the separate peptides and mechanisms involved therein. Furthermore, it has become clear that, since different exogenous opiates and opioids and the endogenous and exogenous opioids have different patterns of receptor phosphorylation, desensitization, and endocytosis and trafficking, one may expect tolerance to develop at different rates to different development of tolerance to

and

opioid receptor ligands. The phenomenon of

opioid receptor agonists has been less extensively studied, and the

specific mechanisms involved are less well defined. Once a

agonist binds to the

opioid receptor on plasma membranes, the receptors are then

phosphorylated by G-coupled kinases (GRKs). This process also facilitates binding by

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-arrestin and

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prevents the

opioid receptor from further coupling to G proteins (primarily G I/O ). The same general

process of phosphorylation and -arrestin binding seems to pertain for the receptors, which are

opioid receptors. The

-arrestin bound, are concentrated in clathrin-coated pits. These endocytotic pits

then undergo dynamin-independent internalization into the early endosomes. Data to date suggest that both

and

receptors are similarly handled up to this point, after which there is a significant

divergence. The internalized

receptors bound to ligands then primarily go to lysosomes, where they

usually undergo degradation and, thus, are down-regulated. In contrast, the

receptors continue to be

trafficked in endosomes, they are dephosphorylated, the ligand comes off the receptors, and the receptor is recycled and placed back in the plasma membrane and thus is again in a sensitized G-coupled protein state, ready for new action. There is also some evidence that

receptors

heterodimerized with

receptors may more effectively undergo internalization and that

heterodimerized with

receptors may allow

seem to internalize after the binding of

receptor internalization, since

ligands. Thus, whereas the

and representation lead rapidly to resensitization, the

receptors

receptors alone do not

opioid receptor internalization

opioid internalization leads to desensitization

and down-regulation. In animal models and in humans, it has been shown that tolerance begins to develop immediately after first exposure to morphine or other potent, primarily

opioid receptor–

directed, agonists, coupled with related changes in levels of expression of diverse genes and thus neuropeptides of multiple genes in the circuitry. It has been shown that in -arrestin-2 knockout mice, a single dose of morphine has an increased acute analgesic effect and that tolerance does not develop during chronic morphine administration; however, it has also been shown that physical dependence does develop (Raehal and Bohn 2005). The precise mechanism of -arrestin in this context is not fully understood. Signal transduction components downstream from the adenylyl cyclase components, followed by an enhanced supersensitive cAMP pathway in the setting of chronic morphine exposure (which is expressed in opiate withdrawal), along with activation of protein kinase C through other signal transduction pathways, have been suggested to be involved in or central to the development of morphine tolerance. There is also ample indirect evidence that N-methyl-D-aspartate (NMDA) receptors may be involved in the development of morphine tolerance, since numerous studies have shown that even modest nonselective NMDA antagonists (such as the active and inactive enantiomers of methadone or MK801) may retard the development of tolerance to morphine. There is increasing evidence that different components of molecular, biochemical, and cell biology may play a relatively greater or lesser role in the development of tolerance in different parts of the brain, or even at different synapses within one region. All these processes become altered through the more general and well-established phenomena of neural plasticity and related adaptive processes. The well-established up-regulation of cyclase activity (or cyclase supersensitivity) is thought to underlie intrinsic neuronal hyperactivity observed in opiate withdrawal (or dependence), but its precise role in tolerance has not been fully elucidated. Many other enigmas persist, including the fact that although morphine leads to the very rapid development of tolerance, it does not undergo widespread, general, and prompt internalization after binding to the

opioid receptor (Alvarez et al. 2002; Haberstock-Debic

et al. 2003, 2005; He and Whistler 2005; He et al. 2002; Keith et al. 1998; von Zastrow 2004; von Zastrow et al. 2003; Whistler et al. 1999, 2002). In contrast, the synthetic opioid methadone and the synthetic peptide DAMGO undergo rapid endocytosis but also rapid representation to the cell surface. Since it has now been established that methadone, both in its active and inactive enantiomers, has modest nonselective NMDA receptor antagonist activities, the clinical observation that tolerance in humans to methadone develops much more slowly than to heroin or to its major metabolite, morphine, may be partly due to the fact that methadone is a more full agonist, undergoes more rapid endocytosis with representation of receptors, and does not lead to down-regulation of the

opioid

receptors, and further, that both enantiomers

of racemic methadone used in therapeutics are modest NMDA antagonists. The lack of down-regulation of

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opioid receptors in stabilized former heroin addicts in long-term methadone treatment has been

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shown directly in positron emission tomography studies conducted on healthy volunteers compared with stable subjects receiving methadone maintenance treatment (Kling et al. 2000). However, prolonged, intermittent administration of short-acting exogenous opiates or opioids may bring about up-regulation or down-regulation of expression of gene messenger ribonucleic acid (mRNA) levels and levels of a variety of gene products, specifically a variety of peptides that may alter or attenuate the initial effects of a

opioid agonist in vivo and, thus, may also contribute to the development of tolerance. Specific

components of mechanisms linked to signal transduction mechanisms, as well as involved cytoskeletal components and chaperone mechanisms, other neuropeptide interactions, and also the presence of multiple opioid receptor variants especially due to splice variants or specific gene variants, may contribute to the differences in the rate of developing tolerance and also to the complete, or alternatively incomplete, cross-tolerance between opiates that have been observed both in animal models and in the clinic (Akbarian et al. 2002; Ammon-Treiber and Hollt 2005; Bernstein and Welch 1998; Bolanos et al. 2005; Borgland 2001; Contet et al. 2004; Cox and Crowder 2004; Evans 2004; Georgescu et al. 2003; Glass et al. 2004, 2005; Gold et al. 2003; He and Whistler 2005; He et al. 2002; Kieffer and Evans 2002; Kieffer and Gaveriaux-Ruff 2002; Kruzich et al. 2003; Leri et al. 2006; Martin et al. 2004; Pasternak 2001; Przewlocki 2004; Qui et al. 2003; Russo et al. 2007; Selley et al. 1997; Sim-Selley et al. 2000; Steffensen et al. 2006; von Zastrow 2004; von Zastrow et al. 2003; X. M. Wang et al. 1999; Whistler et al. 1999, 2002; Williams et al. 2001; Zachariou et al. 2006).

Dependence After chronic opiate exposure, the time to onset of withdrawal signs and symptoms and the objective measures of physical dependence may depend on many factors. First, if the opioid itself has long-acting properties due to either pharmacokinetic profile or receptor occupancy, there will be a delayed onset of withdrawal symptoms and often an attenuation or lessening of signs and symptoms. The signs and symptoms of withdrawal are usually consistent following acute withdrawal ("cold turkey") from a pharmacokinetically short-acting opiate, such as heroin or morphine. However, the signs and symptoms of withdrawal may be different if the compound is a partial agonist (e.g., buprenorphine) as compared with a closer to full agonist (e.g., heroin, morphine), or if the compound is very long acting (e.g., methadone in humans). In humans treated with opiates for chronic pain and in whom the source of pain is removed and the pain itself has gone, there will nevertheless be signs and symptoms of opiate withdrawal, especially if opioids are stopped abruptly. This has led to a standard clinical practice of gradually tapering the dose of an opiate medication following a time of reduced or absent requirement of such treatment. It is in this setting that clinical confusion may arise with respect to whether or not there is persistence of pain and therefore the need for an opiate and to whether protracted abstinence symptoms make medication discontinuation difficult or, alternatively, whether "addiction" has developed. Such changes could be due to the neurobiological alterations or psychological changes attendant to the development of addiction. The debate between persistence of pain and the development of addiction is frequently raised, but in good clinical practice this should be viewed as more of a clinical-scientific question rather than a management question, since the availability of long-acting opioids and the ability to manage with ease either persistent chronic pain or addiction have become so well defined and accepted, and since there is general availability of needed medications so that appropriate management of a former long-term chronic pain patient should not create any problems. However, it is at this juncture that one may need to consider the correct definition of addiction as contrasted with persistent chronic pain of unknown origin. In either case, appropriate pharmacotherapy (with long-acting opioids), with concomitant behavioral treatment, and psychiatric treatment are needed, as well as provision of essential social support. The signs and symptoms of opiate dependence in humans are dramatic and occur within 6–12 hours after the last dose of a short-acting opiate such as heroin. They include severe bone pains, chills, piloerection (gooseflesh), sweating, extreme restlessness, nervousness, constant yawning, rhinorrhea, nausea, vomiting, and diarrhea; in extreme cases, convulsions have been described (though they are rarely seen). In rodents, signs and symptoms of opiate withdrawal include some similar effects, such as

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piloerection, lacrimation, rhinorrhea, diarrhea, teeth chattering as in humans, and some different effects such as jumping, "wet dog shakes," and vocalization. Many very careful scales have been developed to accurately and objectively measure the magnitude of the signs of opiate withdrawal in rats and mice and in humans. When the onset of withdrawal symptoms is acute, such as when precipitated by abrupt cessation of heroin or other short-acting opiate administration, there is rapid onset of withdrawal symptoms, which then crescendo and may be followed by a deep, or so-called yen, sleep, lasting for 1 hour or more. Upon awakening, the opiate-dependent addict in withdrawal suffers a recrudescence of withdrawal symptoms, which then gradually abate over the ensuing 48–96 hours. However, some signs and symptoms of abstinence persist long thereafter—for weeks or months in many cases. Some of the acute signs and symptoms may be ameliorated by clonidine, an

2

noradrenergic agonist, documenting

that many signs and symptoms are part of a cascade of an overactive catecholaminergic system. The brain center of this chronic heroin- or morphine-induced change that leads to overactivity in withdrawal has been shown by many studies to be in the locus coeruleus. In addition, the periaqueductal gray region, and possibly other adjacent regions, are involved in this overactivity of the noradrenergic system following opiate withdrawal. Other studies have shown that the VTA, with its dopaminergic neurons under tonic inhibition by GABAergic compounds, which are in turn inhibited by the

opioid

receptor system, is also involved in opiate withdrawal (McClung et al. 2005). Several studies have shown changes in gene expression (in RNA and peptide levels) in the setting of opiate withdrawal, primarily in rodent models (e.g., Caille et al. 2002; McClung et al. 2005; Shaw-Lutchman et al. 2002; Walker et al. 2002; Zhou et al. 2006). Clonidine does not successfully manage all of the signs and systems, most notably insomnia, restlessness, and inability to concentrate usually coupled with severe drug hunger or drug craving. Therefore, it is preferable to use a

opioid agonist or partial agonist medication with dose tapering and

ultimate reduction to no medication following chronic heroin or other short-acting opiate addiction or chronic treatment for addiction or pain with an opiate or opioid. Methadone or buprenorphine, a

opioid receptor agonist and partial agonist, respectively, can be used

in a tapering-dose paradigm over 7–14 days to markedly reduce most or all signs of opioid withdrawal and abstinence. Although signs and symptoms of opioid abstinence become reduced with time, restlessness, irritability, and inability to concentrate are cardinal symptoms that have been shown in humans to persist for over 3–6 months. Similarly, it has been shown that some objective changes also persist. Some more recent studies have been conducted in which an opioid agonist, primarily methadone, is provided in a 3- to 6-month dose taper to abstinence. Such slow tapering is recommended whenever a decision is made to stop opioid agonist treatment for addiction or for pain. Kreek et al. (1984) has documented persistent changes in the HPA axis stress-responsive system that remain abnormal for very protracted periods of time (more than 1 year following withdrawal of any illicit use of opiates and with no opioid agonist or partial agonist pharmacotherapy, and probably directly connected to the effects of heroin or other short-acting opiate addiction on the molecular neurobiology of the brain).

Addiction An addiction to opiates is neither tolerance nor dependence. It is extremely unfortunate that the DSM criteria have persisted in using the term dependence instead of addiction. The DSM work group probably adopted this approach in an understandable attempt to decrease the enormous stigmatization of the diseases of addiction. However, it has been very misleading, since all persons requiring opiates or opioids on a chronic basis for pain develop both a tolerance and a dependence, but only very few develop an addiction. A somewhat large number of pain patients require persistent management with a long-acting opioid, probably because of neurobiological changes, persistent pain, or possibly an undiagnosed underlying addiction that might emerge if all opioid medication were stopped. This course of events has been observed in a substantial (and increasing) number of chronic pain patients as more individuals are being aggressively treated for all types of pain.

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Addiction is possibly best defined as drug hunger or drug craving with compulsive drug seeking and drug taking despite possible or known negative consequences to the user or to others. This definition embodies the essence of the World Health Organization's definition and my own working definition during research through the 1960s, as well as current definitions of many other organizations (Kreek 2000a; Kreek and Vocci 2002). Much more stringent criteria have been levied for the definition of opiate (usually heroin) addiction in the U.S. federal government requirements for permitting entry into methadone maintenance treatment. These criteria include daily, multiple self-administrations of a shortacting opiate (heroin, morphine, hydromorphone, or other short-acting opiate) for 1 year or more (Kreek 2000a; Kreek and Vocci 2002). Initially, at the beginning of Rockefeller University–based research in 1964 by Vincent P. Dole, Marie Nyswander, and Mary Jeanne Kreek, our self-imposed criteria included 4 years of regular, daily self-administration. By the time the first Code of Federal Regulations was promulgated in 1973, we had reduced this requirement to 2 years of daily, multiple self-administrations of a short-acting opiate. By the early 1980s, the requirement had been reduced in our laboratory to 1 year of self-administration of short-acting opiates, a criterion that was adopted in the 1983 revision of the federal regulations. However, despite the National Academy of Sciences– Institute of Medicine recommendations from 1994 of reducing the requirement down to around 3–6 months of daily self-administration (along with meeting DSM-IV criteria for dependence; American Psychiatric Association 1994), there has been no further change in the Code of Federal Regulations (Rettig and Yarmolinsky 1995). In contrast, there is nothing in the Code of Federal Regulations governing buprenorphine maintenance treatment and buprenorphine-naloxone combination treatment, and the guidelines imposed by the U. S. Food and Drug Administration and U. S. Drug Enforcement Agency are drastically different from those for methadone maintenance; entry into treatment simply requires meeting DSM-IV-TR criteria for opioid dependence (American Psychiatric Association 2000). This definition may be too modest, since no physical stigmata and thus no neurobiological changes of any type are required for the DSM-IV-TR diagnosis of dependence (in contrast to the diagnosis in some earlier DSM editions). However, in the United States, most persons receiving buprenorphine or buprenorphine-naloxone treatment for addiction provided by physicians, all of whom have received the minimum required 8-hour training course in buprenorphine management for treatment of addiction (and in providing treatment using appropriate prescription forms with the required special designation indicating addiction treatment), do meet a criterion of at least 3 months or more of daily self-administration of short-acting opiates, along with development of tolerance, dependence, and compulsive drug-seeking behavior. Furthermore, most of these individuals meet the very strict criteria for entrance into methadone (or L- -acetylmethadol [LAAM]) treatment; that is, 1 year or more of daily self-administration of opiates. The overly strict criteria governing methadone (and LAAM) treatment have deterred many from entering into appropriate and needed pharmacotherapy. Such pharmacotherapy is appropriate for all opiatedependent persons; during the early induction period, pharmacotherapy with methadone or buprenorphine should be coupled with behavioral treatment. New interpretations of the 1973–1987 Code of Federal Regulations governing methadone maintenance treatment have been published in the Federal Register and are now in effect. These allow 31-day take-home medication and formally approved, at a national level, office-based treatment as long as initial treatment and long-term linkage, or cross-referral coordination, are provided in partnership with a more formal opioid treatment program—an approach probably needed for all opiate addicts (heroin or prescription opiates) in any type of pharmacotherapy (methadone, LAAM, buprenorphine, buprenorphine-naloxone, or naltrexone) (Kreek and Vocci 2002). There have been many studies in humans and animal models showing reduction in dopaminergic tone during chronic opiate exposure or self-exposure, coupled with decreased binding capacity of dopamine D2 receptors (e.g., Bart et al. 2003; Kreek et al. 1999; Volkow 2004; Volkow et al. 2003). There are also a few studies suggesting that recovery of this system is extremely slow. Human studies of the stress-responsive HPA axis have clearly suggested that a relative endorphin deficiency develops in illicit

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opiate–free and opioid medication–free former opiate-dependent individuals and that endorphin levels normalize during methadone maintenance treatment (Kosten et al. 1987, 1992; Kreek et al. 1983, 1984; Schluger et al. 2001). However, some HPA axis abnormalities persist during stabilized methadone treatment (Schluger et al. 2003). Work from several laboratories has shown that in paradigms of chronic self-administration of heroin or morphine in animals with prolonged daily access periods of self-administration (6–18 hours), larger escalating doses are employed, the availability of

opioid

receptors for action by endogenous or exogenous opioids (measured by GTP S binding) is significantly reduced (this specifically has been observed to occur in the thalamus and the amygdala [Glass et al. 2004, 2005; Kruzich et al. 2003; Selley et al. 1997; Sim-Selley et al. 2000; Walker et al. 2003]), and other neurobiological changes clearly occur. Recent reports of many studies by other groups have defined many specific neurobiological, as well as behavioral, changes that occur during chronic opiate exposure, either from self-administration (and thus closer to addiction in behavioral context) or during investigator-administration (e.g., above cited and Bossert et al. 2005; Caille et al. 2003; Chen et al. 2006; Goeders 2002; Gracy et al. 2000; Kenny et al. 2006; Lingford-Hughes and Nutt 2003; Lingford-Hughes et al. 2003; Molina 2002; Przewlocki 2004; Shalev et al. 2002; Shippenberg and Elmer 1998; Stinus et al. 2005; Walker et al. 2003). Other and different changes appear in the setting of opiate withdrawal, thus hallmarking the changes that occur in the setting of opioid dependence and/or addiction and further identifying changes that appear to be associated with relapse as measured in self-administration studies or changes in levels of craving or liking, such as in a conditioned place preference paradigm. The

opioid receptor system is

clearly essential for reward (Contet et al. 2004; Kieffer and Gaveriaux-Ruff 2002). Countermodulation of these changes also occurs in part by activation of the

opioid receptor system (e.g., Bart et al. 2003;

Claye et al. 1996; Kreek et al. 1999, 2004b; Portenoy et al. 1999; Specker et al. 1998; X. M. Wang et al. 1999). Much of opiate dependence and also possibly drug craving, drug seeking, and drug taking depends on the rebound from changes caused during chronic opioid administration. The downstream events following enhancement of cAMP, for instance, are observed. Many of the physiological and behavioral changes have been ascribed to be related to opioid-sensitive synapses, increased neurotransmitter release, and hyperexcitability in many brain regions beyond the locus coeruleus, periaqueductal gray, and VTA. Dynorphin gene expression and peptides, which are increased by acute and chronic morphine (similar to the increases during acute and chronic cocaine administration), may become reduced in critical regions, and in particular in the nucleus accumbens or amygdala, in opiate withdrawal. The role of the

opioid receptor–dynorphin system in opiate withdrawal has not been fully elucidated, nor has

the possible role of dysphoria, related to lowered dopaminergic tone and in part due to enhanced dynorphin during morphine administration, been fully elucidated. Parallel changes may also occur in the orphanin/nociceptin gene expression and peptide levels, which, like dynorphin, act to modulate dopamine levels and reward. The multiple and profound neurobiological changes that occur during opiate dependence are due to the fundamental brain properties of synaptic plasticity, with resultant enhancement or attenuation of normal neural pathways or formation of new atypical neural pathways, sometimes possibly augmented by neural neogenesis, all of which contribute to the phenomena that are defined as dependence and addiction. Also, the well-documented changes in the stress-responsive systems, including the HPA axis and in other parts of the brain, have been shown to directly contribute to addiction. Learning and memory also play a major role in the development of, persistence of, and relapse to addiction. There is also evidence that learning and memory may play a role in tolerance and dependence. However, precisely which molecular and synaptic pathway components are involved has not been fully revealed. It is clear from many studies in that

opioid receptor gene deletion (knockout) mice

opioid receptor presence and activity are essential for opiate-induced reward, self-administration,

and conditioned place preference, as well as for analgesia (Contet et al. 2004; Kieffer and

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Gaveriaux-Ruff 2002). Furthermore, it has been shown in animal models that chronic opioid exposure and also access to increasing doses of morphine or heroin increase opiate self-administration in rats (e.g., Kruzich et al. 2003; Sim-Selley et al. 2000; Walker et al. 2003). It is of note that, on one hand, the natural synthetic

ligand, dynorphin, or another naturally occurring product, salvinorin, and many other opioid receptor agonists, directly act at the

receptor to directly reduce dopaminergic tone,

in part through inhibiting dopamine release from presynaptic sites into the synapse (e.g., Butelman et al. 1999a, 1999b, 2004; Zhang et al. 2005). This results in a relatively dysphoric state. On the other hand, it has also been shown in both animal models and human studies that dynorphin may ameliorate the signs and symptoms of opiate withdrawal (Specker et al. 1998). Also, dynorphin has been shown to counter morphine-induced analgesia in some settings in animal models and in humans, but in other settings it has been shown to augment morphine-induced analgesia. For instance, in human subjects with chronic pain, the natural peptide dynorphin may augment the morphine-induced analgesia (Portenoy et al. 1999). The interactions between the

and

systems in the phenomenon of

dependence, as well as in addiction (related to atypical or exaggerated euphoria or reward), may be acting in a countermodulatory manner in some settings and in a synergistic manner in other settings, and these actions may be different in specific brain regions.

ENDOGENOUS AND EXOGENOUS OPIOID ROLE IN STRESS RESPONSIVITY: IMPACT OF RECENT MOLECULAR GENETICS FINDINGS Stress Responsivity and the Addictions From our initial work at the Rockefeller Hospital in 1964, we conceptualized that addictions were diseases of the brain with behavioral manifestations and were not simply traits of a weak or antisocial personality or due to criminal behavior (Dole et al. 1966; Kreek 1996c, 2000a, 2003). Further, we hypothesized that some aspects of normal human neuroendocrine function modulating stress response might be involved in the addictions (Kreek 1973, 1978, 1996c, 1996d, 2000b; Kreek and Koob 1998; Kreek et al. 2002). Therefore, we built into our very earliest studies, both prospective and one-pointin-time studies conducted from 1964 to 1973, ways to address specific questions relating to the integrity of the neuroendocrine system after long cycles of heroin addiction and during stabilization in long-term methadone maintenance treatment (e.g., Kreek 1978, 1992). Furthermore, by the mid-1970s our laboratory hypothesized specifically that an atypical responsivity to stress and stressors may contribute to the persistence of and relapse to addiction and possibly even to the initial acquisition of addiction (e.g., Kreek 1973, 1978). Further, we hypothesized that such atypical responsivity to stress and stressors may be due to preexisting environmental factors and intrinsic genetic factors as well as drug-induced changes, which were later well documented. By 1973, we were able to directly document that whereas during cycles of heroin addiction there is profound disruption of the stress-responsive HPA axis, during methadone maintenance treatment, normalization occurs (Kreek 1973, 1978, 1992; Kreek et al. 1983, 1984, 2002). As soon as the endogenous opioid system was identified and technology allowed us to directly measure levels of

-endorphin, we were further able to determine that profound

disruption occurs during cycles of heroin addiction and normalization of levels and circadian rhythm of this very important, primarily

opioid receptor ligand,

-endorphin, occurs, along with normal

responsivity during methadone maintenance treatment (Kosten et al. 1987, 1992; Kreek et al. 1983, 1984). In contrast, we were able to show that there is a profound disruption of

-endorphin levels,

ACTH, and cortisol levels during chronic naltrexone maintenance treatment for opiate addiction; and activation of these HPA axis hormones also occurs after administration of

opioid receptor antagonists

in healthy, nonaddicted volunteers (Culpepper-Morgan and Kreek 1997; Culpepper-Morgan et al. 1992; Kosten et al. 1986a, 1986b; Schluger et al. 1998). We also learned that the normal feedback control of the HPA axis function is profoundly disrupted during the cycles of heroin addiction, with resultant lowered levels of ACTH,

-endorphin, and cortisol—again, all of which normalize during methadone

maintenance (e.g., Cushman and Kreek 1974a, 1974b; Kreek 1973, 1978). We were able to directly document that response to negative feedback control by glucocorticoids normalizes during methadone maintenance treatment.

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To further assess the disruption of the normal modulation by negative feedback of the glucocorticoid steroid cortisol by the chronic use of the short-acting opiate heroin, we conducted studies using metyrapone, a compound that temporarily blocks 11 -hydroxylation, the last step of cortisol synthesis in the adrenal cortex. In these studies we found that while there is profound disruption of metyrapone response during cycles of heroin addiction, normalization occurs during methadone maintenance treatment (Kreek 1973, 1978; Kreek et al. 1984; Schluger et al. 2003). We also found that when metyrapone was given to well-stabilized, non-drug-abusing patients who have been receiving long-term methadone maintenance treatment, signs and symptoms of opiate withdrawal would ensue transiently, probably because of the internal physiological cues provided by surges of corticotropin-releasing factor (CRF) and, in turn, levels of ACTH; activation of both of these peptide hormones occurs in the opiate withdrawal cascade and thus signals for the former heroin addict the onset of narcotic abstinence syndrome (Kennedy et al. 1990). We were also able to show that very small amounts of the opioid antagonist naloxone, which resulted in modest elevation of ACTH and cortisol levels, actually preceded the signs and symptoms of opiate withdrawal or occurred with no subsequent signs and symptoms (Culpepper-Morgan and Kreek 1997; Culpepper-Morgan et al. 1992; Schluger et al. 1998). In many other studies, we were able to clearly define that administration of a specific opiate antagonist—such as naloxone, naltrexone, or nalmefene—leads to a dose-dependent increase in both ACTH and cortisol levels in healthy volunteers as well as in opiate-dependent individuals (e.g., Kosten et al. 1986a, 1986b; Schluger et al. 1998). In our earlier animal studies, we showed that intermittent morphine administration in the rat (as had been reported by others earlier) acutely and subacutely activates HPA axis hormones (X. M. Wang et al. 1999). However, when a different type of stressor (modest water restriction) was superimposed, administration of morphine actually attenuated the opiate-induced activation (Zhou et al. 1999). Other studies, including our own, have shown that after chronic administration of a short-acting opiate such as morphine or heroin to rodents, depression of the HPA axis hormone is observed, just as it is observed from the first exposure of an opiate in humans. Furthermore, in a rodent model where methadone was administered by pump to achieve a long-acting profile like that naturally occurring in humans (in the rat the half-life of methadone is only 90 minutes and in the mouse only 60 minutes, whereas in humans, the half-life of the racemic mixture is 24 hours and that of the active enantiomer is 28 hours), we found that steady-state methadone does not change mRNA levels (i.e., gene expression) of CRF or pro-opiomelanocortin, nor does it change HPA axis hormone levels (Zhou et al. 1996b). Numerous studies have shown that following opiate withdrawal in rodents, as well as in humans, there is profound activation of each of the components of the HPA axis. There have now been many studies reaffirming that during cycles of heroin addiction there is a lowering, and therefore a disruption, of HPA axis hormones; yet, whenever self-administration of a short-acting opiate, such as heroin, does not promptly follow, there is onset of signs and symptoms of opiate withdrawal, preceded (as stated above) by activation of the HPA axis, with elevation of levels of ACTH and cortisol. It has been established now that the elevation of HPA axis hormones precedes, and thus helps drive, the noxious signs and symptoms of withdrawal, leading to a dysphoric state coupled with a craving to self-administer an opiate (e.g., Culpepper-Morgan and Kreek 1997; Culpepper-Morgan et al. 1992). Alcohol and cocaine both activate HPA axis hormones, but attenuation of this response occurs during chronic administration in rodent models and in humans (Zhou et al. 1996a). There is increasing evidence that alcoholic individuals, and possibly also individuals addicted to cocaine, like and seek modest activation of the HPA axis, which we have shown is facilitated by naltrexone treatment (O'Malley et al. 2002). Heroin addicts, however, do not like such activation because it is reminiscent of (a physiological cue for) opiate withdrawal signs and symptoms (Kennedy et al. 1990). Just as it has been shown in rodent models and in humans that both cocaine and alcohol activate the HPA axis, it has been shown in healthy volunteers that a specific opiate antagonist, such as naloxone, nalmefene, or naltrexone, activates this axis (Schluger et al. 1998). We hypothesized that during naltrexone treatment, there would be the expected modest early (4–6 hours) activation of HPA axis

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hormones after oral naltrexone and a subsequent return of those levels to baseline, but that during a time when naltrexone was still active (24 hours or longer), there would be a relative disinhibition of the normal

opioid receptor inhibition of the HPA axis. A modest amount of alcohol would then be expected

to cause significant activation of this axis. In contrast, we found that a significantly greater amount of alcohol did not cause activation of the HPA axis in a chronic alcoholic individual receiving placebo (O'Malley et al. 2002). Furthermore, after the activation of the HPA axis hormones following consumption of alcohol, the alcoholic individuals had no further urge to drink. In contrast, the alcoholic subjects who were treated with placebo drank over twice as much alcohol and had much lower levels of ACTH and cortisol following alcohol consumption, coupled with an urge to drink (O'Malley et al. 2002). Innumerable studies have shown that in animals trained to self-administer morphine or heroin, as in animals that are trained to self-administer cocaine, relapse will occur after reintroduction of the drug, introduction of a stressor, or signaling of a cue that has been used to create a conditioned response (e.g., Goeders 2002; Shalev et al. 2002; Shippenberg and Elmer 1998). The most potent of the three precipitators of relapse is a small amount of the drug itself. However, the second most potent precipitator of relapse is the imposition of a stressor. Many studies have been conducted by different groups to see if this response can be blocked either at the HPA axis or in other parts of the brain, possibly by a CRF antagonist. Further, it has been established by many groups that stress response systems in many other parts of the brain are affected by chronic exposure to short-acting opiates in rodent models and thus may be involved in the role of stressors in specific addictive diseases. It is quite clear also that the HPA axis and its hormones play a major role, and this role can be directly studied in human subjects.

Genetics In 1998, we reported the discovery of a functional variant of the joined in a collaboration with Lei Yu, who had cloned the first

opioid receptor. In 1994, we had

receptor in rats and then in humans (as

did George Uhl, independently). We hypothesized that there would be functional variants of the

opioid

receptor, specifically in the coding region. Furthermore, we proposed that such variants, if they existed, might be associated with specific addictive diseases. In 1998, we identified multiple variants in the coding region of the

opioid receptor (Bond et al. 1998). Two—C17T and A118G—were of high allelic

frequency, with allelic frequency across ethnic-cultural groups of 6% and 11%, respectively. We had decided in advance that we would study at least one possible functional variant prior to reporting our discoveries. In the ensuing molecular biological and cell biological work, two extremely interesting findings were made. The receptor resulting from the A118G variant, when placed in proper molecularcellular constructs, was functionally different from the prototype receptor, in that the longest of the endogenous opioids, the 31-residue

-endorphin, bound three times more tightly to the

opioid

receptor resulting from this variant than to the prototype receptor. However, all other endogenous opioids, including enkephalins and endomorphins, and all exogenous opiates, including the natural morphine and the synthetic methadone, bound similarly to the two receptors. When we conducted further studies of functionality in proper molecular and cell biological constructs, focused on the GIRKs, we found that when -endorphin (but not other endogenous opioids or exogenous opiates or opioids) was the binding ligand, there was a threefold greater signal transduction by the

receptors resulting

from the A118G variant as compared to the prototype. Therefore, we postulated that physiological differences in those systems modulated by the

opioid

receptor would be identified, in addition hypothesizing possible associations with specific addictive diseases, including opiate addiction and alcoholism (Bond et al. 1998; LaForge et al. 2000). Several studies, led by the study of Wand et al. (2002), showed that, indeed, our first hypothesis was correct (Chong et al. 2006; Hernandez-Avila et al. 2003). The term that we had coined, physiogenetics, suggesting differences in normal physiological functions due to a functional gene variant, was thus documented with "proof of principle." Specifically, in three different studies it was shown that stress responsivity, as objectively measured by HPA axis response to an opioid antagonist, was significantly greater in healthy persons having one or two copies of the A118G variant (Chong et al. 2006;

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Hernandez-Avila et al. 2003; LaForge et al. 2000; Wand et al. 2002). The study paradigm used was to challenge subjects with a specific opioid antagonist, much as in the studies described above (e.g., reviewed in Kreek et al. 2004a, 2005a). In another set of studies, we recently showed that healthy individuals with one or two copies of the A118G single nucleotide polymorphism have higher basal levels of the stress hormone cortisol than do persons with the prototype receptor (Bart et al. 2006). We had also hypothesized that persons with one or more copies of the variant may experience a better response and outcome to treatment of alcoholism with an opioid antagonist such as naltrexone or nalmefene. We hypothesized and subsequently showed that alcoholic individuals seek modest activation of the HPA axis and that even nonalcoholic adults with a family history of alcoholism have a greater response to naltrexone, with respect to HPA axis activation, than do persons with no family history (Bond et al. 1998; King et al. 2002; LaForge et al. 2000; O'Malley et al. 2002). Oslin et al. (2003) reported a study wherein persons who had undergone clinical trials by the groups of O'Brien and Volpicelli and of Kranzler, in which the opioid antagonist naltrexone was used for the treatment of alcoholism, were invited to return and to consent for genetic studies and were then genotyped. Persons with one or more copies of the variant were found to be much more likely to have a positive outcome when the same outcome measures were used as had been used in evaluating the original studies for treatment of alcoholism, including longer time to relapse, decreased numbers of days drinking, and less alcohol consumed on the days of alcohol use. Furthermore, our own laboratory, again pursuing our original hypothesis, conducted studies in Sweden because of the relatively nonadmixed population—around 80% of the central Swedish population have only Swedish heritage and 20% are of different heritage, but to date with little admixture. In two separate sets of studies, we found a highly significant association of the A118G variant with heroin addiction and, further, a highly significant association of the A118G variant with alcoholism (Bart et al. 2004, 2005). Other studies of variants of the specific regions of the opioid receptor gene have been extensively reviewed along with variants of other genes found to be possibly associated with an addiction (Kreek et al. 2004a, 2005a, 2005b; LaForge et al. 2000). Thus, stress responsivity, which has been documented to contribute to the acquisition of, persistence of, and relapse to addictions, may be enhanced by very specific genetic factors that alter stress response in healthy volunteers and thus would be anticipated to further alter stress responsivity in persons with specific addictive diseases. Furthermore, one specific gene variant, the A118G variant of the

opioid

receptor gene, has been confirmed to have significant association with both heroin and alcohol addictions in at least some populations.

KEY POINTS The components of the endogenous opioid system are fully detailed and their function is described to the state of our current knowledge. Tolerance, physical dependence, and addiction are separate and dissociable phenomena. Stress and the responsivity to stress play a significant role in each of the major addictions. Genetics contributes to the vulnerability to develop specific addictions, and functional variants of genes have been documented to alter stress responsivity.

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SUGGESTED READING Kreek MJ: Methadone-related opioid agonist pharmacotherapy for heroin addiction: history, recent molecular and neurochemical research and the future in mainstream medicine. Ann N Y Acad Sci 909:186–216, 2000 Kreek MJ: Opiates, opioids, SNP's and the addictions: Nathan B. Eddy Memorial Award for lifetime excellence in drug abuse research lecture, in Problems of Drug Dependence, 1999; Proceedings of the 61st Annual Scientific Meeting of the College on Problems of Drug Dependence. National Institute of Drug Abuse Research Monograph Series. Edited by Harris LS. Washington, DC, DHHS Publ No ADM-00-4737:180, 2000, pp 3–22 Kreek MJ: Molecular and cellular neurobiology and pathophysiology of opiate addiction, in Neuropsychopharmacology: The Fifth Generation of Progress. Edited by Davis KL. Philadelphia, PA, Lippincott Williams & Wilkins, 2002, pp 1491–1506 Kreek MJ, Koob GF: Drug dependence: stress and dysregulation of brain reward pathways. Drug Alcohol Depend 51:23–47, 1998

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Kreek MJ, LaForge KS, Butelman E: Pharmacotherapy of addictions. Nat Rev Drug Discov 1:710–726, 2002 Kreek MJ, Bart G, Lilly C, et al: Pharmacogenetics and human molecular genetics of opiate and cocaine addictions and their treatments. Pharmacol Rev 57:1–26, 2005 Kreek MJ, Nielsen DA, Butelman ER, et al: Genetic influences on impulsivity, risk-taking, stress responsivity, and vulnerability to drug abuse and addiction. Nat Neurosci 8:1450–1457, 2005 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 19. Detoxification of Opioids

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Soteri Polydorou, Herbert D. Kleber: Chapter 19. Detoxification of Opioids, in The A merican Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.35 1256. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Detoxification of Opioids Soteri Polydorou, M.D. Herbert D. Kleber, M.D.

DETOXIFICATION OF OPIOIDS: INTRODUCTION Thirty-five years ago the senior author of this chapter wrote an article on the history of opioid withdrawal approaches. The introduction remains true today. The history of the treatment of narcotic withdrawal is a long and mainly dishonorable one. The trail is strewn with cures enthusiastically received and then quietly dropped when they turned out to be relatively ineffective or, even worse, productive of greater morbidity and mortality. Because of this history, one must be especially careful in proposing new techniques that they meet the twin demands of safety and efficacy. Any claims for a new method should be put forward with modesty and viewed with skepticism until amply documented by careful experimental procedures. (Kleber and Riordan 1982, p. 30) Opioid detoxification continues to be used for most heroin abusers as a pretreatment procedure before residential therapeutic community treatment, outpatient drug-free treatments, and opioid antagonist maintenance treatment. It is also used by some who do not seek long-term treatment either because they expect that they can remain abstinent from opioids without additional help or because they do not seriously intend to remain abstinent. Although therapeutic community and antagonist maintenance treatments are effective for many patients, the prerequisite detoxification and associated withdrawal discomfort can be a barrier to entering such treatment for many patients. Despite improvements over the past 30 years, most current approaches to detoxification continue to be plagued by high dropout rates and high relapse rates. Because most opioid-dependent individuals have unsuccessfully tried to stop on their own, they often fear the physical discomfort of opioid withdrawal and delay or avoid seeking help for it. Others attempt detoxification with medical assistance but frequently do not complete it because they are just trying to lower the cost of their habit. Finally, even those who successfully complete detoxification have a high relapse rate. These problems have given rise to techniques such as the "ultrarapid" or anesthesia-assisted detoxification and antagonist induction procedures, which are offered at high cost without evidence of improved patient outcomes, despite increased risk. Although many opioid-dependent patients may do better on agonist maintenance (e.g., methadone, buprenorphine), for those who either do not want such treatment or cannot do well on it, there remain drug-free or antagonist maintenance approaches. For such individuals, detoxification is a necessary part of entering treatment, but it has not yet achieved its full potential for the transition. The advent of buprenorphine and better

adrenergic agonists for opioid detoxification may improve this

transition and enable more patients both to enter such treatment and to achieve sustained abstinence from opioids.

DEPENDENCE, TOLERANCE, AND DETOXIFICATION Physical dependence refers to the physiological state that follows chronic, regular use of a substance. It is clinically evidenced by the emergence of a characteristic withdrawal syndrome (for that drug or class of drugs) following a significant reduction in the amount of the drug regularly ingested. The withdrawal syndrome can be understood to be the physiological manifestation of nervous system changes that are unmasked when the drug is no longer present. Tolerance almost always accompanies physical

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dependence. Tolerance describes the phenomenon by which a drug's effectiveness diminishes over time with regular use of the drug. This is seen either when the effects of a fixed amount of drug lessen or when an individual needs greater amounts of the drug to produce the same effects initially produced by smaller amounts. Tolerance typically occurs by reduced end organ response to the drug (pharmacodynamic tolerance) or by increased metabolism of the drug (pharmacokinetic tolerance), although other physiological mechanisms may uncommonly play a role. Addiction is a less precise term, sometimes used synonymously with the DSM-IV-TR (American Psychiatric Association 2000) diagnosis of substance dependence and used to describe compulsive use of a drug and overwhelming involvement with its procurement and use. Tolerance, physical dependence, and withdrawal may be present in the absence of addiction or a DSM-IV-TR diagnosis of dependence. Substance dependence was used instead of addiction to avoid the stigma associated with the latter term, but this can be confusing because individuals receiving chronic opioid analgesia may become "dependent" on the drug but not meet criteria for substance dependence. DSM-V may remedy this by returning to the term addiction. Detoxification refers to the process of taking an individual off of a drug on which he or she has become physically dependent. The detoxification may be done abruptly or gradually (Kleber 1981). A variety of medication options are available for use in opioid detoxification: 1) the drug on which the individual is dependent, 2) other drugs that produce cross-tolerance, 3) medications to provide symptomatic relief, and 4) drugs that affect the mechanisms by which withdrawal is expressed. Settings for detoxification can include inpatient, residential, day, or outpatient programs. Given the current armamentarium of medications, opioid detoxification can be accomplished safely, relatively quickly, and with a minimum of discomfort. Unfortunately, the method chosen often depends more on what is available than on what is ideal. This is a consequence of many factors: physician or patient preference or bias, the availability of physicians trained in detoxification methods, federal and state regulations, insurance or other funding mechanisms, and the methods available in a given setting in a particular geographical area. Some clinicians prefer the term withdrawal to detoxification because of the latter's connotation of opioids as toxic.

GOALS OF DETOXIFICATION The goals of the detoxification process are as follows: 1. To rid the body of the acute physiological dependence associated with chronic daily opioid use 2. To diminish, or ideally to eliminate, the pain and discomfort of opioid withdrawal 3. To provide a safe and humane treatment that assists the individual in remaining abstinent during the acute phase of withdrawal 4. To provide an environment that increases the likelihood of continued treatment and to refer to such treatment centers 5. To identify any medical problems and to treat them or make referrals for additional care following detoxification 6. To begin educating the patient about issues related to health and relapse prevention and to begin exploring issues related to family, vocational, and legal problems that may need referral

WHEN IS DETOXIFICATION SUCCESSFUL? Because relatively few opioid-dependent individuals can sustain abstinence from opioids without additional help immediately after detoxification, detoxification should be viewed as the first stage of treatment. It is unrealistic to expect detoxification alone to produce the more ambitious goals of long-term treatment, including improvements in employment, criminal behavior, interpersonal relationships, and general physical and psychological well-being. Success is a function not only of safety and comfort but also of treatment retention and participation in longer-term treatment. This does not mean that detoxification is necessarily a failure if the person does not agree to long-term treatment.

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Younger patients may see no need for longer-term treatment, but when they return a second or third time, they are frequently more realistic and more willing to consider longer-term treatment. Because of the relapsing nature of opioid dependence, formal detoxification may be required many times over the course of the disorder.

SETTING CHOICE Detoxification can take place in an outpatient, inpatient, or partial hospitalization setting. Outpatient treatment is the least expensive setting and may enable the patient to continue working or carrying on his or her life. It has the potential advantage of forcing a person to confront the home environment, with its usual drug cues, and immediately find alternatives to use in response to these cues. The disadvantages of outpatient detoxification include immediate access to drugs when drug craving may be extremely high, more difficulty assessing and dealing with other medical conditions, the possible need for detoxification to proceed more slowly, and its low success rate. During inpatient detoxification, access to drugs or to craving-inducing stimuli can be minimized, the patient can be observed more closely for medical problems or complications, and the withdrawal can be more rapid. If the program is comprehensive, more attention can be focused on other aspects of the patient's life in the family, vocational, medical, and psychiatric arenas. The disadvantages are primarily the cost and the disruption in the patient's life caused by the need to be away from work and home. Partial hospitalization programs are considerably less expensive than inpatient programs, while retaining some of the inpatient advantages; nevertheless, they are not widely available. The clinician is usually forced to choose between inpatient and outpatient settings, and the choices are often limited by factors such as insurance coverage and the availability of programs. As a result of managed care restrictions, inpatient detoxification has become primarily for those patients who are homeless, have serious medical or psychiatric problems, or have repeatedly failed outpatient detoxification. Although inpatient detoxification has a much higher completion rate (up to 80%) compared with outpatient programs (as low as 17%; Gossop et al. 1986), its long-term advantages related to relapse are less definite. Some patients need inpatient detoxification to achieve initial abstinence. Work is still needed in accurately identifying which patients require inpatient treatment and which would do well with an outpatient approach.

HISTORICAL OVERVIEW In the past century, many treatments have been introduced for relieving the symptoms of opioid withdrawal. Many of these treatments have proven either more addicting than the drug being withdrawn or more dangerous than untreated withdrawal. In a masterful review, Kolb and Himmelsbach (1938) looked back on 40 years of mostly futile attempts to treat narcotic withdrawal, including the use of autohemotherapy (injection of blood previously withdrawn from the patient), water balance therapy, and numerous toxic chemicals, alone or in combination. Kleber and Riordan (1982) reviewed the earlier work by these writers and updated it with the techniques that had been used in the 40 years since that article was published. Since that 1982 review, the most common approach—methadone substitution and gradual withdrawal—has declined in popularity, and the newer approaches described in this chapter have gained favor but may yet be discarded if they are found wanting.

CLINICAL CHARACTERISTICS OF THE OPIOID ( AGONIST) WITHDRAWAL SYNDROME Naturally occurring opiates such as opium, morphine, and codeine; derivatives such as heroin, hydromorphone, and dihydrocodeine; and synthetics such as methadone, meperidine, and fentanyl are capable of creating physical dependence and may require detoxification if they have been taken in sufficient quantities over time. In general, clinically significant withdrawal syndromes do not develop after less than 2 weeks of daily opiate use (Jaffe and Martin 1975), but individuals previously dependent on opioids may redevelop physical dependence much more quickly.

Factors Influencing Symptom Severity

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The nature and severity of withdrawal symptoms when opioid-type drugs are halted relate to a variety of factors: Specific drug used. Rapidly metabolized drugs such as heroin are generally associated with more severe but shorter-lived withdrawal phenomena, whereas drugs that dissociate slowly from the opioid receptor, such as buprenorphine, or that are slowly excreted from the body, such as methadone, have a slower onset with a less intense but more protracted withdrawal syndrome. In general, the longer the duration of drug action, the less intense but longer lasting the withdrawal symptoms. Total daily amount used. In general, the more opioids ingested daily, the more severe the withdrawal syndrome. However, some researchers have suggested that dosage does not correlate well with severity of withdrawal symptoms (Gossop et al. 1987). Duration and regularity of use. Although some withdrawal can be seen when a single dose of morphine is followed a few hours later by a narcotic antagonist (Heishman et al. 1989), clinically significant withdrawal usually requires daily use of an adequate amount of the opioid for at least 2–3 weeks (Jaffe and Martin 1975). In contrast, duration of use much beyond 2–3 months does not appear to be associated with any greater severity. A good rule of thumb regarding the regularity of use and its association with symptom severity is that the more intermittent the drug use, the less severe the withdrawal. Psychological and individual factors. In general, the greater the patient's expectation that his or her suffering would be relieved by an available medication, the more severe the reported withdrawal symptoms. Thus, if an individual expects little symptom relief, there seems to be a diminution in the withdrawal intensity reported. Anticipatory anxiety appears to increase withdrawal severity (Phillips et al. 1986). The patient's personality and state of mind can also influence withdrawal severity, as can his or her general physical health and ability to handle stress. Finally, some individuals appear to be far more sensitive to opioid withdrawal symptoms than others.

Signs and Symptoms of Opioid Withdrawal The

agonist withdrawal syndrome can be conceptualized as rebound hyperactivity in the biological

systems suppressed by the agonists. (For a more detailed description of the neurochemical mechanisms involved, see Chapter 18 of this volume, "Neurobiology of Opioids.") Withdrawal phenomena are generally the opposite of the acute agonistic effects of the opioid (e.g., acute opioids cause constipation and pupillary constriction, whereas withdrawal is associated with diarrhea and pupillary dilatation). The clinical characteristics of opioid withdrawal may be described in several ways. Some authors separate objective signs from subjective symptoms, whereas others separate signs and symptoms into grades on the basis of severity. No single classification is totally satisfactory. Subjective symptoms, even under controlled conditions, are often more distressing than objective signs. It also has been shown that opioid-dependent patients may experience major withdrawal symptoms with minimal or no objective signs to confirm this discomfort. Table 19–1 lists the most common signs and symptoms, which are divided into two categories based on their approximate order of appearance. When a short-acting opioid such as heroin has been taken chronically, the onset of withdrawal begins with anxiety and craving about 8–12 hours after the last dose (see Table 19–2). This progresses to dysphoria, yawning, lacrimation, rhinorrhea, perspiration, restlessness, and broken sleep. Later, there are waves of gooseflesh, hot and cold flashes, aching of bones and muscles, nausea, vomiting, diarrhea, abdominal cramps, weight loss, and low-grade fever. An untreated individual in opioid withdrawal may lie in a fetal position (to ease abdominal cramping) and request blankets, even on warm days (because of the hot and cold flashes). The individual's skin may be exquisitely sensitive to the touch. The heroin withdrawal syndrome typically reaches its peak between 36 and 72 hours after the last dose, and the acute symptoms subside substantially within 5 days. With methadone withdrawal, in contrast, the peak occurs between days 4 and 6, and symptoms do not substantially subside for 14–21 days (Kleber 1996).

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With a more short-acting opioid, such as meperidine, craving may be intense, but the autonomic signs, such as pupillary dilatation, are not particularly prominent. Usually, little nausea, vomiting, or diarrhea occurs, but at peak intensity, the muscle twitching, restlessness, and nervousness may be worse than during morphine withdrawal (Jaffe and Martin 1975). Regardless of which opioid is used, the acute symptoms are followed by a more protracted abstinence syndrome, with subtle disturbances of mood and sleep that can persist for 6–8 months (Martin and Jasinski 1969). An addicted individual may not feel normal for months after the last drug use. Fatigue, dysphoria, irritability, and insomnia may all increase the likelihood of relapse. Protracted abstinence may involve both conditioning and physiological factors (Satel et al. 1993).

EVALUATION AND DIAGNOSIS When the clinician first sees a patient, the patient should be evaluated to determine whether detoxification is needed. Once this is determined, a more complete assessment is necessary to devise an individual treatment plan. Thus, information needs to be gathered on a wider range of areas, including psychological, psychosocial, and physical status.

The Interview While gathering information in the interview, especially the drug history, a nonjudgmental attitude on the part of the interviewer is more likely to elicit accurate data. Disdainful behavior may produce false information and even drive the patient away.

Drug history A review of current and past drug and alcohol use and abuse is necessary for adequate patient assessment. The following information should be obtained for each current substance or group of substances, with special emphasis on substance use during the past week: Name of drug used, length of time used, frequency of use Date or time of last use Route of administration Amount Cost Purpose (e.g., to get high, to relieve depression or boredom, to sleep, for energy, to relieve side effects of other drugs, to avoid withdrawal) For drugs previously used: name, age at which drug use started, length of time used, adverse effects Previous treatment experiences: where, what kind, outcome Prescription drugs currently used: name, reason for use, amount, frequency, duration of use, and last dose

Other medical history The medical history includes serious illnesses, chronic diseases, accidents, and hospitalizations. In addition to the usual medical history, special attention should be given to the possible medical complications of drug abuse. The medical history also includes the existence of current symptoms in the various body systems. It is important to look for illnesses that may complicate withdrawal and those that previously may have been ignored or missed because of the patient's chaotic lifestyle. Medical conditions that can complicate withdrawal include many cardiovascular diseases, diabetes mellitus, and others. The physiological stress induced by withdrawal may make the management of these diseases more difficult. Patients with a history of cardiovascular disease or at significant risk should have withdrawal signs of tachycardia and hypertension closely monitored and managed. Glycemic control in diabetic patients may be markedly affected by the decreased oral intake, vomiting, and diarrhea seen during detoxification. A comprehensive medical history will assist in determining the method and setting most appropriate for detoxification.

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Social functioning Information with regard to social functioning should be gathered on the following topics: 1) living arrangements (e.g., alone, with family); 2) marital status; 3) sexual orientation and functioning; 4) employment and/or educational status; 5) family members' (e.g., parents, siblings, spouse, other key members) occupations, education, psychological state, and history of drug or alcohol problems; 6) friends (in particular, are there non-drug-using ones?); 7) recreational and leisure-time activities; and 8) current and past legal status. The Addiction Severity Index is a useful instrument for gathering this information (McLellan et al. 1985). The interviewer should try to get a feel for the emotional and factual aspects of the interview topics. For example: What is the patient's attitude toward his or her job, and what type of job is it? What is the quality of the patient's marital or family relationships? How does the patient cope with spare time at nights and on weekends when relapse is most likely to occur? Such questions can identify the patient's social supports and aid in planning for postdetoxification treatment. Prior attempts at withdrawal and factors associated with relapse should be especially explored.

Psychological status When carried out by a nonpsychiatrist physician, psychological evaluation may single out patients who need early psychiatric referral for possible psychosis, delirium, psychiatric syndromes secondary to medical conditions, serious depression, suicide, or tendency for violence. The psychiatrist, in addition to exploring factors that could complicate withdrawal, should evaluate for the presence of less obvious comorbid psychiatric syndromes. When possible, the evaluator should ascertain whether psychiatric conditions preceded or followed the drug abuse. Some patients take drugs to self-medicate dysphoric states of loneliness, depression, or anxiety or to control unacceptable, usually aggressive, impulses. Conversely, continued use of certain drugs may lead to or exacerbate psychiatric states not previously evident. Opioids seem to have antipsychotic effects in some patients, and withdrawal can lead to an exacerbation or sudden appearance of psychotic symptoms. As part of the psychological state evaluation, a mental status examination should be carried out and include orientation for place, person, and date; presence or absence of hallucinations, delusions, or suicidal ideation; memory; intelligence, mood, and affect; thought processes; preoccupations and behavior during the interview; judgment; and insight.

Physical Examination Although there is no special physical examination for opioid-dependent individuals, certain conditions could be either direct or indirect sequelae of drug abuse. Although some of these findings appear in nondependent individuals and some dependent individuals may have few or none of them, their presence aids proper diagnosis.

Cutaneous signs The following cutaneous signs may be directly or indirectly associated with drug abuse: Needle puncture marks. Needle marks are usually found over veins, especially in the antecubital area, back of the hands, and forearms, but can be found anywhere on the body where a vein is reachable, including the neck, tongue, dorsal vein of the penis, and between the toes. "Tracks." Tracks, or track marks, are one of the most common and readily recognizable signs of chronic injection drug abuse. They are usually hyperpigmented linear scars located along veins. They result both from frequent unsterile injections and from the deposit of carbon following needle sterilization performed with a match or other sooty heating procedure. Tracks tend to lighten over time but may never totally disappear. Tattoos. Addicted individuals may try to hide tracks with tattoos over the area. Hand edema. When addicted individuals run out of antecubital and forearm veins, they often

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turn to veins in the fingers and back of the hands, which can lead to hand edema. Such edema can persist for months. Thrombophlebitis. Thrombophlebitis (blockage or inflammation of veins) may be found on the limbs of injection drug users because their injections are often unsterile and because irritation is produced by adulterants. Arm or leg edema. Edema of an extremity can be a sign of vein thrombosis. Intravenous drug use can increase a person's risk of thrombosis because of thrombophlebitis or the trauma inflicted on veins by repeated injections. Abscesses and ulcers. Abscesses and ulcers are particularly common among individuals who are intravenous drug users, because of the irritating quality of many chemicals. When secondary to heroin injection, they are more likely to be septic and in the vicinity of veins. Ulceration or perforation of the nasal septum. Frequent snorting of heroin can lead to ulceration of the septum, whereas similar chronic use of cocaine can cause septal perforation secondary to vasoconstriction. Cigarette burns or scars from old burns. Cigarette burns or scars can result from drug-induced drowsiness. It has been estimated that more than 90% of drug- and alcohol-dependent individuals smoke tobacco. Piloerection. Piloerection, a sign of opioid withdrawal, is usually found on the arms and trunk due to spasm of the muscles around the hair follicle. Truncal piloerection is unusual in the absence of opioid withdrawal. Cheilosis. Cheilosis (cracking of skin at the corners of the mouth) is especially seen in chronic amphetamine-using individuals and in opioid-addicted individuals prior to or during detoxification. Contact dermatitis. In solvent-abusing individuals, contact dermatitis is seen around the nose, mouth, and hands and is sometimes called glue-sniffer's rash. In other abusers, it may occur around areas of injection secondary to use of chemicals to cleanse the skin. Jaundice. Jaundice due to hepatitis is usually from use of unsterilized shared needles and syringes. Hepatitis C infection among injection drug users in New York City has been reported to be between 80% and 90%. Monilial infection. Monilial infection, typically oral thrush, is a common finding in individuals with AIDS.

Additional signs and symptoms Fever. Although uncommon, a temperature of 100.4°F or greater can be seen during uncomplicated withdrawal. However, substance abuse patients are at elevated risk for various other causes of fever, including infectious diseases. Therefore, etiologies causing fever other than withdrawal should always be considered. Constipation. Constipation is a common side effect of opioid use, caused by the drugs' effects on receptors in the brain, spinal cord, and enteric nervous systems. Bronchospasm. Bronchospasm can be induced directly from opioids' effect on histamine release. Seizure. Seizures are not part of the withdrawal syndrome but can develop from the accumulation of tramadol or a proconvulsant metabolite of meperidine.

Laboratory tests The following laboratory tests should usually be performed: Urine screening for drugs, including barbiturates, opioids, amphetamines, cocaine, benzodiazepines, phencyclidine, and marijuana. The prescription opioids oxycodone, hydrocodone, fentanyl, and buprenorphine require special dipsticks to be detected. Complete blood count and differential; leukocytosis is common, and white blood cell counts greater than 14,000/mm 3 are not unusual. Urinalysis

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Blood chemistry profile (e.g., sequential multiple analysis 20 with serum amylase and magnesium) Syphilis serology HIV test (permission from the patient is necessary in many states) Hepatitis antigen and antibody test Chest X ray Electrocardiogram in patients older than age 40 years Pregnancy test in women (hold chest X ray until test is complete) Tuberculin skin test (purified protein derivative) Any other necessary test suggested by the history or physical examination

OPIOID AGONIST SUBSTITUTION AND TAPER Because of cross-tolerance and cross-dependence among all opioids, one could, in theory, use almost any opioid to prevent withdrawal and gradually detoxify opioid-dependent individuals. Two opioids, however, deserve special attention for this purpose: methadone and buprenorphine.

Methadone Until the approval of buprenorphine in 2002 for opioid detoxification and maintenance, the most common detoxification method was methadone substitution and taper, although the method declined in popularity even before buprenorphine became widely available. Methadone has several advantages over most other agents for detoxification: It is orally effective, which eliminates the need for continued injection drug use. Longer-acting opioids produce withdrawal syndromes that are milder but longer lasting and need to be given less often, thus producing smoother withdrawal. However, at lower dosages methadone may need to be given two times a day or more. It is safe, provided that appropriate care is taken with initial dosing. In general, a more addictive drug should not be used to detoxify a patient from a less addictive one. In practice, this means that although methadone can be used to withdraw patients from narcotics such as heroin, morphine, hydromorphone, oxycodone, or meperidine, it should be avoided for drugs such as propoxyphene or pentazocine, for which the withdrawal should be handled by gradually decreasing the dosage of the agent itself or by an agent such as clonidine. Buprenorphine, given sublingually, will probably become the opioid of choice for withdrawal from most opioids. U.S. Food and Drug Administration (FDA) guidelines for narcotic detoxification describe two types of detoxification: short-term and long-term. Short-term detoxification is for a period not more than 30 days; long-term detoxification is for a period not more than 180 days. Short-term detoxification is most likely to occur with individuals currently dependent on opioids other than methadone. Long-term detoxification is used for individuals already taking methadone and wishing to stop it, although in some programs, individuals are taken directly from heroin to long-term detoxification with methadone over a 6-month period. Prolonged detoxification avoids some of the withdrawal symptoms that occur in more rapid detoxification and provides a setting in which psychosocial rehabilitation can take place. However, the long-term effectiveness of this option, as opposed to shorter-term detoxification or methadone maintenance, has not been shown.

Initiation of detoxification If the patient has been taking opioids for medical purposes, and the physician is reasonably sure about the amount being ingested, Table 19–3 can be used to convert the narcotic dosage into a methadone dosage. With illicit drug use, the picture is very different. Knowledge of the exact dosage is usually not available. The amount of narcotics in illegal "bags" can vary from dealer to dealer, city to city, and even day to day. The physician must thus guess at the initial methadone dosage. Given that the purity of heroin on the street has ranged from 50% to 80% in recent years, the choice of an initial dosage is very important. It needs to be high enough to suppress withdrawal symptoms so that the patient does not

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leave the program but low enough so that if the patient's habit were lower than presumed, the dosage would not be health- or life-threatening. Because 40 mg of methadone can be a fatal dose in some nontolerant individuals, the initial dose should be less than 40 mg. One common approach to ensuring safety is to start with an oral dose of 10–20 mg, large enough to control many heroin habits yet small enough to be safe for virtually everyone. If a patient cannot initially tolerate oral methadone, then 5–10 mg or 50% of the planned oral dose can be given as an intramuscular injection. The patient should be kept under observation to assess the effect of the initial methadone dose. If withdrawal symptoms are initially present, the dose should suppress them within 30–60 minutes; if withdrawal symptoms persist an hour after dosing, an additional 5–10 mg of methadone can be given. When withdrawal symptoms are not initially present, the patient should be observed for drowsiness or depressed respiration an hour after dosing. When 10–20 mg is given as the initial dose, a similar amount may be given 12 hours later if necessary. This split-dosing approach is usually not practical in outpatient detoxification but can be used in inpatient settings. Unless evidence of narcotic use in excess of 40 mg of methadone equivalent per day is documented, the initial dose should not exceed 30 mg, and the total 24-hour dose should not exceed 40 mg the first few days. A safe initial dose in a nontolerant individual can become dangerous if continued beyond 1 or 2 days, because of rising blood levels of methadone. A dangerous dose manifests itself in drowsiness and/or signs of motor impairment, as well as miosis, nausea, and possible mild hypothermia. Some clinicians disagree as to whether to start the withdrawal regimen in the absence of withdrawal signs and symptoms. It is sometimes difficult to know with certainty that an individual is currently physically dependent unless the clinician has observed the signs and symptoms of opioid withdrawal. The history of drug taking may be unreliable, as a result of overreporting drug use to increase the dose of prescribed opioid or underreporting to conceal a habit (more common among addicted health care professionals). The drug history may be misleading even when the patient is trying to be honest, because of the variable nature of illicitly obtained drugs. Physical signs such as tracks tell of past drug use, not necessarily current use. Fresh needle marks may provide little information about the frequency, nature, and amount of what was injected. Urinalyses positive for drugs suggest recent use but do not establish the need for detoxification. Heroin, detected as morphine in the urine, can be found up to approximately 48 hours after the last use among infrequent users. Definitive evidence of physical dependence can be collected in two ways: 1) by waiting until the patient develops withdrawal signs and symptoms or 2) by producing withdrawal through administration of naloxone. Parenteral naloxone can distinguish opioid-dependent from nondependent individuals through the severity of withdrawal related to the naloxone dose. A common method is to inject 0.2 mg of naloxone subcutaneously, followed by 0.4 mg 30 minutes later if the results from the smaller dose are inconclusive. Some physicians recommend an initial dose of 0.6–0.8 mg to speed up the process and rule out false negative results. Because of the possibility of fetal injury or induced miscarriage, the naloxone test should not be done if the patient is pregnant. Whether the program is inpatient or outpatient, the availability of trained medical personnel will often determine how the program will establish the need for medical detoxification. If, as is commonly the case, the program uses the combined evidence of the medical history, physical examination, and urine toxicology screening, it should still be prepared to wait for withdrawal signs or administer a naloxone challenge test in borderline or doubtful situations. Once the need for medical detoxification has been established, decisions still have to be made regarding the setting, the specific method of detoxification, and the need for concurrent treatment of comorbid physical or emotional problems. When serious physical or emotional problems are present, it is not uncommon to delay the opioid taper by temporarily maintaining the individual on methadone, attending to the acute problem, and then beginning the methadone taper once some stability has been achieved in the other areas.

Length of withdrawal The total methadone dosage necessary to stabilize a patient for the first 24 hours should be repeated on

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day 2, either in one dose for outpatients or in divided doses for inpatients. Dosage adjustments can then be made if the patient is sedated or remains in some withdrawal. Revision to a higher dosage should preferably be made on the basis of objective signs of opioid withdrawal rather than on subjective complaints alone. This is not always easy because certain signs, including pupillary dilatation, may be modified by the methadone, even when the patient is undermedicated. After the patient is stabilized, the dosage can then be gradually reduced. Two common approaches are either to decrease the methadone dosage by 5 mg/day until zero dosage is reached or to decrease it by 10 mg/day until a dosage of 10 mg/day is reached and then decrease it more slowly (e.g., by 2 mg/day). For individuals who have large initial habits, the first method may be better, whereas in those with a starting dosage of less than 50 mg/day of methadone, the latter approach leads to more rapid passing of the withdrawal syndrome without any significant increase in withdrawal severity or dropout rate (Strang and Gossop 1990). Inpatient methadone substitution and taper is usually accomplished in 5–7 days, whereas outpatient detoxification is often extended to minimize withdrawal symptoms and to decrease the likelihood of dropout and relapse. Some inpatient programs complete the process in as few as 4 days, whereas some outpatient programs last for months. Symptoms of insomnia, fatigue, and irritability or anxiety may linger for weeks or months. The acute phase of opioid withdrawal may be considered complete and the patient discharged from the detoxification program when no objective signs of opioid withdrawal occur for 48 hours in the absence of any opioid.

Withdrawal from methadone maintenance For a patient withdrawing from methadone maintenance, the detoxification approach used tends to be a function of the reasons for terminating methadone maintenance treatment. Patients in good standing who desire to become drug free should be tapered off methadone slowly over a 3- to 6-month period. The most difficult period for patients usually occurs at methadone dosages less than 25 mg/day because at these lower dosages, withdrawal symptoms may emerge sooner than 24 hours after a dose. Split doses, typically given two times a day, may help counter this problem; however, they are not always possible or practical. The dosage of methadone is usually reduced by 5–10 mg/week until it reaches 25 mg/day. At that point, a reduction of no more than 5 mg/week is often recommended. If the patient needs to be withdrawn more rapidly because he or she is being discharged in bad standing, must leave the geographical area, or may be going to prison, then withdrawal usually takes place during a 10- to 30-day period. For example, the patient dosage may be decreased by 10 mg/day until a total dosage of 40 mg/day is reached, and then it is decreased by 5 mg/day until the dosage of 5 mg/day is reached, at which point that dosage is given for 2–3 days. If the patient is on an inpatient or residential unit, divided doses are helpful, especially when the total dosage is less than 25 mg/day.

Other drugs and supportive measures Even with gradual withdrawal, some withdrawal symptoms usually emerge, and certain mild symptoms may persist for many days after treatment has been completed. There is no consensus on the use of other drugs during these periods. Tranquilizers or bedtime sedation can help allay the patient's anxiety and minimize the craving for opioids, but nonopioid medications are, at best, only partially effective in relieving the specific symptoms of opioid abstinence, with the exception of

2

adrenergic agonists (e.g.,

clonidine or lofexidine; see the section "Other Detoxification Agents and Methods" later in this chapter). If insomnia and other withdrawal symptoms are unusually severe, especially in older patients, an incremental increase in the next dose of methadone and, therefore, a slower withdrawal schedule can provide relief. Insomnia not only is one of the more debilitating withdrawal symptoms but also diminishes a patient's ability to cope with other withdrawal symptoms. Barbiturates should generally not be used to treat insomnia because of their abuse liability and low therapeutic index. Sedating medications, including flurazepam, clonazepam, oxazepam, zolpidem, diphenhydramine, hydroxyzine, and antidepressants such as trazodone have all been proposed for withdrawal-related insomnia. Because many opioid-

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dependent individuals may also abuse benzodiazepines, the choice of those agents needs to be made carefully. Generally, few or no problems result when benzodiazepines are used for up to a week in inpatient detoxification settings. Outpatient detoxification presents more problems because there is no control over benzodiazepine use, misuse, or diversion. Comfort medications used to treat ancillary withdrawal symptoms include nonsteroidal anti-inflammatory drugs (e.g., 600–800 mg of ibuprofen every 6–8 hours or 30 mg of ketorolac tromethamine intramuscularly every 6 hours for no more than 5 days) for muscle cramps or pain; dicyclomine 10 mg every 6 hours for abdominal cramps; bismuth subsalicylate 30 cc after each loose stool; prochlorperazine 10 mg intramuscularly three times a day or ondansetron 8 mg orally every 8 hours for nausea and vomiting; and 2 adrenergic agents (e.g., clonidine, guanfacine, lofexidine) for flu-like symptoms. Psychosocial support can also play an important role. A warm, kind, and reassuring attitude from the treatment staff is most helpful. Involvement of patients in their own detoxification schedule helps with inpatient, but not outpatient, detoxification (Dawe et al. 1991). The fewer the struggles over medication dosing, the better the alliance can be with the patient. Visitors, however, can be a problem and should be limited to immediate family members (i.e., parents or spouse) who are known not to abuse drugs. Even parents have been known to smuggle in drugs under the pressure of a patient's entreaties that the staff does not understand the patient's distress. A watchful presence is therefore necessary around all visitors. Such attempts at deception may be less likely to occur if family meetings are held and parents and significant others are well informed about the approach to detoxification. Other potentially helpful measures include warm baths, exercise, and various diets. Except when specific nutritional deficiencies are present, there is no evidence for benefits from any particular dietary regimen. However, because opioid-dependent patients are often malnourished, general vitamin and mineral supplements should be given.

Buprenorphine Buprenorphine is a partial

receptor agonist and

receptor antagonist. Although initially marketed in

the United States as a parenteral analgesic (Buprenex), buprenorphine was approved by the FDA in late 2002 in sublingual tablet formulations for both detoxification and maintenance treatment of opioid dependence. Buprenorphine sublingual tablets are available with buprenorphine only (Subutex) and in combination with naloxone (Suboxone) in a 4:1 ratio. The addition of naloxone is intended to reduce the risk of buprenorphine abuse by injection. Naloxone is not readily bioavailable with sublingual administration because the potency ratio of parenteral to sublingual naloxone is 15:1. Therefore, the small quantities of naloxone absorbed by the sublingual route will generally not precipitate withdrawal. If, however, the sublingual tablet is crushed and snorted or dissolved and injected, it may precipitate withdrawal, especially among heroin users, and thus significantly reduce the risk of buprenorphine diversion. It is not entirely clear what dose of injected naloxone will precipitate withdrawal in individuals receiving buprenorphine maintenance (Eissenberg et al. 1996; Jasinski et al. 1978; Kosten et al. 1990; Mendelson and Jones 2003) because buprenorphine has a long receptor half-life and greater affinity for opioid receptors than does naloxone. Many of the advantages noted earlier for methadone in detoxification apply equally to buprenorphine, which is also long-acting, safe, and effective by a nonparenteral route of administration. Initiation of buprenorphine for detoxification differs from methadone initiation in that buprenorphine may precipitate withdrawal symptoms if it is given too soon following use of an opioid agonist. When using buprenorphine for detoxification, one waits until the patient shows some withdrawal symptoms (e.g., Clinical Opiate Withdrawal Scale score of 12 or more), at which point buprenorphine usually serves to relieve these symptoms and is less likely to precipitate withdrawal. When some of the older literature on buprenorphine is considered, one must keep in mind that until the mid-1990s, buprenorphine was usually administered in an aqueous alcohol solution, which is approximately twice as bioavailable as the tablet formulations now available.

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A typical approach to managing heroin detoxification is to administer buprenorphine 2–4 mg sublingually after the emergence of mild to moderate withdrawal (usually at least 12 hours after the last use of heroin). Another 2- to 4-mg dose of buprenorphine sublingually may be administered approximately 1 hour later, depending on the patient's comfort level. Usually, a total of 8 mg of buprenorphine is sufficient on the first day of detoxification, but 12 mg may be necessary in patients with larger habits. On subsequent days, doses of buprenorphine between 8 and 16 mg sublingually are usually sufficient to relieve withdrawal symptoms. Data are insufficient to make definitive recommendations about the optimal subsequent duration of buprenorphine treatment in detoxification. Some studies have used high-dose buprenorphine for as little as 1 day (Hopper et al. 2005; Kutz and Reznik 2001), whereas others have tapered buprenorphine over 13 days (Amass et al. 2004; Ling et al. 2005). For most patients, however, a slow taper over a few days after reaching adequate withdrawal relief remains a safe and well-tolerated detoxification strategy. Buprenorphine in doses of 16 mg or less may not suppress all signs and symptoms of withdrawal; muscle ache, restlessness, yawning, mydriasis, and tremor have been reported (Lintzeris et al. 2002). One study reported that approximately 80% of participants treated with buprenorphine received at least one ancillary medication for withdrawal symptoms, most commonly insomnia, anxiety, restlessness, and arthralgias (Ling et al. 2005). The latter three symptoms usually respond readily to

2

adrenergic

agonists (e.g., 0.1 mg of clonidine every 4–6 hours). When buprenorphine is stopped abruptly, the exact duration of withdrawal is not well known and may vary considerably from patient to patient. Various periods have been reported, ranging from no signs of abstinence after receiving 8 mg for 10 days (Mello and Mendelson 1980), to mild symptoms appearing after 2–3 days and peaking at approximately 2 weeks after the last dose (Jasinski et al. 1978), to mild symptoms peaking at 3–5 days and going away after another 5 days (Fudala et al. 1990). Individual differences may be quite important, because a recent study suggested that about one-fifth of the patients receiving daily buprenorphine maintenance therapy of 16 mg sublingually for 10 days experienced significant end-of-dose withdrawal symptoms (Lopatko et al. 2003). However, some studies have suggested that opioid withdrawal symptoms in less-than-daily buprenorphine maintenance regimens are minimal to very mild for up to 96 hours (Gross et al. 2001; Petry et al. 1999). As the dosage of buprenorphine is increased, a ceiling effect of about 32 mg of buprenorphine (comparable with approximately 20–30 mg of parenteral morphine) is reached. Buprenorphine is thus less likely to produce the severe respiratory depression found with full

agonists. Nevertheless, deaths

have been attributed to respiratory depression in patients treated with buprenorphine, but in most cases the respiratory depression was attributed to concomitant use or abuse of benzodiazepines (Reynaud et al. 1998; Tracqui et al. 1998). It is possible to use buprenorphine to help individuals detoxify from methadone maintenance, either to achieve a drug-free state or to transition to buprenorphine maintenance. A handful of laboratory studies have been done (Mendelson et al. 1997; Preston et al. 1988; Strain et al. 1992, 1995; Walsh et al. 1995) of the effects of buprenorphine in populations receiving methadone maintenance treatment. The results from these studies have been mixed and conflicting, with some suggesting that higher doses of methadone and higher doses of buprenorphine produce more severe precipitated withdrawal when buprenorphine is given to methadone-maintained individuals and others suggesting that higher doses of buprenorphine produce more agonist effect and make the transition easier. The timing of buprenorphine administration relative to the last use of methadone is another important variable. In general, however, as with detoxification from heroin, the patient should be at least in mild withdrawal, suggesting a minimum of 36 hours after the last full methadone dose. Also, most researchers suggest tapering the methadone dose down to 40 mg or less prior to buprenorphine induction. Two studies that used this procedure tapered methadone nearly to zero before buprenorphine induction (Janiri et al. 1994; Levin et al. 1997). One study transitioned 51 patients receiving long-term methadone maintenance therapy of 30 mg or less onto buprenorphine, with subsequent reductions, and reported no precipitated withdrawal during induction and found the process feasible, safe, and acceptable to both patients and clinical staff

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(Breen et al. 2003). The possibility of using buprenorphine in rapid antagonist induction also has been studied. A 12-week randomized study compared anesthesia-assisted versus buprenorphine- or clonidine-assisted detoxification followed by antagonist induction (Collins et al. 2005). The buprenorphine group received a single dose of 8 mg on day 0 and none on day 1, and naltrexone was started on day 2 at 12.5 mg and titrated up to a dosage of 50 mg/day. The senior author has since modified this method by giving the 1-month depot naltrexone (Vivitrol) on day 3 or 4 once the 25-mg oral naltrexone dose has been reached (Comer et al. 2006). The anesthesia group was induced onto naltrexone 50 mg/day while under general anesthesia. Both groups received adjuvant medications. The clonidine group had withdrawal symptoms treated with clonidine and other adjuvant medications and was induced onto naltrexone the following week. All three groups were found to have comparable mean withdrawal. Additional findings from this study will be presented later in this chapter (see "Rapid Antagonist Induction Under General Anesthesia"). In another study, 23 patients receiving a dosage of 3–6 mg/day of buprenorphine solution (more bioavailable than the tablets) for 1 month were abruptly given increasing dosages of naltrexone over 4 days, starting 24 hours after the last buprenorphine dose (Kosten et al. 1991). Minimal withdrawal occurred, and 20 of the patients took the initial 6-mg naltrexone dose. However, only 4 patients continued the naltrexone at 50 mg/day beyond the 2 weeks. More recently, patients were given buprenorphine solution 3 mg/day sublingually for 3 days followed by 25 mg of naltrexone plus clonidine on day 4 and 50 mg of naltrexone on day 5 (O'Connor et al. 1997). The individuals in the buprenorphine group had milder withdrawal and were more likely to complete detoxification (81%) than were those in the clonidine group (65%). The buprenorphine group had detoxification completion rates comparable with the clonidine-naltrexone comparison group (also 81%), but no difference in naltrexone retention was found at 8 days. A small study used a 7-day buprenorphine stabilization prior to anesthesia-assisted naltrexone induction, with less postprocedure morbidity than a historical control population inducted onto naltrexone under anesthesia without buprenorphine stabilization (Bochud Tornay et al. 2003). It would appear that a rapid detoxification method involving buprenorphine as a bridge to antagonist induction and maintenance may ultimately be the least painful and the most successful. The high naltrexone dropout rate may be improved by transitioning quickly, as noted earlier, to the injectable 1-month naltrexone depot. (Note: as of this writing, use of this agent for treating opiate dependence is an off-label use, because the injectable is approved only for alcoholism.) A recent systematic review compared buprenorphine treatment of withdrawal with other detoxification strategies (Gowing et al. 2006a). Relative to clonidine, buprenorphine was found to be more effective in ameliorating the symptoms of withdrawal; patients stayed in treatment longer, particularly in outpatient settings, and were more likely to complete withdrawal treatment. In addition, no significant difference in the incidence of adverse effects was found between clonidine and buprenorphine. Buprenorphine, when compared with methadone treatment of withdrawal, revealed no significant difference in terms of completion of treatment or severity of withdrawal, and withdrawal symptoms resolved more quickly.

Summary Studies examining gradual methadone withdrawal suggest the following: Inpatient withdrawal has a significantly higher retention rate (about 80%) than short-term outpatient withdrawal (as low as 13%–17%). Although little evidence indicates that this initial higher rate is associated with better-sustained abstinence 4–6 months later, more research is necessary to determine which patients need inpatient withdrawal. The success rate for short-term outpatient withdrawal appears about the same as reported by addicted individuals attempting self-withdrawal. The success rate for outpatient withdrawal appears to be improved substantially (up to 62%) if longer periods (e.g., 4–6 months) and higher dosages are used.

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Attention to psychosocial factors during outpatient withdrawal is associated with better retention and less use of heroin. Regardless of duration or dosage, once methadone is stopped, a rebound in withdrawal symptoms lasting somewhat longer than 1 month occurs; these symptoms are probably connected with the high postwithdrawal relapse rate. Studies of buprenorphine in opioid detoxification suggest the following: Buprenorphine shares many of the advantages of methadone in opioid detoxification—it is safe, long-acting, and available for sublingual administration, thus diminishing the potential for misuse and abuse of the drug. It may also have less post-withdrawal relapse, but further study is required. Detoxification from buprenorphine is less severe than heroin or methadone withdrawal, even with abrupt cessation of buprenorphine, but there are conflicting reports as to the timing of peak withdrawal intensity, ranging between several days and several weeks. Buprenorphine may play important roles in two procedures related to detoxification: 1) the transition of patients in methadone maintenance to buprenorphine maintenance and potentially to drug-free treatments and 2) the rapid induction of naltrexone in heroin-dependent patients who desire antagonist maintenance treatment. More research is needed in both of these areas.

OTHER DETOXIFICATION AGENTS AND METHODS Clonidine The

2

adrenergic agonist drug clonidine, marketed as an antihypertensive, has been used to facilitate

opioid withdrawal in both inpatient and outpatient settings (Charney et al. 1986; Gold et al. 1978; Kleber et al. 1985). Clonidine at dosages of 0.6–2.0 mg/day reduces many of the autonomic components of the opioid withdrawal syndrome, although craving, lethargy, insomnia, restlessness, and muscle aches are not well suppressed (Charney et al. 1981; Jasinski et al. 1985). Clonidine is believed to exert its ameliorative actions by binding to

2

autoreceptors in the brain (e.g., locus coeruleus) and

spinal cord. Both opioids and clonidine can suppress the activity of the locus coeruleus, which is hyperactive during opioid withdrawal. Inpatients stabilized at 50 mg/day or less of methadone can be switched abruptly to clonidine. Dosages reaching 2.5 mg/day during precipitated withdrawal and antagonist induction have been used, with careful monitoring of heart rate and blood pressure to minimize the risk of significant hypotension and/or syncope. Sedation and hypotension have been the major side effects. The high clonidine dosages are possible because precipitated withdrawal is hypertensive. Clonidine also has been used for outpatient detoxification from either heroin or methadone maintenance. Patients receiving methadone maintenance therapy at 20 mg/day or less are about as successful after abrupt substitution of clonidine as after reduction of methadone by 1 mg/day (Kleber et al. 1985). With experienced personnel, addicted persons can be successfully withdrawn by using clonidine in a primary care setting. O'Connor et al. (1997) found that 65% of such patients completed detoxification and entered the next phase of treatment. Clonidine has not been given official FDA approval for use in controlling withdrawal, but it has been used so widely now, both in the United States and abroad, that it has become accepted as an alternative to gradual methadone reduction. Although the group that originated the techniques also conducted many of the clonidine studies, a number of both open and controlled studies have been published since the mid-1980s (Cami et al. 1985; Gerra et al. 1995; Pini et al. 1991; San et al. 1990). Studies show that clonidine (and other

2

adrenergic agonists such as lofexidine and guanfacine) are about as effective as gradual methadone withdrawal, with the following differences: 1) methadone detoxification has fewer symptoms early in withdrawal and more at the end; 2) clonidine has the opposite profile: dropouts are more likely to occur early with clonidine and later with methadone; 3) clonidine has more side effects, especially hypotension and sedation; and 4) clonidine is less likely to be associated with post-withdrawal rebound. It also

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appears that clonidine is more effective if given in the context of abrupt opioid withdrawal rather than as an adjunct during gradual methadone tapering (Ghodse et al. 1994). In a direct comparison of clonidine with buprenorphine for short-term heroin detoxification, however, the group receiving buprenorphine fared better on measures of retention in detoxification, heroin use, and withdrawal severity scores than did the clonidine group (Lintzeris et al. 2002).

Techniques of clonidine-aided detoxification On the day before the start of clonidine detoxification, the usual dosage of opioid is given. On day 1 of the detoxification, the opioid is stopped abruptly, and clonidine is given in divided doses as shown in Table 19–4. Clonidine is to be used with caution in patients who have hypotension or who are taking antihypertensive medications. Use of tricyclic antidepressants within 3 weeks precludes use of clonidine because these agents render the

2

receptors hyposensitive to clonidine. Other exclusions include

pregnancy, history of psychosis, cardiac arrhythmias, and other medical conditions in which use of clonidine might aggravate the associated medical problems. Because clonidine can cause sedation, patients should be cautioned about driving and operating equipment. When clonidine is used on an outpatient basis, it is usually advisable not to give the patient more than a 2-day supply at one time if the circumstances permit. The patient should not drive during the first few days. The patient's blood pressure should be checked at the next visit. If dizziness occurs, the clinician should instruct the patient to cut back on the dosage, increase fluid intake, and/or lie down. Lower clonidine dosages are used on day 1 because opioid withdrawal is less severe at that point, and the patient usually needs time to adjust to the sedative effects of clonidine. It is useful to give 0.1 mg of clonidine as the initial dose and observe the patient's reaction and blood pressure over the next hour or two. The total daily dose should be divided into three doses given at 4- to 6-hour intervals. Unless the patient is either very thin or very obese, standard dosages are used rather than basing the dosage on body weight. The dosages from days 2 to 10 usually do not exceed 17 g/kg/day (approximately 1.3 mg/day). During withdrawal from long-acting opioids such as methadone, clonidine dosages can be increased gradually over several days. In treating withdrawal from short-acting opioids, however, dosages of clonidine are increased (i.e., titrated to symptoms) as rapidly as side effects permit because serious withdrawal symptoms appear earlier. However, the total duration of clonidine dosing is shorter. Antiwithdrawal effects usually begin within 30 minutes and peak at 2–3 hours following oral administration of clonidine. For inpatients, blood pressure should be checked before each dose; if it is 85/55 mm Hg or lower, subsequent doses should be withheld until the pressure stabilizes. Dizziness between doses is best handled by monitoring blood pressure and having the patient lie down and increase fluid intake. If the pressure is too low, the dosage should be reduced. Sedation is commonly experienced, especially within the first few days, but usually remits by day 3 or 4. Dry mouth and facial pain are less common. Insomnia is not usually a problem until day 3 or 4 of methadone withdrawal but occurs by day 2 or 3 with short-acting opioids. Paradoxically, clonidine may worsen the insomnia associated with detoxification even while causing sedation during the day. Other withdrawal symptoms not relieved by clonidine are primarily muscle aches, nervousness, and irritability. Benzodiazepines may be used for both the muscle aches and the insomnia, but they should be given with caution, particularly in outpatients, because many substance-dependent individuals abuse this class of drugs. Clonidine is known to have mild analgesic effects. Thus, in withdrawing medical opioid addicts, analgesia may not be needed during the withdrawal period, even though the original painful condition persists to some extent. Pain usually returns 24–48 hours after the last clonidine dose; if naltrexone is to be used, pain needs to be treated with nonopioid analgesics.

Clonidine patches

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In some settings, clonidine is administered via transdermal patches (Spencer and Gregory 1989). The patch, available in three different doses, supplies clonidine for up to 7 days and is removed if systolic blood pressure falls below 80 mm Hg or diastolic blood pressure falls below 50 mm Hg. The patches are removed after the first week of treatment and replaced by half the dosage on another area of the upper body, if needed. Oral clonidine needs to be given during the first 2 days because the steady-state levels of the transdermal medication are not reached for 24–48 hours after application of the patch. Transdermal clonidine offers several advantages over the oral form, including supplying an even blood level of medication without peaks and troughs and preventing the buildup of withdrawal symptoms during the night. However, symptoms of clonidine toxicity, including hypotension, bradycardia, somnolence, miosis, decreased respiratory rate, and hypothermia, have been reported after oral ingestion (Horowitz et al. 2005). Physicians should be aware of the potential for accidental overdose, especially among children, and warn patients to monitor access to the medication. A patch designed to deliver 0.2 mg/day of clonidine after 7 days of use may still contain 1.0–3.7 mg of active drug (MacGregor et al. 1985). In summary, clonidine appears to be a safe and effective alternative to the gradual reduction of methadone for opioid detoxification. Its disadvantages include more side effects and less coverage of the entire spectrum of withdrawal symptoms. Its advantages include much lower potential for diversion, because it is not an opioid, and more important, avoidance of the long residual withdrawal symptoms that persist for weeks after methadone withdrawal. The availability of buprenorphine for office-based prescribing has decreased interest in use of clonidine for opioid detoxification except as an adjuvant to the buprenorphine.

Lofexidine Hypotensive effects may limit the optimal dosing of clonidine for opioid withdrawal because some patients cannot safely receive the recommended doses of clonidine without experiencing significant hypotension. The

2

adrenergic agonist lofexidine, an analogue of clonidine, may be as effective as

clonidine for opioid withdrawal while producing less hypotension and sedation (Carnwath and Hardman 1998; Kahn et al. 1997). The drug has been approved in England for opioid withdrawal, and it is estimated that more than 70,000 patients have received it to date. Lofexidine is being studied for possible submission to the FDA for use in opioid withdrawal.

Utility of 2 Adrenergic Agonists A recent systematic review of 2 adrenergic agonists in opioid detoxification (Gowing et al. 2002) reported that these drugs are associated with similar or slightly greater opioid withdrawal symptoms than a methadone taper, although withdrawal signs and symptoms resolved sooner with the

2

agonists. Completion of detoxification is also slightly higher with methadone, and there are more adverse effects with clonidine or lofexidine. This meta-analysis also confirmed that lofexidine produces less hypotension than clonidine but is otherwise similar. The utility of the

2

agonists alone may not be

as great as that of buprenorphine alone, but they will continue to be useful adjuncts in heroin detoxification, especially for physicians who do not have the necessary waiver for buprenorphine prescribing.

Clonidine-Naltrexone Detoxification and Antagonist Induction Although clonidine can be an effective alternative to methadone for opioid withdrawal, it does not shorten substantially the time required for withdrawal. Furthermore, the success rate in outpatient withdrawal leaves much to be desired. To solve these two problems, researchers first combined clonidine and naloxone and then subsequently clonidine and naltrexone to provide a safe, effective, and more rapid withdrawal with quick induction of antagonist maintenance for patients detoxifying from either heroin or methadone. The method (Riordan and Kleber 1980) combines naltrexone's rapid, precipitated displacement of opioids from endogenous opioid receptors and consequent severe withdrawal symptoms with aggressive use of clonidine prior to and following naltrexone to provide

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withdrawal symptom relief. For those symptoms not adequately controlled by clonidine, other medications are used, such as clonazepam or oxazepam for muscle spasms and insomnia and antiemetics for nausea and vomiting. Vining et al. (1988) described the method in detail, and O'Connor et al. (1995) provided an update aimed at primary care practitioners. Other authors (Gerra et al. 1995; Senft 1991) have also successfully used this procedure. In the O'Connor study (N = 68), 94% of the patients were able to complete detoxification successfully and move on to the next phase of treatment. After 1 month, however, there was no difference in treatment retention between the clonidine-alone and the clonidinenaltrexone groups. The biggest limitation of this method is the need to monitor patients for at least 8 hours on day 1 because of the potential severity of withdrawal that typically occurs after the first dose of naltrexone, including possible delirium, and because of the need for careful blood pressure monitoring during the detoxification procedure. Thus, trained staff and appropriate space are necessary for this procedure. An even more rapid version of the clonidine-naltrexone method was developed for inpatient use (Brewer et al. 1988). Use of higher dosages of naltrexone and clonidine on day 1 as well as heavy doses of diazepam reduced the average detoxification time to approximately 2 days. It has been hypothesized that because the dosage of clonidine needed decreases after the first day, even though the dosage of naltrexone is increasing, naltrexone is rapidly normalizing the number and sensitivity of opioid receptors and reversing the opioid-induced central noradrenergic hypersensitivity (Kleber et al. 1987). The clonidine-naltrexone detoxification and antagonist induction technique appears to be a safe, effective, and economical alternative to either gradual methadone taper or clonidine detoxification. Its advantages, in trained hands, include a dramatic reduction in the time necessary to complete detoxification, high completion rates (e.g., 55%–95%), and the ability to move rapidly to the next stage of rehabilitation with fewer lingering withdrawal symptoms. The shortened time frame also has economic advantages independent of the detoxification setting. Its disadvantages include generally poorer patient acceptance, compared with other techniques; the need for intensive monitoring by experienced staff, especially during the first day of treatment; and the need for sufficient space in outpatient settings to accommodate potentially very sick patients. More intensive variations on this approach, which may shorten the duration of symptoms, tend to require hospitalization and do not appear to offer any significant advantage. No significant evidence indicates that the technique is associated with any longer abstinence or retention on naltrexone (Gowing et al. 2006b).

Rapid Antagonist Induction Under General Anesthesia The rate-limiting factor of the clonidine-naltrexone method is the ability to find medications that adequately relieve the symptoms of the precipitated withdrawal in the conscious patient. The approach to the clonidine-naltrexone procedure used initially by Brewer et al. (1988) represents one of the earliest attempts to address this problem. The procedure was further shortened and advanced by being carryed out under general anesthesia (Loimer et al. 1989) (an ironic throwback to the hibernation therapy of 1941, in which the patient was kept asleep from 1 to 3 days). Since that time, the technique has been modified and improved (for review, see Brewer 1997). The current method commonly uses naltrexone, propofol anesthesia, the antiemetic ondansetron, the antidiarrheal octreotide, and clonidine and benzodiazepines for other withdrawal symptoms. Heavy sedation via midazolam has been used instead of anesthesia. Endotracheal intubation is usually used with general anesthesia but not with heavy sedation. At times, the opioid antagonist nalmefene or naloxone is used prior to or instead of naltrexone. Some clinicians do the procedure on an inpatient basis, others on an outpatient basis; some encourage naltrexone maintenance and/or therapy after detoxification, and others simply refer the patient to Narcotics Anonymous. What tends to be common is high price, usually ranging from $3,000 or more for the outpatient approach to more than $10,000 for the inpatient procedure. Claims of high rates of abstinence months after detoxification have been made, but no objective verification exists, and the samples are not representative of the heroin- or opioid-dependent population as a whole.

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Although some clinicians argue that these techniques are a magic bullet, others see them as exploitation of opioid-dependent individuals and the general public: use of a technique with potential serious morbidity and mortality to achieve opioid detoxification when safer (essentially no mortality) and less expensive methods may readily be used instead (Collins et al. 2005; Kleber 1998). Advocates of the anesthesia approach argue that it is acceptable to expose individuals to significant risks, including mortality, given the potentially life-threatening consequences of their underlying illness. The high levels of patient interest in these approaches reflect the nearly universal desire for a pain-free detoxification procedure. Some practitioners of these approaches suggest that their patients are "detoxified in a day." However, research with these procedures suggests that significant withdrawal symptoms persist for several days or even weeks after the procedure (Collins et al. 2005; Scherbaum et al. 1998). Furthermore, intermediate- and long-term outcome data are limited. In a review of nine published anesthesia studies, only two had outcome data beyond 7 days (O'Connor and Kosten 1998). The authors deplored the lack of randomized design or control groups, the short-term outcomes studied, and the inadequate assessment of risks. In one randomized trial of anesthesia-assisted antagonist induction/detoxification, the anesthesia technique offered no advantage in treatment outcomes at 3 months following detoxification (McGregor et al. 2002). Another randomized trial (Collins et al. 2005) comparing anesthesia-assisted antagonist induction with buprenorphine-mediated naltrexone induction and clonidine-assisted antagonist induction found the anesthesia group to have comparable levels of withdrawal symptoms with the buprenorphine and clonidine groups. In addition, no significant differences in any of the three groups were found with respect to treatment retention or mean opioidpositive urine specimens over the course of the 12-week study. Three serious adverse events were reported in the general anesthesia group, whereas none were reported in either the buprenorphine or clonidine groups. Another randomized study (De Jong et al. 2005) of 272 opioid-dependent patients compared rapid detoxification using clonidine with general anesthesia; both groups were started on antagonist treatment on day 1. The study found no significant difference in opioid abstinence rates at 1 month or in severity of withdrawal. The average 1-month cost for the rapid detoxification with general anesthesia group was 76% higher than that for the clonidine group. Although no adverse events were reported in the clonidine group, the general anesthesia group had five adverse events requiring hospitalization. The morbidity of the procedure continues to raise the level of concern about its ultimate utility, even if one were to accept that the procedure might offer a means to attract highly resistant patients into treatment. Several studies suggest that the procedure produces profound increases in plasma catecholamines (Kienbaum et al. 1998, 2000). A series of six cases of individuals presenting to Philadelphia-area emergency departments cited complications of pulmonary edema, prolonged withdrawal, drug toxicity, rupture of varices, aspiration pneumonia, and death (Hamilton et al. 2002). In fact, at least seven deaths have occurred within 72 hours of the procedure (Gevirtz 2002). Obviously, more deaths could occur if the approach were extended to dual-dependent patients or those with cardiac or liver disease. Studies to date suggest that the procedure will ultimately have at best a limited place in the treatment armamentarium for opioid dependence.

Tramadol Tramadol hydrochloride is a centrally acting analgesic with partial opiate activity and inhibition of serotonin and norepinephrine reuptake (Hennies et al. 1988). Partial opiate activity is due to low-affinity binding of the parent compound and higher-affinity binding of the O-demethylated metabolite M1 to opioid receptors (Gillen et al. 2000). Tramadol has been associated with a withdrawal syndrome characterized by signs and symptoms of anxiety, diarrhea, hallucinations, nausea, pain, piloerection, rigors, sweating, and tremor. This withdrawal syndrome is thought to be due to its activity at the opioid receptor. Tramadol has been available in the United States for more than a decade and has low abuse potential (Cicero et al. 1999; Epstein et al. 2006). Few studies have investigated it for any utility as a potential detoxification agent. A retrospective chart review compared 59 patients detoxified with tramadol with

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85 patients detoxified with clonidine on rates of leaving treatment against medical advice (Sobey et al. 2003). The study found that patients detoxified with tramadol had a 23% greater risk of leaving against staff advice compared with patients detoxified with clonidine. A retrospective cohort control study compared tramadol with buprenorphine for inpatient detoxification in 64 heroin-dependent patients (Tamaskar et al. 2003). Length of stay and maximum withdrawal symptoms, as assessed by the Clinical Institute Narcotic Assessment, were similar for both groups. Although these initial studies provide some encouragement for future research on tramadol's utility as a detoxification agent, there remains a major limiting factor with the medication. Tramadol has the potential to induce seizures at dosages above 400 mg/day, thereby reducing its therapeutic range for detoxification. Both studies (Sobey et al. 2003; Tamaskar et al. 2003) used a fixed-dose tramadol detoxification protocol in which patients received 600 mg on day 1 and were tapered down thereafter. Available evidence to date suggests using better-established treatments for opioid detoxification, such as methadone, buprenorphine, or clonidine, as opposed to tramadol.

SPECIAL PROBLEMS Seizures Opioid withdrawal or intoxication usually does not lead to seizures; however, seizures may occasionally occur with chronic use of meperidine or intoxication with propoxyphene or tramadol. A seizure may signify undiagnosed sedative-hypnotic withdrawal, stimulant intoxication, another medical condition (e.g., head injury or epilepsy), or a faked or hysterical seizure. Because most addicted individuals are polydrug users, possible abuse of sedative-type drugs (including alcohol, barbiturates, and benzodiazepines) must be considered when providing treatment. If a patient is suspected of sedativehypnotic dependence, a pentobarbital challenge will help clarify the picture (Smith and Wesson 1970; Wikler 1968). The challenge involves administration of 200 mg of pentobarbital orally. An hour later, a nontolerant individual administered this dose will either be asleep or show coarse nystagmus, gross ataxia, a positive Romberg's sign, and dysarthria. If these signs are lacking, physical dependence on one or more sedative-hypnotic drugs should be presumed and treated correspondingly.

Mixed Addictions Sedative-hypnotic (e.g., alcohol, benzodiazepine, barbiturate) dependence can lead to serious hazards, including seizures, toxic psychosis, hyperthermia, and even death. Withdrawal from stimulant-type drugs is much less of a physical hazard, although it can be associated with severe depression and even suicide. If sedative-hypnotic dependence is present, it may be preferable to maintain the patient on methadone or buprenorphine, withdraw the sedative gradually, and then withdraw the methadone.

Vomiting Although vomiting can be a symptom of withdrawal, it can occur with no relation to the degree of physical abstinence and in spite of all kinds of support measures, including reintoxication with opioids. It usually can be handled by intramuscular injections of a drug such as trimethobenzamide or prochlorperazine. As noted earlier, ondansetron, available in both oral and parenteral forms, can be very effective in alleviating severe nausea and vomiting. Patients sometimes vomit so that they will receive repeat medication or intramuscular doses (especially when opioids may be given). Observation of the patient for 15–30 minutes after an opioid medication dose usually eliminates this behavior.

Intoxication Dosing to opioid intoxication is not necessary to prevent withdrawal symptoms and can prolong and complicate the detoxification. If intoxication occurs, the next opioid dose should be decreased sufficiently to prevent it at the next medication administration. Smoking while intoxicated or otherwise impaired from the withdrawal-suppressing medications being used should not be permitted, for obvious safety reasons, and when patients are ambulatory, they should be assisted so as to avoid injury.

Repetitive Withdrawal

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Addicted individuals often have a characteristic withdrawal syndrome focused on a particular organ system. For one patient, withdrawal may involve the gastrointestinal system, commonly with significant abdominal cramping; for another, the musculoskeletal system, typically with aching in the bones or muscles. A supportive, reassuring, but firm approach usually helps patients with these symptoms. In the absence of psychosis, antipsychotic medications are rarely necessary.

Other Medical Conditions Opioid withdrawal is usually not accompanied by high fever, although low-grade temperature elevation can occur (rarely above 100.4°F or 38°C). Acute febrile illnesses may temporarily increase the severity of withdrawal symptoms, thus necessitating more methadone or buprenorphine. When serious medical or surgical problems are present, withdrawal should be delayed or done very gradually to minimize the degree of stress. The patient should be brought to the point of tolerance, kept there for several days, and then slowly withdrawn. With certain illnesses (e.g., acute myocardial infarction, renal colic), the patient should be maintained on methadone until stable enough to permit withdrawal. The patient also should be evaluated carefully to determine whether longer-term agonist maintenance is preferable to detoxification. When withdrawal does take place, giving methadone or buprenorphine three or four times per day instead of two times can minimize discomfort and stress.

Pregnancy When pregnancy is complicated by heroin addiction, the patient and her physician are forced to choose from several relatively undesirable alternatives. The ideal outcome would be for the woman to abstain totally from drugs, licit and illicit, during the entire pregnancy. Unfortunately, this usually does not occur. On an outpatient drug-free regimen, many patients cycle in and out of opioid use, subjecting the fetus to periods of intoxication and withdrawal and a risk of spontaneous abortion, stillbirth, prematurity, and possible developmental anomalies. The drug effects can be compounded by the patient's lifestyle, such as poor prenatal care, inadequate diet, and drug adulterants. Residential placement to ensure drug-free status is usually resisted, especially if other children are at home, or it may be difficult to find, even when desired. The optimal practical approach to the opioid-dependent pregnant woman avoids the risks of miscarriage and premature birth associated with detoxification, although some have suggested that carefully selected women may be safely withdrawn from opioids (Dashe et al. 1998). The FDA has not approved any agonist or antagonist maintenance therapies for use in the management of opioid dependence during pregnancy. Antagonist (naltrexone) maintenance is typically avoided because the prerequisite detoxification increases the risk of miscarriage and premature birth and because compliance problems increase the likelihood of cycling between dependence and withdrawal. Nevertheless, some authors have reported successful outcomes of naltrexone maintenance with small numbers of pregnant women (Hulse et al. 2001). Methadone maintenance has been used for many years and is generally accepted as the standard approach to the pregnant patient (Jarvis and Schnoll 1994). Dosing can be problematic because the increased metabolism of methadone during pregnancy can render the usual dosage inadequate and require an increased dosage rather than a decreased one (Jarvis et al. 1999). This can often be handled by split dosing during the day. The infant will be born physically dependent on methadone and will need to be withdrawn, but if prenatal care is adequate, no known birth defects are associated with prenatal methadone exposure. If withdrawal from methadone maintenance is necessary, it should occur during the second trimester at a rate no greater than 5 mg/week. During the first trimester, withdrawal may be especially deleterious to fetal development; during the third trimester, withdrawal may trigger premature labor. A relatively recent alternative for the pregnant heroin-dependent patient is maintenance on buprenorphine. There is much less experience with buprenorphine than with methadone in pregnancy, but there have been various reports of treatment success with pregnant heroin users, with good fetal outcomes (Johnson et al. 2001; Schindler et al. 2003). One randomized, double-blind study compared buprenorphine with methadone maintenance in 30 pregnant opioid-dependent patients beginning at an

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estimated gestational age of 16 weeks (Jones et al. 2005). Peak neonatal abstinence syndrome total scores did not significantly differ between groups. Studies to date suggest that buprenorphine is comparable with methadone on outcome measures assessed by neonatal abstinence syndrome and maternal and neonatal safety (Fischer et al. 2006; Jones et al. 2005; Lejeune et al. 2006; Schindler et al. 2003). However, more research is needed to help establish the parameters of its use in pregnancy and to further define its effects on newborns beyond the neonatal period.

EXPERIMENTAL MEDICATIONS Some investigators have suggested the possibility of other detoxification agents, none of which has been researched thoroughly enough to be recommended at this time but for which there may be some efficacy in the future (Herman and O'Brien 1997). These agents include low-affinity, noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists such as dextromethorphan and memantine; serotonergic agents such as the serotonin type 1A partial receptor agonist buspirone; and the neutral endopeptidase inhibitor acetorphan. The effect of buspirone on withdrawal symptoms in heroin addicts was recently compared with placebo and a methadone taper (Buydens-Branchey et al. 2005). All groups initially completed a 5-day maintenance course of methadone, with a last dose of 30 mg. No significant differences in withdrawal severity were found for up to 7 days after completion of the maintenance phase between the groups receiving a methadone taper or 30 mg/day or 45 mg/day of buspirone. One imperfectly controlled study suggested that massive doses of vitamin C (300 mg/kg), supplemented with vitamin E, reduced opioid withdrawal symptoms in most patients studied (Evangelou et al. 2000). We expect that advances in neuropharmacology and other areas of brain science will continue to provide promising candidate medications for use in opioid detoxification.

ALTERNATIVE/COMPLEMENTARY MEDICINE Despite considerable attention to alternative/complementary medicine approaches in other areas of medicine, opioid detoxification has received little of this attention, outside of the focus given over the last 30 years to acupuncture (discussed in the next section). A recent controlled study of the traditional Chinese medicine practice of qigong suggested that it produces better withdrawal relief than lofexidine (Li et al. 2002). In addition, some plant preparations, such as the West African hallucinogen ibogaine, have developed enthusiastic followings, but lack support in controlled studies of safety and efficacy. It has been reported that at least eight people have died following ingestion of ibogaine (Alper 2001; Kontrimaviciute et al. 2006; Maas et al. 2006). 18-Methoxycoronaridine, an ibogaine derivative, which may be safer than the original ibogaine plant extract, is under study. The Chinese herbal compound WeiniCom compared favorably with buprenorphine on measures of withdrawal severity and heroin craving (Hao and Zhao 2000). More research is needed to assess what role, if any, complementary medicine may play in the future of opioid detoxification.

ACUPUNCTURE Although acupuncture has been used for thousands of years in Chinese medicine to relieve pain, its use in the treatment of narcotic withdrawal is much more recent. Wen and Cheung (1973) reported more or less favorable results in 40 patients who received acupuncture with electrical stimulation. A review 5 years later (Whitehead 1978) concluded that because the studies used inadequate controls, they did not prove that the procedure worked. Acupuncture consists of the use of thin needles inserted subcutaneously at points on the body believed to be related to the body functions that need to be stimulated. For detoxification, points on the external ear are usually used. Electroacupuncture involves applying small amounts of electricity to needles, which are inserted in those acupuncture points on the external ear believed to affect opioid withdrawal. Evidence from animal studies indicates that electroacupuncture is mediated through the endorphin system, and its effects can be blocked by the use of naloxone. A small laboratory study with heroindependent volunteers suggested that auricular acupuncture effects are mediated through the endogenous opioid system, and it noted that 20% of patients are resistant to acupuncture effects (Timofeev 1999).

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Some studies or reviews have asserted that acupuncture and its closely related variants, including electroacupuncture, are effective, whereas others have asserted that they are not (Alling et al. 1990; Brewington et al. 1994; Jordan 2006; National Council Against Health Fraud 1991; Ter Riet et al. 1990; Ulett 1992). Most studies have been flawed by the lack of random assignment or the lack of a placebo control. One recent sham-controlled study of electroacupuncture suggested that both objective and subjective symptoms of opioid withdrawal were reduced with active treatment compared with the inactive control (Zhang et al. 2000). Although some studies suggest that acupuncture detoxification can be as effective as gradual methadone withdrawal in symptom alleviation, retention, and relapse rates, better-controlled studies are needed to confirm this conclusion. Studies of these approaches have several methodological problems, including high dropout rates, inconsistent placement of electrodes, inconsistent electrical parameters, and problems in blinding patients and staff. In general, programs that use acupuncture and its related variants tend to be enthusiastic about the results; published reviews tend to be more critical. Acupuncture may be useful for some patients, but many questions remain about its use. The optimal technique for detoxification remains to be clarified. It also remains to be determined how acupuncture compares with other detoxification methods described earlier in this chapter, especially methadone, buprenorphine, and clonidine detoxifications. For those who prefer not to use medications, clearly there is something appealing about a nonpharmaceutical technique. Additional questions include the following: What are the characteristics of individuals most likely to benefit from acupuncture during opioid withdrawal? For example, Washburn et al. (1993) suggested that heroin users with smaller habits stay in treatment longer than those with larger habits. What are the optimal circumstances and complementary approaches to be used during the procedure? As Brumbaugh (1993, p. 36) noted, "Acupuncture is not a panacea, and it loses much of its efficacy. . .when practiced in isolation from the more traditional Western modalities of counseling, pharmaceutical therapies, 12-step programs, and urine testing. It is best seen as an adjunct or a complement to these other forms." Acupuncture will become an important and standard part of opioid detoxification treatments only after well-controlled studies establish its utility and begin to answer some of these more specific questions.

CONCLUSION For most opioid-dependent individuals, detoxification is only the first step in the long process of remaining abstinent from illicit drugs. Success is a function not only of how comfortable the procedure can be made but also of how well patients can be retained in both detoxification and longer-term treatment. Whatever method is chosen, appropriate psychosocial interventions and education must be available to prepare the patient for this next step. More information is needed as to the best combinations of withdrawal techniques and patient characteristics. The ideal detoxification method would be relatively rapid, inexpensive, comfortable, safe, and available on an outpatient basis; it would also increase the likelihood that patients seek longer-term help. Although none of the techniques reviewed in this chapter meets this ideal, significant progress has been made in improving the pharmacology of opioid withdrawal. The recent FDA approval of buprenorphine for opioid detoxification and maintenance therapy should make opioid dependence treatments much more widely available. The more urgent area for future research is in improving treatment retention at all phases of opioid dependence treatment. Compared with 60 years ago, the current detoxification methods are faster and more comfortable. In the future, there may be pharmacological approaches that decrease relapse by restoring the disordered neurochemistry associated with protracted withdrawal, cue-induced craving, and comorbid psychiatric illness.

KEY POINTS Although detoxification allows patients to initially overcome their physical dependence, without follow-up treatment it is unlikely to lead to long-term recovery. Various medications are used for opioid detoxification, including full opioid agonists (e.g., methadone), partial opioid agonists (e.g., buprenorphine), opioid antagonists (e.g., naltrexone),

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adrenergic agonists (e.g., clonidine), and adjuvant medications (e.g., clonazepam, ibuprofen, bismuth subsalicylate) for symptomatic relief. Since its introduction to the United States in 2002, buprenorphine has been effectively used for detoxification and maintenance because it is long-acting, can suppress withdrawal symptoms at least as well as methadone, causes less severe withdrawal than heroin or methadone when abruptly stopped, allows for outpatient use, and is safe when used by experienced physicians. Recent studies on rapid antagonist induction under general anesthesia have revealed little benefit while leading to significant adverse events. Various alternatives to current detoxification strategies, including the use of tramadol, ibogaine, acupuncture, and others, require further study before their routine use can be supported.

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SUGGESTED READING American Society of Addiction Medicine: http://www.asam.org Center for Substance Abuse Treatment: Detoxification and Substance Abuse Treatment. TIP Series #45 (DHHS Publ No SMA-06-4131). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2006 National Institute on Drug Abuse: http://www.nida.nih.gov.ezproxy2.library.usyd.edu.au Substance Abuse and Mental Health Services Administration National Clearinghouse for Alcohol and Drug Information: http://ncadi.samhsa.gov Substance Abuse and Mental Health Services Administration Substance Abuse Treatment Facility Locator: http://dasis3.samhsa.gov Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 20. Opioid Maintenance Treatment

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Richard S. Schottenfeld: Chapter 20. Opioid Maintenance Treatment, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.351947. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Opioid Maintenance Treatment Richard S. Schottenfeld, M.D.

OPIOID MAINTENANCE TREATMENT: INTRODUCTION Opioid dependence (i.e., dependence on opiate or opiate-like drugs) is a chronic and severe psychiatric disorder associated with substantial risk of mortality, medical and other psychiatric morbidity, and adverse social, vocational, familial, and legal consequences. As with other chronic and severe medical or psychiatric disorders, the goals of treatment are to prevent or reduce the adverse medical, psychiatric, and other consequences of the disorder and to improve the patient's functioning, quality of life, and overall well-being. Since its development in the 1960s as a treatment for opioid dependence, opioid agonist maintenance treatment, initially with methadone and more recently with L- -acetyl-methadone (LAAM) or the partial agonist buprenorphine, has proven to be the most effective treatment for opioid dependence. This treatment greatly reduces the risk of mortality, morbidity, and other adverse consequences of the disorder. Methadone or other opioid agonist maintenance treatment generally refers to a comprehensive treatment approach that includes the continuing administration of opioid medications under medical supervision in combination with drug counseling, behavioral monitoring and intervention, and provision of other psychiatric, medical, and vocational services as clinically indicated. Medically supervised provision of methadone maintenance alone, in the absence of counseling or other services (referred to as interim methadone maintenance in the United States), however, may still lead to substantial benefits compared with not providing methadone maintenance (Schwartz et al. 2007). Although other treatments (e.g., medically supervised withdrawal followed by opioid antagonist maintenance treatment or long-term residential therapeutic community treatment) are efficacious for some patients, the widespread patient appeal of opioid agonist maintenance treatment, high treatment retention, substantial reductions of illicit drug use and criminal activity, and improvement in medical, social, family, and vocational functioning during opioid agonist maintenance treatment combine to make it the most effective approach for individuals meeting eligibility requirements for it. Nevertheless, the rationale for methadone or other opioid agonist maintenance treatment is often misunderstood; social and political opposition to methadone maintenance treatment limits its use in many regions of the world and within the United States; access to the treatment is often limited by inadequate treatment resources (lack of programs or treatment "slots") and reimbursement; and methadone or other opioid agonist maintenance treatment is often suboptimal and provided without adhering to research-based principles that are known to improve its efficacy. In this chapter, I review the rationale for opioid agonist maintenance treatment and the clinical pharmacology, medication interactions, and adverse effects of methadone; the research supporting the efficacy and effectiveness of methadone maintenance treatment overall and the efficacy of specific components of treatment (dose, counseling, duration of treatment); special treatment issues (comorbid other substance use, psychiatric disorders, and medical disorders; pain management; pregnancy); federal rules governing opioid agonist maintenance treatment; and opioid agonist maintenance treatment in primary care clinics and physician offices. The clinical pharmacology of buprenorphine, the third medication approved by the U.S. Food and Drug Administration (FDA) for opioid agonist maintenance treatment, is reviewed in Chapter 21,

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"Buprenorphine Maintenance," in this volume.

OPIOID DEPENDENCE: EPIDEMIOLOGY AND NATURAL HISTORY Recent studies point to an increase in illicit opioid use and dependence in the United States during the past decade and indicate that approximately 2 million adults are dependent on heroin or nonmedically prescribed prescription opioids (SAMHSA 2006). Initiation of illicit opioid use most often begins in late adolescence and early adulthood and is generally preceded by use of cigarettes, alcohol, and other drugs. The latency period for the transition from occasional use to dependence is variable and may last only a few weeks to several years or more. The number of new users of nonmedically prescribed opioids (by oral, intranasal, or injection routes) has increased in the United States from an estimated 600,000 individuals in 1990 to 2.2 million individuals in 2006 and has become the drug category with the largest number of new users each year (SAMHSA 2007). The availability of high-purity heroin, which may be used by nasal insufflation or smoking, may also have lowered the threshold for initial experimentation with heroin and attracted many new users (Bach and Lantos 1999). Heroin continues to be used primarily by injection in many regions in the United States, but in some regions of the country most patients addicted to heroin entering treatment now report noninjection routes of administration (National Institute on Drug Abuse 2005). Although these other routes of administration reduce the risk of infectious diseases (e.g., HIV, hepatitis, endocarditis), the risk of transition from nonmedically prescribed opioids to heroin and from noninjection to injection use is high—one study estimated that 15% of intranasal heroin users convert to injection use each year (Neaigus 1998)—and the incidence of infectious diseases increases dramatically following transition to injection use. Drug overdose is also a significant risk with insufflation or smoking of heroin or with oral, intranasal, or injection use of prescription opioids, although many users are not aware of this risk. The transition from heroin use to dependence carries a dire prognosis, with a risk of dying of approximately 2% per year, and sustained remission is difficult to achieve. A little more than 30 years after admission to compulsory drug abuse treatment in California, nearly half of the 581 heroin-addicted men followed up on in one cohort study had died (Hser et al. 2001). At the time of admission, most of these heroin-addicted men were in their 20s and 30s, and the results of this and other studies indicate that, in comparison with peers matched for age, gender, and socioeconomic status, the annual risk of dying for a heroin-addicted person is increased 6- to 20-fold. Most of the excess mortality is due to drug overdose, suicide, violence, accidents, infection, or chronic liver disease. Only 23% of the original cohort of addicted men in California were not currently using illicit opiates 33 years after admission; the rest were currently using (9%), refused to provide a urine specimen for toxicology testing (4%), were in prison (6%), were not interviewed (10%), or were dead (49%). Notably, only about one out of six of those who were continuing to use 20 years after admission and about the same proportion of those who had been abstinent for less than 5 years at that time point were abstinent 10 years later. One-quarter of those who had been abstinent for more than 15 years at the 20-year follow-up also relapsed over the next 10 years. These findings point to the persistence of the disorder and the high risk of relapse even after long periods of remission. Less than 10% of the cohort participated in methadone maintenance treatment in any given year, but heroin use was reduced in those who participated in this treatment. As has been so vividly demonstrated in the results of this and other long-term follow-up studies (Vaillant 1973), after its onset, the course of heroin or other opioid dependence is chronic and persistent, marked by periods of abstinence that are often followed by relapse, and associated with a severe risk of death or disability.

CLINICAL PHARMACOLOGY OF METHADONE AND LAAM Methadone is a synthetic, long-acting, orally available opioid that acts primarily as a high-affinity agonist at

and

opiate receptors; methadone also acts as an N-methyl-D-aspartate (NMDA)

antagonist (Gutstein and Akil 2001). After oral administration, methadone is rapidly and nearly completely (85%–90%) absorbed in the intestine. Absorption can be delayed by reductions in gastric emptying caused by food, by hypertonic sucrose solutions often used to dissolve methadone (in order to

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deter its injection), or by methadone itself. Peak plasma levels of methadone occur 2–6 hours after oral administration. Methadone is highly lipophilic, has a large volume of distribution, and accumulates in high concentrations in solid organs (liver, kidney, lungs, and brain) (Wolff et al. 1997). Generally administered as a racemic mixture, R-methadone has substantially higher affinity and efficacy at

and

opioid receptors and lower protein binding in plasma compared with the S-enantiomer.

S-methadone is not inactive, however, and has comparable NMDA antagonist activity to R-methadone and, compared with R-methadone, is associated with an opposite profile of effects on mood (negative mood states) and withdrawal symptoms (increased rather than relieved), especially at higher daily doses of the racemic mixture (Mitchell et al. 2004). Methadone undergoes N-demethylation to a highly unstable compound, which undergoes rapid and spontaneous cyclization and dehydration to the major inactive methadone metabolites. The major route of methadone metabolism is through cytochrome P450 (CYP) enzymes, predominantly involving the CYP3A4 pathway but also involving CYP2B6, CYP2C19, CYP2D6, CYP2C9, and possibly also CYP1A2 and CYP2C8 (Crettol et al. 2006); methadone also inhibits CYP2D6 (Eap et al. 2001). After oral administration, methadone and its metabolites are excreted in approximately equal amounts in urine, and urinary excretion accounts for about 50% of the dose. The long plasma half-life of methadone (averaging 24 hours, with a range of 13–50 hours) after repeated daily dosing results in part from accumulation of methadone in organ systems, and achievement of steady-state plasma levels may take 5–10 days. Its long half-life permits once-a-day methadone dosing during maintenance treatment. During maintenance treatment, peak-to-trough plasma ratios generally range from 2:1 to 4:1 (Foster et al. 2001). Trough concentrations exceeding 200 ng/mL are usually sufficient to prevent withdrawal, although some studies suggest that an increased rate of decline, associated with more rapid metabolism of methadone, even with adequate trough levels, also may be associated with withdrawal symptoms (Dyer et al. 1999). There are considerable interindividual differences in methadone metabolism, which may be mediated by genetic polymorphisms affecting the activity of CYP isoforms as well as by medications that induce or inhibit these enzymes or by liver disease. Although clinically significant diurnal alterations in mood state are not observed or reported during methadone maintenance treatment for most patients, mood changes associated with changes in methadone plasma concentration have been observed after administration of a sensitive assessment measure, the Profile of Mood States. These changes are more pronounced before patients have developed full tolerance to their daily dose and in patients who report experiencing withdrawal symptoms even while taking a stable methadone dose compared with patients who do not report withdrawal (Dyer et al. 2001). As a result, some patients with very rapid methadone metabolism may benefit from methadone dosing two times a day (split dosing). LAAM, a methadone derivative also approved by the FDA for opioid agonist maintenance treatment, has a longer half-life than methadone (2 days) and is metabolized by CYP enzymes (primarily CYP3A4) to two active metabolites with half-lives of 2 days (nor-LAAM) and 4 days (dinor-LAAM) (Neff and Moody 2001). Like methadone, LAAM acts as a full agonist at opiate receptors and is absorbed from the gastrointestinal tract after oral administration, with initial effects appearing within 1 or 2 hours. Because LAAM is slowly metabolized to two active metabolites, which are somewhat more potent than LAAM, steady-state levels of LAAM and its active metabolites and its full effects are achieved after 1–3 weeks. Daily dosing can lead to excessive accumulation of active medication and metabolites, and MondayWednesday-Friday dosing is recommended. The longer period required to achieve a full maintenance dose is thought to be responsible for the greater early attrition from treatment found during induction onto LAAM compared with methadone. The abuse liability of LAAM is comparable with that of methadone, and consequently, use of LAAM is restricted to approved narcotic treatment programs, which diminished its appeal to patients. Reports of clinically significant prolongation of the QT interval and torsades de pointes associated with LAAM led to its removal from the European Union and a black box warning in the United States, and LAAM is no longer being marketed in the United States.

MEDICATION INTERACTIONS

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Knowledge of possible interactions between opioid agonist medications used for maintenance treatment and other prescribed or herbal medications or use of other substances is essential to ensure the safety and efficacy of methadone dosing and dosing with other medications. Medication interactions with methadone have been more thoroughly evaluated than with buprenorphine or LAAM, and interaction effects with LAAM are complicated because its major metabolites are active. Methadone metabolism may be increased substantially by concomitant administration of medications that induce CYP hepatic enzymes (e.g., carbamazepine, phenytoin, rifampicin, efavirenz, nevirapine, ritonavir, nelfinavir, phenobarbital, dexamethasone, spironolactone, and possibly risperidone), and initiation of treatment with any of these medications may lead to withdrawal symptoms in a methadone-maintained patient (Rainey 2002). Initiation of risperidone treatment during methadone maintenance also has been associated with precipitation of opioid withdrawal, possibly through induction of methadone metabolism, interference with methadone absorption, or a direct effect of risperidone on opioid receptors (Wines and Weiss 1999). Methadone also induces its own metabolism during the first 2–3 weeks of administration, and the elimination half-life of methadone early in treatment is considerably longer (median 128 hours) than after patients have been treated for more prolonged periods (median 48 hours) (Wolff et al. 2000). Initiation of St. John's wort, which induces CYP3A4, was reported to reduce methadone trough plasma concentrations substantially (19%–60%) in four patients and to lead to withdrawal symptoms in two of the patients (Eich-Höchli et al. 2003). Medications that inhibit CYP enzymes, including some macrolide antibiotics (e.g., erythromycin or azithromycin), fluoroquinolones (e.g., ciprofloxacin), azole antifungals (e.g., ketoconazole or voriconazole), and some selective serotonin reuptake inhibitors (e.g., sertraline, fluoxetine, or fluvoxamine), may cause inhibition of methadone metabolism and symptoms associated with increased methadone plasma levels, including sedation, confusion, or possibly respiratory depression. The effects can be quite severe, as illustrated by a case report of a 42-year-old woman treated with 140 mg/day of methadone for 6 years who experienced sedation, confusion, and respiratory depression when treated for recurrent urinary tract infections with ciprofloxacin, a potent inhibitor of CYP1A2 and CYP3A4 (Herrlin et al. 2000). Concurrent treatment with venlafaxine (or on one occasion with fluoxetine), cigarette smoking, and acute infection may have contributed to the severity of her symptoms. Fluoxetine and fluvoxamine, inhibitors of CYP2D6 and CYP1A2, respectively, as well as paroxetine and fluconazole cause delayed metabolism and increases in plasma methadone half-life (Begre et al. 2002). Grapefruit juice also inhibits CYP3A4 and may lead to modest increases in peak and 24-hour area-under-the-curve plasma methadone concentrations. Increases in methadone plasma levels due to inhibition of methadone metabolism are most likely to cause clinically significant symptoms at the onset of methadone treatment (when patients have the lowest tolerance) and in patients with underlying liver disease. Methadone treatment also affects the metabolism of other medications and causes increased plasma levels of desipramine, amitriptyline, and zidovudine. Table 20–1 shows some of the reported and possible medication interactions with methadone. Methadone interactions with antiretroviral medications and with medications used to treat hepatitis C are of particular interest because of the high prevalence of HIV and hepatitis C infection among injection drug users (Rainey 2002). Although protease inhibitors are potent inhibitors of CYP3A4, nelfinavir causes substantial decreases (40%) in plasma methadone, which can be associated with withdrawal symptoms, possibly as a result of also inducing CYP enzymes or increasing the free (unbound) fraction of methadone in plasma. Methadone inhibition of the glucuronidation of zidovudine increases the plasma concentrations of this medication and the potential for dose-related toxicity. Methadone-induced decreased gastrointestinal motility, however, leads to increased gastrointestinal degradation of stavudine and didanosine and significant decreases in plasma concentrations of these medications. No significant interactions have been found between methadone and either peg interferon or ribavirin, both of which are used to treat hepatitis C (Sulkowski et al. 2005).

RATIONALE FOR OPIOID AGONIST SUBSTITUTION TREATMENT WITH METHADONE

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The main, planned, and desired pharmacological effects of methadone, LAAM, or buprenorphine when used for opioid agonist maintenance treatment are to prevent withdrawal and craving and to block or attenuate the euphoric or other rewarding effects of heroin or other illicit opioid use. Oral methadone dosages of 20–40 mg/day are generally sufficient to prevent or at least greatly attenuate opiate withdrawal symptoms. Because craving for opiates is one of the earliest and most powerful hallmarks of withdrawal, preventing withdrawal greatly reduces craving or the urge to use illicit opioids. Preventing withdrawal also eliminates the repeated negative reinforcement that occurs when heroin or other illicit opioids are self-administered to relieve withdrawal. Chronic administration of higher doses of methadone, buprenorphine, or LAAM may directly reduce craving (possibly by preventing more subtle manifestations of withdrawal) and also induce dose-dependent tolerance to the effects of street doses of heroin and other illicit opioids, so that individuals receiving sufficiently high doses experience little or no direct reinforcement from illicit opioid use (Donny et al. 2002, 2005). Additional advantages of the medications used for opioid agonist maintenance treatment are that all of them have long-lasting effects on opiate receptors and substitute a less dangerous and less reinforcing method of administration (oral or sublingual) for more dangerous and reinforcing routes (injection, smoking, nasal insufflation). Unlike the fluctuations in mood and consciousness associated with repeated illicit administration of heroin and other short-acting opioids, administration of long-acting maintenance medications during maintenance treatment normalizes most neuroendocrine alterations found with use of short-acting opioids and does not substantially alter mood or alertness throughout the day (Kreek and Koob 1998). Oral or sublingual routes of administration lead to a relatively slow rate of increase in plasma (and brain) levels and are thus less euphorigenic and inherently less reinforcing than routes associated with faster rates of increase. During maintenance treatment, patients develop tolerance to the effects of their daily methadone dose and generally experience no or only very limited and transient effects of their daily dose. By preventing withdrawal, attenuating euphoric effects of illicit opioid use, reducing illicit opioid use, and stabilizing mood, opioid agonist substitution treatment also provides a stable medication platform facilitating provision of drug abuse counseling and other effective rehabilitation services.

SAFETY AND TOXICITY More than 40 years of clinical experience with methadone maintenance treatment, involving hundreds of thousands of patients worldwide, has established the overall safety of methadone when used for opioid agonist maintenance treatment. When used for maintenance treatment, methadone has not been found to produce any long-term damage to heart, lung, kidney, liver, brain, or other organ systems (Kreek 2000). Heroin and other opioid dependence is associated with alterations of hypothalamic-pituitaryadrenal (HPA) axis and immune system functioning, whereas methadone maintenance treatment generally leads to normalization of most measures of HPA axis and immune system functioning and overall improvement in health status, although some alterations of corticotropin releasing factor responsivity and other neuroendocrine measures may persist (Schluger et al. 2003). The most commonly reported adverse effects of methadone when used for maintenance treatment include constipation, which may be quite severe; sweating; and urinary retention. Additionally, methadone maintenance treatment may be associated with lymphocytosis and increased prolactin, albumin, and globulins. Adverse effects of methadone early in treatment may also include nausea and vomiting, lightheadedness, hypotension, dizziness, anorexia, and dry mouth. Methadone dose-related orgasm dysfunction (anorgasmia or delayed orgasm) has recently been reported in men receiving methadone maintenance treatment, but other measures of sexual dysfunction were not more prevalent in this population of men than in the general population (Brown et al. 2005). Decreased respiratory sensitivity to carbon dioxide and sleep apnea have also been reported for patients receiving methadone maintenance treatment, but cigarette smoking may represent an important confound (Greenwald 2004). Similarly, low bone density has also been reported among methadone-maintained patients, but a variety of (potentially treatable) underlying medical conditions and dietary factors may account for this (Kim et al. 2006).

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Although methadone is generally quite safe for maintenance treatment, methadone overdose can cause severe sedation, respiratory depression, and death (Wolff 2002). Signs of methadone overdose include drowsiness or coma, limpness, depressed respiratory rate and depth, loud snoring, pin-point pupils, hypotension, and bradycardia. Methadone overdose may also lead to pulmonary edema or aspiration. Overdose is particularly a problem with regard to accidental ingestion by children, use by nondependent opioid users who experiment with methadone or self-administer it, or at the initiation of methadone maintenance treatment if the initial doses are too high or the methadone dose increased too rapidly. There are reports of apnea and coma in children after ingestion of 5 mg of methadone and of death following ingestion of 10 mg of methadone, although prompt treatment of overdose has led to complete recovery in children after ingestion of much higher doses. Because of its long elimination half-life and the possibility of delayed absorption, methadone overdose requires prolonged treatment. Death has been reported to occur more than 24 hours after ingestion (and several hours after discontinuation of naloxone treatment). Several studies report increased mortality rates during the initial 2 weeks of methadone maintenance treatment compared with mortality rates later in methadone maintenance treatment, with much of the increased mortality attributed to overdose deaths. Methadone dosages in excess of 40–50 mg/day at the onset of methadone maintenance treatment, when methadone has not yet induced its own metabolism and its elimination half-life is quite prolonged, may lead to methadone accumulation and overdose death even in individuals who report large heroin habits but who are not fully tolerant to the full effects at both

and

receptors of methadone. Fatalities may

occur after several days of dosing if the methadone dose is started too high or increased too rapidly (Buster et al. 2002). The risk of methadone overdose is increased by concomitant use of medications interfering with methadone metabolism (e.g., medications that inhibit CYP3A4) or use of alcohol or sedating drugs (e.g., benzodiazepines, chloral hydrate). Individuals with reduced methadone metabolism due to genetic factors or liver disease and individuals with underlying pulmonary, cardiac, liver, or renal disease may also be at increased risk for overdose (Corkery et al. 2004). Recent guidelines for induction onto methadone maintenance treatment recommend starting dosages of no more than 30–35 mg/day and gradual dosage increases (5–10 mg no more frequently than every 2–3 days). Considerably lower starting dosages may be advisable for patients at higher risk for overdose, including patients with underlying severe respiratory or liver disease, patients treated with sedating medications or medications inhibiting CYP3A4, or patients with lower baseline tolerance to opioids (Srivastava and Kahan 2006). Recent reports indicate an association between methadone and cardiac conduction defects (prolonged QTc interval) and torsades de pointes (Krantz et al. 2002), an association previously noted for LAAM. A black box warning about these effects was added to the prescribing information for methadone in December 2006. Methadone may also induce bradycardia through its effects on calcium channels, as illustrated in a recent case report of bradycardia associated with methadone administration to a patient dependent on both opioids and benzodiazepines (Ashwath et al. 2005). Clinically significant prolongation of the QTc interval (>500 ms) during methadone treatment has been reported in association with high methadone doses (mean ± SD 231 ± 201 mg in one review of cases; Justo et al. 2006), but 29% of cases reported to the FDA were in patients treated at dosages of 60–100 mg/day (Pearson and Woosley 2005). The incidence of clinically significant prolongation of the QTc interval among methadonemaintained patients has not been sufficiently studied; one small study found it in 2 of 83 methadonemaintained patients (Maremmani et al. 2005), whereas another study in a program using higher methadone dosages found it in 3 of 138 patients (Peles et al. 2006). Additional risk factors for prolongation of the QTc interval in methadone-maintained patients include concomitant use of other medications causing QTc prolongation or arrhythmias (e.g., haloperidol, class I or II antiarrhythmics, tricyclic antidepressants, or calcium channel blockers), inhibiting methadone metabolism, or causing electrolyte disturbances (e.g., diuretics); hypokalemia; liver dysfunction; heart disease; or cocaine use. Methadone effects on the QTc interval may result from blockade of ionic current through potassium channels composed of subunits expressed by the human ether-a-go-go–related gene. These considerations suggest the need for caution and possibly repeat electrocardiogram testing when

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prescribing higher dosages of methadone (e.g., greater than 120 mg/day) and when prescribing methadone for patients with prolonged QTc intervals or with other risk factors for QTc prolongation or cardiac arrhythmias, including, for example, cardiac hypertrophy (Deamer et al. 2001). Although methadone causes sedation in individuals who have not developed tolerance, methadone maintenance treatment is generally not associated with significant sedative effects once patients have developed tolerance to their daily methadone dose, nor is it associated with alterations of neuropsychological functioning. With regard to driving, an evidence-based review of methadone maintenance effects on driving performance concluded that there is relatively strong and consistent evidence that the driving ability of patients stabilized on long-term opioid treatment is not impaired by their regular doses of opioid medication (Fishbain et al. 2003). Patients should be advised not to drive if they feel sedated, not to drive after using alcohol (or illicit drugs), and to be particularly cautious if they are using medications that may increase sedation (e.g., antihistamines, benzodiazepines) or after a dose increase. A range of neuropsychological impairments has been reported in heroin- or other opioiddependent individuals, however, including problems in executive functioning (impulse control, planning, and decision making), verbal and visual memory, attention, processing speed, and response inhibition. These deficits may persist after prolonged periods of abstinence from illicit opioid use and may reflect preexisting deficits or result from alcohol or drug abuse. Notably, however, stabilized patients receiving methadone maintenance treatment with no evidence of illicit drug use for the preceding 18 months do not differ in measures of neuropsychological functioning from former heroin users abstinent from illicit drug use for the past 18 months (Prosser et al. 2006). During methadone induction or before patients have developed tolerance to their methadone dose, methadone dose administration may be associated with some effects on mood and cognition, including some impairment of delayed verbal recall (Curran et al. 2001). One recent study documented significant improvement from pretreatment baseline after 2 months of methadone maintenance treatment on measures of learning, memory, and psychomotor performance (Gruber et al. 2006). The underlying cognitive impairments of opioid-dependent patients (including memory and attention deficits) suggest the importance of carefully tailoring drug counseling to the cognitive abilities of the patient, especially at the beginning of methadone maintenance treatment, when these deficits may be most pronounced.

EFFECTIVENESS OF OPIOID AGONIST MAINTENANCE TREATMENT The effectiveness of methadone and other opioid agonist maintenance treatments for reducing illicit drug use, reducing mortality and morbidity, and improving social, vocational, and legal functioning has been established in randomized, controlled clinical trials and quasi-experimental and observational studies and has been validated in several recent meta-analyses (Institute of Medicine Committee on the Prevention of HIV Infection Among Injecting Drug Users in High Risk Countries 2006). Mortality rates are reduced substantially during methadone maintenance treatment, although they remain somewhat higher than for the general population because of the impaired health of many patients at treatment entry (e.g., HIV infection, hepatitis C). The risk of new infection with HIV is substantially reduced in patients receiving methadone maintenance treatment compared with untreated heroin-addicted patients in the same geographic setting, and the risk decreases in association with the length of time continuously treated with methadone maintenance (Metzger et al. 1993). Criminal activity decreases during treatment and has been found to increase substantially among individuals discharged from treatment because of the closing of public methadone programs after financial cutbacks (Anglin et al. 1989). Follow-up data from the National Treatment Outcome Study confirm the findings of previous national studies of drug abuse treatment regarding the effectiveness of methadone maintenance treatment for reducing illicit drug use and criminal activity (Hubbard et al. 1997). Most studies of the long-term effects of treatment are based on methadone maintenance, but shorter-term studies (generally lasting up to 6 months) suggest that the effectiveness of maintenance treatment with LAAM or buprenorphine is comparable with that with methadone. Early attrition from LAAM compared with methadone has been a problem in some studies (Clark et al. 2002), but results for methadone, buprenorphine, and LAAM, when provided at sufficient doses, were comparable (and

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significantly better than the results for a group treated with low-dose methadone) in a large, double-blind clinical trial (Johnson et al. 2000). Recent meta-analyses suggest that methadone may be associated with somewhat better overall reductions in illicit opiate use compared with buprenorphine maintenance, although sufficient doses of both methadone and buprenorphine are more efficacious than low maintenance doses of either medication (Mattick et al. 2004). Advantages of buprenorphine compared with methadone, including a decreased risk of respiratory depression, led to buprenorphine being classified as a Schedule III narcotic and thus permitted to be prescribed by specially certified physicians in office-based practices, whereas methadone is a Schedule II narcotic and may only be dispensed for methadone maintenance treatment in specialized narcotic treatment programs. Despite the overwhelming scientific evidence establishing the efficacy and effectiveness of opioid agonist maintenance treatment, misunderstanding of, prejudice toward, and political opposition to methadone treatment persist and continue to interfere with efforts to increase access to and availability of this treatment modality in the United States and elsewhere in the world. At present, only about 240,000 of the estimated 2 million individuals dependent on heroin or other opioids in the United States are enrolled in opioid agonist maintenance treatment. When methadone maintenance treatment has been made widely available, free or at low cost, and publicized, 90% or more of the heroin-addicted population have been attracted into treatment (Hartgers et al. 1992). Economic factors, including medical insurance coverage (or the lack of coverage) for methadone maintenance treatment, affect both entry and retention in methadone maintenance treatment. In Oregon, 1-year retention in methadone maintenance increased from 28% to 51% when managed care picked up the costs, whereas exclusion of methadone coverage from Medicaid led to decreased entry into methadone maintenance treatment (Deck and Carlson 2005; Deck et al. 2006). These findings indicate that the low market penetration of methadone maintenance treatment results primarily from the lack of its availability in many geographic areas and the long waiting lists and costs of treatment even in areas where programs are available, rather than from a lack of potential need, interest, or demand for treatment. Considerable program-to-program variability in how treatment is provided and in the effectiveness of agonist maintenance treatment (as measured by the prevalence of continued illicit drug use during treatment and other outcome measures) has drawn attention to identifying the key components of methadone maintenance treatment (e.g., dose, duration of treatment, counseling, program structure) and improving the quality of treatment programs (Ball and Ross 1991). The most recent national survey of methadone treatment practices found that substantial progress had been made in improving treatment practices compared with earlier surveys but still pointed to continuing problems with inadequate methadone doses in many programs (D'Aunno and Pollack 2002).

METHADONE DOSE AND TREATMENT DURATION The efficacy and effectiveness of maintenance treatment with methadone, as with LAAM and buprenorphine, are dose dependent, and effective dosages generally fall within a targeted range of 60–120 mg/day or higher for methadone, 8–16 mg/day or higher for buprenorphine, and 80–140 mg three times per week for LAAM. The optimal dosage for a given patient, however, should be based on the patient's response to treatment. Early observational studies pointed to the dose-dependent efficacy of methadone for maintenance treatment, and more recent randomized, double-blind clinical trials and experimental studies confirmed the earlier observations with regard to methadone and established the dose-dependent efficacy of buprenorphine and LAAM. Although methadone dosages of 20–30 mg/day lead to greater retention in treatment compared with placebo doses, illicit opioid use is dose-dependently reduced at moderate (60–75 mg) daily doses and reduced even more at higher (100 mg) daily doses (Strain et al. 1993, 1999). In experimental studies, dosages of 30 mg/day and 60 mg/day are sufficient to suppress most withdrawal symptoms for more than 48 hours, but full attenuation of the subjective and reinforcing effects of heroin (up to 20 mg/70 kg) occurs only with a higher methadone dosage (100–150 mg/day) (Donny et al. 2002, 2005). Increased craving for opiates has been observed 24 hours after a 25% reduction in the daily methadone dose, consistent with clinical observations and patient reports of

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withdrawal-related discomfort and increased risk for resumption of illicit opioid use following a missed daily methadone dose (Greenwald 2002). Clinically, patients who continue illicit opioid use at a given daily methadone dose often reduce or eliminate illicit opioid use when the daily methadone dose is increased gradually over several weeks to a sufficiently high dose. Several studies suggest that some poor responders to methadone dosages of 80–100 mg/day have increased metabolism of methadone and suboptimal trough plasma methadone levels or increased rates of clearance; increasing the methadone dose to achieve trough levels greater than 200 ng/mL, or providing methadone in split doses to prevent trough levels from declining too rapidly or below this target, can help to reduce or eliminate continued illicit opiate use (Dyer et al. 2001). Duration of treatment is also a critical factor, and premature discontinuation of methadone treatment leads to relapse. In one randomized clinical trial, tapering of methadone dose to zero over 60 days (methadone detoxification) after 4 months of methadone maintenance treatment led to accelerated attrition from treatment and significant increases in illicit opioid use in the test group compared with a group assigned to continued methadone maintenance treatment (Sees et al. 2000). Substantial and sustained changes in vocational or social functioning and lifestyle may take years to achieve for many patients (Gunne et al. 2002). Even then, the risk of relapse after discontinuation of methadone maintenance remains high even for patients who have been receiving methadone maintenance treatment for prolonged periods and have made substantial changes in lifestyle and achieved stable recovery while receiving treatment. Because of the difficulties experienced by many patients who attempt tapering and detoxification (Calsyn et al. 2006), the high risk of relapse after discontinuing methadone maintenance treatment, and the very high risk of severe adverse consequences associated with relapse, many patients may benefit optimally from lifetime maintenance. Decisions about whether or when to discontinue methadone treatment for patients who are benefiting from it should always be made collaboratively and with the patient's fully informed and voluntary consent. Taken together, the results of observational studies, experimental human laboratory studies, and randomized clinical trials are compelling: methadone maintenance dose-dependently decreases illicit opioid use; its beneficial effects on health and social and vocational functioning may occur gradually over prolonged periods; and the effectiveness of methadone maintenance treatment diminishes substantially when methadone doses are lowered or discontinued, even when patients can continue to receive enhanced psychosocial services.

DRUG COUNSELING AND BEHAVIORAL COMPONENTS OF AGONIST MAINTENANCE TREATMENT As with many other medical or psychiatric disorders, the effectiveness of medication treatment can be greatly enhanced by combining medication administration with counseling aimed at promoting treatment adherence and lifestyle change. The seminal study establishing the treatment effects of counseling evaluated treatment outcomes for 92 patients randomly assigned to one of three levels of services (minimal counseling, standard drug counseling, or standard drug counseling plus enhanced vocational, legal, and medical services) (McLellan et al. 1993). All patients received identical standard daily methadone doses. The prevalence of continued illicit opioid use and of cocaine use was substantially higher among patients in the minimal counseling group, who received only brief contact with a counselor once per month, compared with patients in the standard counseling group, who received weekly or more frequent counseling until achieving sustained abstinence, or the enhanced services group. By the end of 12 weeks, 69% of the patients in the minimal counseling group had triggered the criteria for protective transfer (unremitting drug use, as evidenced by 8 consecutive weeks of illicit opiate or cocaine use or three emergency situations requiring immediate health care interventions), whereas 41% of those receiving standard counseling and 19% of those receiving enhanced services met the criteria. Although enhanced services led to the best outcomes overall, standard drug counseling was found to be the most cost-effective approach. Subsequent studies have found no overall advantage for requiring an intensive day treatment program at program entry compared with weekly drug counseling, and some patients (e.g., those with social

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anxiety) may benefit more from weekly individual drug counseling than from day treatment (Avants et al. 1998, 1999). A variety of different types of counseling approaches, including cognitive and behavioral treatment, the community reinforcement approach, 12-step facilitation counseling, and counseling combining the different approaches, can be effective as long as they are performed consistently and with a high degree of competence. In addition to the specific counseling provided, behavioral monitoring (e.g., urine toxicology testing) during treatment and consistent behavioral responses to patient's behavior (e.g., providing take-home methadone to patients who become abstinent or increasing the frequency and intensity of required counseling for patients with continued illicit drug use) contributes greatly to improved treatment outcomes (Brooner et al. 2007). Although effective counseling improves outcomes for many patients, it is unclear whether all patients require counseling to benefit from treatment, and the optimal frequency, intensity, and duration of counseling have not been well established. Recent randomized clinical trials have shown substantial benefits of providing methadone maintenance in the absence of any counseling services, compared with waiting list control groups, with regard to reductions in illicit drug use and subsequent enrollment in a full-service methadone maintenance treatment program (Schwartz et al. 2006, 2007; Yancovitz et al. 1991). Interim methadone maintenance is permitted for up to 120 days under federal regulations in the United States that were designed to improve access to methadone maintenance treatment in areas that have long waiting lists for entering full-service narcotic treatment programs.

CO-OCCURRING PSYCHIATRIC DISORDERS The prevalence of co-occurring substance use and other psychiatric disorders among opiate-dependent individuals entering methadone maintenance treatment greatly exceeds the prevalence found in the general population, even controlling for age, gender, socioeconomic status, and other factors, as has consistently been shown in studies conducted over the past 25 years in several different geographic areas (Brooner et al. 1997; Rounsaville et al. 1982). Left untreated, many of these disorders are associated with an adverse prognosis and an overall poorer response to methadone maintenance treatment. Thus, careful psychiatric assessment of patients entering methadone or other agonist maintenance treatment and early institution of treatment interventions for co-occurring disorders are essential. A high prevalence of co-occurring alcohol abuse or dependence was noted in early studies of patients receiving methadone maintenance treatment, and several studies suggested that treatment with disulfiram administration (after detoxification, if necessary) supervised at the time of methadone ingestion, led to improvement of alcohol dependence, illicit drug use, and social functioning. Marijuana use is also very common among patients receiving opioid agonist maintenance treatment, but the clinical significance of marijuana use in this population is a matter of some controversy. Some studies suggest that marijuana use is not associated with other illicit drug use during opioid agonist maintenance treatment, but marijuana use still may interfere with full participation in treatment and rehabilitation (Nirenberg et al. 1996; Saxon et al. 1993). Beginning in the early 1980s, cocaine abuse and dependence became epidemic among opioid-dependent individuals. Although the prevalence of cocaine abuse and dependence has declined substantially in the general population since then, these problems have remained endemic among opioid-dependent individuals. The reported prevalence of cocaine abuse or dependence among new admissions to methadone treatment ranges from 15% to 40% or more in the United States. Although the prevalence of frequent cocaine use decreases substantially during opioid agonist maintenance treatment (from 36% at treatment entry to 22% after 1 year in the Treatment Outcome Prospective Study; Fairbank et al. 1993), continued cocaine abuse is associated with continued illicit opiate use, injection drug use, increased risk of HIV and other infectious diseases, increased risk of cardiac toxicity, and criminal activity. Promising treatment interventions for cocaine abuse during opioid agonist maintenance treatment include behavioral treatments such as contingency management, in which vouchers with a monetary

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value are used to reward cocaine-free urine tests (Schottenfeld et al. 2005). Notably, in this study, patients randomly assigned to methadone (60–90 mg/day) reduced illicit opiate and cocaine use significantly more than patients assigned to buprenorphine (12–16 mg/day). Several studies suggest that supervised administration of disulfiram also reduces cocaine use during methadone or buprenorphine maintenance treatment (George et al. 2000; Petrakis et al. 2000), independent of its effects on reducing alcohol use, but this is not an FDA-approved indication for disulfiram. The potential severity of disulfiram-alcohol-cocaine interactions in patients who use both cocaine and alcohol while taking disulfiram, as well as the potential risks of disulfiram-induced hepatotoxicity or neuropathy, raise safety concerns about its use for this indication. Recent preclinical and clinical studies suggest that increasing the methadone dose may decrease cocaine as well as illicit opioid use. High-dose methadone is reported to block conditioned place preference to cocaine and both spontaneous and cocaineprecipitated cocaine seeking in rats (Leri et al. 2006), and some earlier clinical studies reported greater reductions in cocaine use with higher compared with lower methadone doses (Stine and Kosten 1992). Benzodiazepine abuse and dependence are also a problem for a high proportion (generally comparable with the prevalence of cocaine abuse) of individuals receiving opioid agonist maintenance treatment. As with concurrent cocaine abuse and dependence, benzodiazepine abuse and dependence are associated with continued heroin or other illicit drug use, injection drug use, increased risk of infection, and continued involvement in drug subcultures (Darke et al. 1993). Benzodiazepine abuse also increases the risk of oversedation and respiratory depression in patients receiving methadone maintenance treatment. Benzodiazepine use during agonist maintenance treatment poses a difficult challenge for psychiatrists and treatment programs because many patients experience anxiety disorders that could be treated with benzodiazepines, but benzodiazepines are frequently misused by patients receiving opioid agonist maintenance treatment (Spiga et al. 2001). Approximately one-third of the benzodiazepine-using patients in one study reported taking higher benzodiazepine doses than prescribed, and many took very high doses around the time of ingesting their daily methadone to boost the methadone effects (Stitzer et al. 1981). Gradual tapering and then discontinuation of benzodiazepines may be possible on an ambulatory basis, but many patients require inpatient treatment to complete detoxification successfully. Substitution with a longer-acting benzodiazepine, such as clonazepam, followed by gradual tapering and discontinuation may offer some advantages. In one study comparing clonazepam tapering and discontinuation with clonazepam maintenance, clonazepam maintenance was associated with better retention and decreased benzodiazepine abuse (assessed by self-report only) (Weizman et al. 2003). Clonazepam may also be administered under direct observation at the time of methadone dispensing to reduce its potential for abuse or diversion. Mood disorders, anxiety disorders, and personality disorders, which are also considerably more prevalent among opioid agonist–maintained patients than in the general population, also may adversely affect response to agonist maintenance treatment. Treatment of current depression, found in approximately 15%–25% of those entering treatment, may lead to improvements in mood and other depression outcome measures and also to reductions in illicit drug use (Nunes et al. 1998, 2004). Treatment of anxiety disorders in agonist-maintained patients is complicated by the high abuse liability of benzodiazepines in this population. Cognitive and behavioral treatments for anxiety disorders either alone or, when indicated, in combination with medications with little or no abuse liability (e.g., buspirone, citalopram) can be beneficial for patients. A recent clinical trial found no beneficial effect of buspirone for reducing anxiety symptoms in patients receiving methadone maintenance treatment, however, although depressive symptoms were reduced in these patients (McRae et al. 2004). Antisocial personality disorder, found in approximately 25% of patients, has in some but not all studies been associated with a relatively less optimal response to methadone maintenance treatment (Alterman et al. 1996).

CO-OCCURRING MEDICAL DISORDERS AND PROVISION OF MEDICAL CARE

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Patients receiving opioid agonist maintenance treatment may experience health problems associated with opioid dependence (e.g., AIDS, hepatitis B or C, tuberculosis) or common in the general population (e.g., hypertension, diabetes, heart and lung disease), and the stabilizing effects of maintenance treatment on patients' overall functioning facilitate implementation of effective medical treatment for these health problems and preventive health services. A study conducted by the Centers for Disease Control and Prevention among 1,717 injection drug users entering treatment in six cities in the United States found that 50%–81% had evidence of hepatitis B, 66%–93% had hepatitis C, and infection with HIV ranged from 3%–5% in cities in the Midwest and West to 28%–29% in the Northeast (Murrill et al. 2002). The prevalence of infection with hepatitis B, hepatitis C, or HIV was significantly higher for older injection drug users than for younger users. With the advent of effective treatments for HIV and hepatitis C, it is essential to screen patients for these conditions at admission and at regular intervals during opioid agonist maintenance treatment and to refer patients with these disorders for treatment. Several recent studies have shown the safety and efficacy of peg interferon and ribavirin treatment for patients with hepatitis C receiving methadone maintenance treatment. Peg interferon does not alter methadone metabolism or pharmacokinetics, and patients receiving methadone maintenance treatment show good virologic response to treatment (Mauss et al. 2004; Sulkowski et al. 2005). Coordination of addiction treatment and medical treatments can improve medication adherence, adherence to medical treatment recommendations, and response to medical treatment. Several studies suggest that provision of onsite primary care medical services improves primary care attendance and initial retention in methadone maintenance treatment (Saxon et al. 2006). Treatment for hepatitis C can be integrated into methadone maintenance programs (Litwin et al. 2005) and is cost-effective (Sheerin et al. 2004). Interactions between opioid agonist maintenance medications and some medications to treat medical conditions may necessitate dose adjustments or consideration of alternative medication treatments, as noted earlier in this chapter in the section "Medication Interactions." Other preventive health services that benefit patients include immunizations (e.g., for hepatitis B, for antibody- and antigen-negative patients who are at risk for infection; for tetanus; and for pneumococcal pneumonia) as well as testing for tuberculosis and syphilis and treatment for those with evidence of infection. Adherence to medical treatment, such as prophylactic isoniazid treatment, can also be improved through directly observed treatment at the time of methadone dispensing. Because of the extremely high prevalence of cigarette smoking among opioid-dependent individuals, health problems associated with cigarette smoking (e.g., emphysema, cancer, cardiovascular disease) are common among patients receiving opioid agonist maintenance treatment. Smoking cessation interventions may lead to considerable health benefits for patients receiving methadone maintenance treatment, and many such patients are interested in stopping smoking. Some studies suggest that smoking cessation is difficult to achieve or sustain for many of these patients, and at present few methadone treatment programs offer smoking cessation treatment (Nahvi et al. 2006; Richter et al. 2004).

PAIN MANAGEMENT DURING OPIOID AGONIST MAINTENANCE TREATMENT Pain is an important clinical problem among patients receiving methadone maintenance treatment, and appropriate management and treatment of pain is essential for optimal care. A recent survey of patients receiving methadone maintenance treatment in two methadone programs found that 37% of patients experienced chronic pain (i.e., lasting 6 months or longer) of moderate or greater severity, most often involving the musculoskeletal system (back or leg pain) or headache. Two-thirds of these patients reported that pain interfered substantially with their functioning, and many reported using illicit drugs to treat pain during the preceding 3 months (Rosenblum et al. 2003). In one study, opioid-dependent patients with chronic pain at entry into methadone maintenance treatment had comparable retention and drug use outcomes as patients without chronic pain, but they continued to have problems with pain and worse psychological functioning, compared with patients without chronic pain, even after 1 year of methadone maintenance treatment (Ilgen et al. 2006).

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Treatment of acute or chronic pain among patients receiving methadone maintenance treatment is complicated by the difficulties, common to both opioid-dependent patients and patients without any history of drug abuse, of assessing pain severity objectively, diagnosing underlying etiologies of painful conditions, and prescribing optimal treatment regimens that reduce pain and improve patient functioning and well-being with the fewest adverse effects. These difficulties are further complicated in patients receiving methadone maintenance treatment by the effects of methadone maintenance on pain sensitivity and tolerance to opioid analgesia as well as by concerns about the potential abuse liability of opioids prescribed for analgesia to patients with a history of drug abuse. Because methadone is used for the treatment of chronic pain, some physicians mistakenly assume that patients receiving methadone maintenance treatment do not require opioid analgesic medications in addition to their daily methadone dose to treat either acute or chronic painful conditions. To the contrary, such patients develop tolerance to the analgesic effects of their daily dose and may also become cross-tolerant to the analgesic effects of morphine or other opioids administered for pain relief (Athanasos et al. 2006). Additionally, acute or chronic opioid administration may lead to increased sensitivity to pain. Increased pain sensitivity has been found in association with administration of heroin, morphine, methadone, and other opioids, possibly through up-regulation of spinal dynorphin (Gardell et al. 2002), and has also been reported in patients receiving methadone maintenance treatment (Compton et al. 2001). Some physicians may be reluctant to prescribe opioid analgesics to patients receiving methadone maintenance treatment because of concerns about precipitating relapse to illicit drug use. Administration of opioid analgesics to these patients for the treatment of acute pain has not been found to lead to relapse or even to the need for higher methadone doses after the painful condition has resolved (Kantor et al. 1980). Recommendations for managing acute pain in a patient receiving methadone maintenance treatment include continued provision of the patient's regular daily methadone dose and administration of additional analgesic medications, including non-opioid analgesics or short-acting opioids, as clinically indicated (Alford et al. 2006; Mehta and Langford 2006). During methadone maintenance treatment, results of positron emission tomography studies suggest that methadone occupies 19%–32% of the opioid receptor, leaving a substantial proportion of unoccupied receptors available for analgesic response to opioid medications (Kling et al. 2000). When opioid analgesics are required, patients receiving methadone maintenance treatment may require even higher doses or more frequent administration of opioid analgesic medications to ameliorate pain than do patients who are not opioid dependent or receiving methadone maintenance treatment. In a recent study, patients receiving methadone maintenance treatment undergoing liver transplantation needed higher doses of intraoperative and postoperative opioid analgesia than did other liver transplant recipients (Weinrieb et al. 2004). When opioid analgesics are required for such individuals, it is important to use only medications that act as full (rather than partial) agonists at opioid receptors; administration of a partial agonist (e.g., pentazocine or buprenorphine) may precipitate withdrawal.

PREGNANCY AND OPIOID DEPENDENCE Opioid dependence during pregnancy has adverse health effects on the pregnant woman, fetus, and neonate, resulting from a combination of direct drug effects, withdrawal, infections associated with injection drug use and addiction, the detrimental effect of addiction on nutrition, and the possible exposure to violence. Opiate withdrawal during pregnancy, especially when it occurs without medical treatment or supervision, causes significant fetal stress and is associated with spontaneous abortion and fetal demise (Archie 1998). Early studies found that methadone maintenance treatment led to substantial reductions in opiate use and improvements in nutrition, health status, and participation in prenatal care for heroin-dependent pregnant women and also to improved fetal growth and perinatal outcomes in their offspring. These findings led to the recommendation to provide comprehensive methadone treatment to heroin-dependent pregnant women, with services including prenatal and obstetrical treatment, nutritional supplementation, and counseling in addition to methadone maintenance medications (Kaltenbach et al. 1998).

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Determination of the optimal methadone dose during pregnancy requires recognition of the effects of pregnancy on methadone metabolism and disposition and careful balancing between the risks of continued illicit opiate use, if the methadone dose is too low, and the risks of the neonatal abstinence syndrome (NAS), which may be associated with higher methadone doses. Methadone plasma elimination rate is increased and its plasma half-life is decreased substantially during pregnancy, most likely as a result of increased volume of distribution and increased liver metabolism and placental and fetal metabolism. Consequently, methadone doses may need to be increased and administered more frequently (two or three times per day) during pregnancy in order to prevent withdrawal and craving and to obtain optimal reductions of illicit opioid use. In one study, mean methadone trough plasma levels were approximately 0.3 mg/L in pregnant women who did not experience withdrawal symptoms and significantly lower (0.175 mg/L) in pregnant women who did experience withdrawal symptoms, despite somewhat higher daily methadone doses administered to women who experienced withdrawal (Drozdick et al. 2002). Methadone doses of 50–150 mg, or occasionally even higher, and split dosing may be needed in pregnant women who experience withdrawal symptoms, in order to achieve methadone trough levels of 0.2–0.4 mg/L, which are likely to suppress withdrawal and reduce illicit opioid use. Opiate dependence and opioid agonist maintenance treatment during pregnancy are both associated with NAS. NAS is characterized by central nervous system irritability and disturbances of gastrointestinal, respiratory, and autonomic nervous system function. Features of NAS may include high-pitched crying, yawning, sneezing, tremors, increased muscle tone, feeding difficulties, diarrhea, rapid respiratory rate or periods of apnea, and seizure (Kaltenbach et al. 1998). Findings regarding the relationship between maternal methadone dose and the incidence of NAS have been inconsistent, and continued heroin or other illicit opioid use among patients treated with lower methadone doses may complicate analysis of the relationship. In one study, methadone dose and heroin use during the pregnancy were both significantly correlated with NAS. Continuing heroin use during pregnancy was found in 31% of the women; 68% of the neonates of women who continued to use heroin during pregnancy required treatment for withdrawal, whereas 35% of the neonates of women with no evidence of illicit opioid use required treatment. The correlation between methadone dose and NAS remained significant, however, even when controlling for heroin use (Dashe et al. 2002). In that study, approximately 12% of the neonates born to mothers who were treated with less than 20 mg/day of methadone required treatment for withdrawal, whereas 90% of those born to mothers receiving 40 mg/day or more of methadone required treatment. A more recent study found that approximately half of the neonates born to mothers treated with methadone doses greater than 100 mg/day, and a comparable proportion of those born to mothers treated with less than this daily dose, required treatment for NAS (McCarthy et al. 2005). In this study, pregnant women were maintained at a full range of dosages (14–190 mg/day), titrated to prevent craving and withdrawal. Illicit opioid or other drug use was relatively low during treatment; 18% of the newborns tested positive for illicit drugs at delivery. Higher maternal methadone doses, although not associated with NAS, were associated with less illicit drug use. Differences among studies in the symptom thresholds for initiating treatment and differences in the rates of continuing illicit opioid use may account for differences in the rates of neonates needing treatment for withdrawal. Methadone is secreted into breast milk, and it is estimated that breastfed infants may absorb approximately 2%–3% of the maternal methadone dose (Begg et al. 2001). There is some controversy regarding the risks and benefits of women breastfeeding during methadone treatment. The "Patient Information" section on methadone published by the U.S. Food and Drug Administration states that methadone "passes through your breast milk and may harm your baby" (U. S. Food and Drug Administration 2007). The advisory sheet regarding maintenance treatment for pregnant women published by the Substance Abuse and Mental Health Service Administration, however, reaffirms earlier guidelines (Center for Substance Abuse Treatment 2005) that in most situations the benefits of breastfeeding outweigh the potential risks of the small amounts of methadone contained in breast milk (SAMHSA 2007). The risks to the baby are likely to be greatest if very high dosages of methadone are

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prescribed for pain management or the baby was not exposed to methadone in utero and has not developed tolerance to it. Despite the overall favorable safety and efficacy profile of methadone maintenance during pregnancy and after childbirth, illicit or harmful substance use (including abuse of opioids, cocaine, benzodiazepines, marijuana, cigarettes, and alcohol) during methadone maintenance treatment may reduce some of the beneficial effects of methadone maintenance treatment during pregnancy or after childbirth on maternal health and well-being as well as on fetal growth, perinatal outcome, and child development. These considerations have led to some calls for a reappraisal of the role of methadone maintenance treatment during pregnancy (Brown et al. 1998), but high rates of continued illicit opioid use in some studies may reflect less than optimal methadone dosing. Carefully supervised medical withdrawal of an opioid-dependent pregnant woman may be considered for women who request medical withdrawal and can maintain abstinence from illicit opioids without maintenance treatment (e.g., women treated in residential programs) or when opioid agonist maintenance treatment is not available. Some studies suggest that opiate detoxification can be performed safely during pregnancy under careful medical supervision (Dashe et al. 1998, 2002). Of course, withdrawal during pregnancy reduces the likelihood of neonatal abstinence and other perinatal complications only if the pregnant woman remains abstinent following completion of withdrawal and adheres to other medical and nutritional recommendations.

FEDERAL RULES GOVERNING OPIOID AGONIST MAINTENANCE TREATMENT Many aspects of opioid agonist maintenance treatment, including patient eligibility criteria, medications that can be used for opioid agonist maintenance treatment, medication dispensing, and program guidelines, are tightly regulated by federal and state rules and guidelines. Although physicians may prescribe opioids for analgesia according to the usual guidelines for prescribing controlled substances, methadone may only be dispensed for opioid detoxification or maintenance treatment in accordance with federal and state regulations. With the exception of patients hospitalized for conditions other than opioid dependence or during emergency periods of up to 3 days pending admission for more definitive treatment of addiction, methadone may only be dispensed for opioid detoxification or maintenance treatment by opioid treatment programs that have been certified by the Substance Abuse and Mental Health Services Administration and approved by the appropriate state agency. The regulations are designed to ensure appropriate use of this treatment modality, maintain effectiveness by encouraging optimal treatment and program structure, and limit diversion of prescribed medications to illicit use. Recent revisions in federal regulations regarding maintenance treatment with methadone have introduced quality assurance monitoring and program certification requirements and also have made changes in the provisions for take-home medications (U.S. Department of Health and Human Services 2001). The current regulations define the required administrative and organizational structure of the program, including the need for a medical director, and require the availability of counseling and medical services and referral for other service needs. Eligibility for maintenance treatment with methadone generally remains restricted to individuals ages 18 years or older who have been dependent on opioids for a minimum of 1 year before admission. The 1-year history of dependence may be waived for pregnant or previously treated patients or following prison release. Individuals younger than age 18 years may be admitted if they have a history of repeated treatment failure (two or more documented attempts at short-term detoxification or drug-free treatment within past 12 months); parent or guardian consent is required for individuals younger than age 18 years. Depending on their response to treatment, patients may receive up to a 6-day supply of take-home medications by the end of the first year in treatment, up to a 2-week supply after 1 year in treatment, and a maximum of a 1-month supply after 2 years in treatment. An amendment to the Controlled Substances Act (Drug Addiction Treatment Act of 2000) enables qualified physicians meeting defined training and certification criteria to prescribe office-based opioid agonist detoxification or maintenance treatment using Schedule III, IV, or V medications that have been approved for these indications by the FDA. In October 2002, buprenorphine became the first Schedule III narcotic to be approved for these indications (Drug Enforcement Administration 2002) and is now

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available through office-based prescription by physicians. The current regulations governing narcotic treatment programs also permit office-based physicians to become part of the medical staff of a narcotic treatment program or to obtain a license as a satellite medication dispensing unit and thereby provide a form of office-based prescription of methadone maintenance treatment. Individual physicians also may obtain a special narcotic treatment program license, but the requirements for obtaining the license and operating as a narcotic treatment program are considered too cumbersome by many physicians to make use of this mechanism.

OFFICE-BASED OPIOID AGONIST MAINTENANCE TREATMENT Historically, opioid agonist maintenance treatment in the United States was provided almost entirely to patients enrolled in licensed narcotic treatment programs, whereas physician office-based treatment is widely available in Canada, England, France, and other countries. Despite the laudable goals of restricting opioid agonist maintenance treatment to specially licensed narcotic treatment programs (e.g., facilitating quality improvement goals and adherence to patient eligibility criteria and decreasing the likelihood of diversion of prescribed opioid agonist medications to illicit use), the restriction contributes to the lack of availability and difficulties in gaining access to this treatment. Recent studies suggest that some opioid-dependent individuals refrain from enrolling in narcotic treatment programs because of concerns about being recognized by others in the program and identified as an addicted person and the possibility that this might jeopardize his or her employment, family, or social situation. Additionally, some patients who have achieved sustained recovery from illicit drug use during opioid agonist maintenance treatment indicate a strong preference for "medical maintenance" by an office-based physician in order to move away from continuing contact in clinics with many active drug users, to reduce the perceived stigma of continuing attendance in a narcotic treatment program, and to gain greater flexibility in prescribing and dispensing procedures (Fiellin et al. 2001). The effectiveness of medical maintenance for stable patients receiving methadone maintenance treatment has been evaluated in several studies, and many patients who have been abstinent from illicit drugs for prolonged periods are able to make the transition to medical maintenance successfully (Fiellin et al. 2001; King et al. 2002) and remain stable in medical maintenance for prolonged periods (Harris et al. 2006; King et al. 2006; Merrill et al. 2005). One of the main limitations noted in most of the studies is that only a small proportion of patients in methadone maintenance treatment programs meet the stability criteria for medical maintenance, suggesting that this approach will lead to only a modest increase in treatment capacity by freeing up treatment slots in narcotic treatment programs (Fiellin et al. 2001; Rich et al. 2005). In one study that used hair toxicology testing, a surprisingly high prevalence of previously undetected, recent illicit drug use was found among patients meeting clinical criteria for medical maintenance (Fiellin et al. 2001). Patients with recent illicit drug use were substantially more likely than documented abstinent patients to use illicit drugs in the next 6 months, but the likelihood of illicit drug use did not differ between patients randomly assigned to medical maintenance in a physician's office and patients receiving continued treatment in the narcotic treatment program. Qualified physicians who obtain special Drug Enforcement Administration registrations can now provide office-based buprenorphine maintenance treatment for new admissions to maintenance treatment, but relatively few studies have evaluated this setting and approach in the United States. The initial studies of buprenorphine maintenance in a primary care clinic support the feasibility and potential efficacy of this approach and suggest that many patients may benefit from physician-prescribed buprenorphine maintenance and relatively brief weekly nurse-administered counseling (Fiellin et al. 2006). Adherence to buprenorphine was quite variable, however, and better adherence was associated with greater reductions in illicit drug use and retention in treatment. The success of this approach for office-based opioid agonist maintenance treatment raises important questions about the feasibility and potential efficacy of providing methadone maintenance in these settings, although the potential abuse and diversion liability of methadone limits dispensing options. As we enter an era of expanded access to opioid agonist maintenance treatment and approval of new medications, settings, and dispensing options for this treatment, it will be essential to evaluate the counseling requirements and the treatment

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protocols and treatment algorithms that lead to optimal outcomes for patients (Kakko et al. 2007).

METHADONE MAINTENANCE TREATMENT IN PRISONS AND JAILS The prevalence of opioid dependence and other substance use disorders among individuals incarcerated in prisons or jails is substantially higher than in the general population in the United States and throughout the world (Fazel et al. 2006). Additionally, although methadone maintenance treatment reduces criminal activity, patients receiving methadone maintenance treatment who become incarcerated experience significant difficulties. Surveys of jails indicate that only about 1 in 4 contact the methadone program to verify the patient's dose; very few continue methadone maintenance while the patient is in jail; and many do not provide any efficacious medical treatment to manage withdrawal (Fiscella et al. 2004a, 2004b). Despite the high risk of relapse to heroin after incarceration, the surveys also suggest that few prisons or jails refer inmates at the time of release for drug abuse treatment. Methadone maintenance treatment during incarceration may improve postrelease entry and retention in community-based methadone treatment programs and possibly lower reincarceration rates (Magura et al. 1993). Additionally, despite efforts to prevent drug use during incarceration, drug use and injection drug use may occur. The potential for HIV or hepatitis C or B transmission associated with injection drug use in prisons or jails is particularly high, because inmates may share needles and injection equipment in an attempt to minimize the risk of being detected for possessing injection equipment (Calzavara et al. 2003; Macalino et al. 2004; Zamani et al. 2006). The potential benefits of methadone maintenance treatment during incarceration for reducing the risks both during periods of incarceration and after release have led to the development of methadone treatment programs in prisons in a number of countries. In one randomized clinical trial of methadone maintenance in prison, heroin use and HIV and hepatitis C risk behaviors were significantly reduced in prison inmates assigned to methadone maintenance treatment in prison compared with a waiting list control (Dolan et al. 2003). The costs of providing methadone maintenance in prison and its cost-effectiveness were comparable with the costs and cost-effectiveness of methadone maintenance in community programs (Warren et al. 2006).

KEY POINTS More than 40 years of clinical research and clinical experience with methadone maintenance treatment have established the efficacy and effectiveness of this treatment for reducing illicit opioid use and for reducing the mortality and morbidity associated with opioid dependence. Based on a thorough and critical review of the literature, a recent Institute of Medicine committee concluded that the scientific evidence supports the effectiveness of methadone maintenance treatment for reducing heroin and other illicit opioid use, retaining patients in treatment, and reducing criminal activity, mortality, drug-related HIV risk behaviors, and the risk of HIV transmission associated with heroin dependence (Institute of Medicine Committee on the Prevention of HIV Infection among Injecting Drug Users in High Risk Countries 2006). Critical factors determining the effectiveness of methadone maintenance treatment include treatment duration, methadone dose, and provision of counseling and other services. The Institute of Medicine committee also concluded that longer-term maintenance treatment is more effective than shorter-term treatment and that the effectiveness of methadone maintenance is improved when sufficient daily methadone dosages are provided and when patients receiving methadone maintenance treatment are provided drug counseling and ancillary vocational, medical, or other needed services. Clinical challenges during methadone maintenance treatment include co-occurring other substance use and psychiatric or medical disorders. These co-occurring disorders respond to specific treatments, and treatment for co-occurring disorders is facilitated by integrating or coordinating it with methadone maintenance treatment. From a public health standpoint, the most important challenge is to improve the availability and accessibility of methadone or other opioid agonist maintenance treatment so that all heroin- or other opioid–dependent patients can receive this treatment for as long as needed.

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SUGGESTED READING Addiction Treatment Forum, includes newsletter with up-to-date information on methadone maintenance treatment: http://www.atforum.com/index.shtml Hser YI, Hoffman V, Grella CE, et al: A 33-year follow-up of narcotics addicts. Arch Gen Psychiatry 58:503–508, 2001 McLellan AT, Arndt IO, Metzger DS, et al: The effects of psychosocial services in substance abuse treatment. JAMA 269:1953–1959, 1993 Schottenfeld RS, Chawarski MC, Pakes J, et al: Methadone vs. buprenorphine with contingency management or performance feedback for cocaine and opioid dependence. Am J Psychiatry 162:340–349, 2005 Schwartz RP, Highfield DA, Jaffe JH, et al.: A randomized controlled trial of interim methadone maintenance. Arch Gen Psychiatry 63:102–109, 2006 Sees KL, Delucchi KL, Masson C, et al: Methadone maintenance vs 180-day psychosocially enriched detoxification for treatment of opioid dependence: a randomized controlled trial. JAMA 283:1303–1310, 2000 Treatment Improvement Protocols developed for the Center on Substance Abuse Treatment: http://www.treatment.org/Externals/tips.html Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 21. Buprenorphine Maintenance

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Eric C. Strain, Michelle R. Lofwall: Chapter 21. Buprenorphine Maintenance, in The A merican Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. C opyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.352360. Printed 1 0/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Buprenorphine Maintenance Eric C. Strain, M.D. Michelle R. Lofwall, M.D.

BUPRENORPHINE MAINTENANCE: INTRODUCTION Buprenorphine is a partial

opioid agonist and

antagonist that was synthesized in 1973 and initially used for

the treatment of pain. In the 1990s there developed growing evidence that buprenorphine was also efficacious for the treatment of opioid dependence; individuals addicted to heroin submitted fewer opioidpositive urine tests and reported less participation in illegal activities while receiving sublingual buprenorphine maintenance treatment (Bickel et al. 1988b; Johnson et al. 1992, 1995b; Ling et al. 1996, 1998; Schottenfeld et al. 1997; Strain et al. 1994). Outside of the United States, several countries, such as France, made buprenorphine available to general practitioners to prescribe in office-based settings for the treatment of opioid addiction and results also were positive (Strain et al. 2003). However, in the United States during the 1990s, the Harrison Narcotic Act of 1914 continued to make it illegal for physicians to prescribe opioids in an office-based setting for opioid addiction. Methadone remained the primary opioid maintenance medication treatment, but its availability was limited and many individuals who were addicted to opioids remained out of treatment despite having sought treatment. In 2000, Congress passed the Drug Abuse Treatment Act (DATA), and in 2002, the U.S. Food and Drug Administration (FDA) approved buprenorphine for the treatment of opioid dependence. The DATA allows Schedule III, IV, and V medications approved by the FDA for the treatment of opioid dependence to be prescribed by qualified physicians in office-based practice. Buprenorphine is a Schedule III controlled substance. Thus, buprenorphine is the first and currently only opioid available to U.S. physicians for prescription in office-based opioid treatment (OBOT). The hope is that more physicians will begin treating opioid-dependent adults, thereby increasing the availability of treatment for opioid addiction. Opioid addiction is often a chronic relapsing disorder (McLellan et al. 2000), and the movement of opioid addiction treatment into a physician office–based setting is consistent with the treatment of other chronic medical illnesses. Increased access to physicians also may aid in the prevention, diagnosis, and treatment of common medical and psychiatric comorbidities (Brooner et al. 1997; Fingerhood et al. 1993). The purpose of this chapter is to provide an overview to buprenorphine treatment beginning with a discussion of buprenorphine's pharmacology. Evidence for buprenorphine's clinical efficacy and recommendations for use in OBOT within the United States and within special populations (e.g., pregnant women) is discussed. While the focus here is on buprenorphine OBOT in the United States, it should be acknowledged that buprenorphine can be prescribed within methadone maintenance clinics in the United States and that other countries outside the United States utilize buprenorphine in OBOT but have different regulations governing its usage and employ different practice models that are beyond the scope of this chapter (Fiellin and Strain 2006). Preparation of this chapter was supported in part by National Institute of Health grants K12 DA14040, K02 DA00332, and R01 DA08045.

PHARMACOLOGY OF BUPRENORPHINE Buprenorphine Doses and Formulations Buprenorphine is available in sublingual tablets in two doses, 2 mg and 8 mg, both with and without naloxone. Buprenorphine alone is marketed as Subutex, and combined with naloxone it is marketed as Suboxone. Combination tablets are available in two doses: one with 2 mg of buprenorphine and 0.5 mg of naloxone and one with 8 mg of buprenorphine and 2 mg of naloxone. The combination tablets are recommended for OBOT, therefore mention of buprenorphine in clinical contexts will refer to the combination

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product unless otherwise specified. Sublingual buprenorphine solution was used in many of the initial clinical trials before the tablet formulation was available, but the solution is not currently available for opioid dependence treatment. There is a parenteral form of buprenorphine, but this is approved for pain treatment and it is not approved for opioid addiction treatment. A depot form of buprenorphine is under investigation for use in opioid addiction treatment (Sigmon et al. 2004, 2006).

Receptor Profile Buprenorphine is a partial

opioid agonist and

antagonist that is often referred to as a partial

agonist/antagonist or mixed agonist/antagonist. Buprenorphine's activity at the

opioid receptor is primarily

responsible for its efficacy in treating opioid addiction. Figure 21–1 illustrates the difference between a partial and full opioid agonist. A partial agonist is defined as a drug that will bind to a receptor and activate that receptor, but as the dose of the partial agonist increases, it will not produce the same degree or intensity of maximal drug effects as can be produced by a full agonist. That is, there is a ceiling to maximal opioid agonist effects (e.g., respiratory depression) that a partial opioid agonist like buprenorphine can produce that is lower than the effects produced by a full opioid agonist such as methadone (Walsh et al. 1994). The partial opioid agonist activity of buprenorphine enhances its safety profile as compared with full opioid agonists. FIGURE 21–1. Hypothetical dose response curve for a partial and full

opioid agonist.

Bioavailability, Metabolism, and Half-Life Buprenorphine has poor bioavailability when swallowed but fair bioavailability when taken sublingually. Naloxone has poor sublingual bioavailability, therefore the combination tablet results primarily in a buprenorphine effect when taken as prescribed (Strain et al. 2004). However, if the combination tablet is crushed and injected intravenously in an attempt to get high, both drugs will be bioavailable. If the person is physically dependent on opioids, naloxone will precipitate opioid withdrawal, deterring future misuse by this route. Thus, the combination formulation was meant to decrease buprenorphine diversion (e.g., selling on the street) and parenteral misuse/abuse that has been reported by other countries that have only buprenorphine monotablets available (Lavelle et al. 1991; Robinson et al. 1993); San et al. 1989; VidalTrecan et al. 2003).

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Buprenorphine is highly lipid soluble, crosses the blood brain barrier, circulates within the blood highly plasma protein bound (96%), and undergoes metabolism by the liver primarily by the cytochrome P450 3A4 enzyme system (Marquet 2002; Zhang et al. 2003). Physicians should be aware of medications that may interact with the P450 3A4 enzyme system and consequently alter the metabolism of buprenorphine. A table of P450 3A4 inducers, substrates, and inhibitors is available and periodically updated online at http://medicine.iupui.edu /flockhart/table.htm (see also Cozza et al. 2003). The primary metabolite of buprenorphine is norbuprenorphine, which is also a partial

opioid agonist (Huang

et al. 2001), although it differs from buprenorphine in several ways. Norbuprenorphine has only a fraction (2%–25%) of buprenorphine's analgesic activity and it remains predominantly outside the central nervous system (Marquet 2002; Ohtani et al. 1995). Both drugs are eliminated through the feces and urine (Cone et al. 1984). Buprenorphine has a slow onset and offset of drug effects and a mean terminal half-life of 37 hours (U.S. Food and Drug Administration 2002). This long half-life has made less-than-daily opioid maintenance dosing possible (Johnson et al. 1995a, 2000).

Opioid Blockade One of the important pharmacological features of any opioid agonist medication used to treat opioid dependence is that, when taken as prescribed, the medication should block the effects of other opioids. That is, if the person lapses and ingests another opioid while taking buprenorphine, buprenorphine should, if dosed adequately, block the feeling high and good effects from that ingested opioid. Laboratory studies with human volunteers who were addicted to opioids (primarily heroin) and receiving buprenorphine maintenance treatment have demonstrated buprenorphine's opioid blockade effects (Bickel et al. 1988a; Correia et al. 2006; Jasinski et al. 1978; Rosen et al. 1994; Schuh et al. 1999; Strain et al. 1997, 2002). In addition, individuals self-administer less heroin when receiving buprenorphine mainentance doses that suppress typical opioid agonist effects (Comer et al. 2001; Mello and Mendelson 1980; Mello et al. 1982), indicating that opioid blockade decreases the drive and/or desire to use opioids. Thus, if a patient lapses while taking buprenorphine and reports significant opioid agonist effects, a buprenorphine dose increase should be strongly considered (Strain 2006b).

Withdrawal Suppression A pharmacological advantage of opioid agonist medications over non-opioid agonist medications in treating opioid dependence is that they will suppress opioid withdrawal symptoms among those who are physically dependent, which in turn increases patient compliance and treatment retention, and decreases illicit opioid use. Opioid withdrawal can be a contributing component to continued illicit opioid use. Buprenorphine decreases withdrawal signs and symptoms more than placebo among heroin addicts in opioid withdrawal (Mendelson et al. 1996), and buprenorphine prevents the emergence of opioid withdrawal when substituted for morphine in adults who are physically dependent on morphine (Jasinski et al. 1984). Compared with individuals receiving clonidine, patients treated with buprenorphine were more likely to complete a 5-day detoxification protocol (Fingerhood et al. 2001) and report more early opioid withdrawal symptom relief (Cheskin et al. 1994).

Precipitated Withdrawal Buprenorphine has a high affinity for the

opioid receptor and because it is a partial opioid agonist, it is

possible that under certain conditions it could displace a full opioid agonist from the

opioid receptor resulting

in less receptor stimulation. This decrease in receptor stimulation could precipitate opioid withdrawal, although notably the withdrawal syndrome is not as severe as that produced by an opioid antagonist (e.g., naloxone). There are three factors that appear to play a role in the occurrence of buprenorphine-precipitated opioid withdrawal. 1. The current level of opioid physical dependence. The higher the level of current opioid physical dependence, the more likely that buprenorphine will induce opioid withdrawal. For example, among opioid-dependent research volunteers receiving 30 mg/day of oral methadone, acute doses of buprenorphine (administered 40 hours after the last methadone dose) produced no observable signs of opioid withdrawal, but there was evidence of opioid withdrawal among volunteers receiving 60 mg/day of methadone who were administered the same acute doses of buprenorphine (Walsh et al. 1995).

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2. Time since the last opioid dose was taken. The shorter the duration of time since last opioid use, the greater the likelihood that buprenorphine will induce opioid withdrawal. For example, buprenorphine produced signs of opioid withdrawal 2 hours after the last methadone dose among volunteers receiving 30 mg/day of methadone, but did not produce opioid withdrawal signs when given 20 hours after the last methadone dose (Strain et al. 1992, 1995). 3. The dose of buprenorphine administered. The higher the dose of buprenorphine administered, the more likely that buprenorphine will precipitate opioid withdrawal (Strain et al. 1995; Walsh et al. 1995). Thus, in order to avoid buprenorphine-related precipitated withdrawal, it is recommended that patients present in mild, observable, spontaneous opioid withdrawal on the day of buprenorphine induction. Patients physically dependent on methadone and requesting transfer to buprenorphine maintenance treatment should decrease their methadone dosage to approximately 40 mg/day prior to buprenorphine induction. Buprenorphine induction doses should be given at least 20 hours after the last methadone dose and with observable signs of opioid withdrawal present in order to minimize the risk of precipitated withdrawal.

BUPRENORPHINE VERSUS PLACEBO AND METHADONE Compared with placebo, buprenorphine has superior outcomes on measures of treatment retention, illicit opioid use, and opioid craving (Fudala et al. 2003; Johnson et al. 1995b; Kakko et al. 2003; Ling et al. 1998). Daily buprenorphine (approximately 12 mg sublingually) appears to be as effective as 50–60 mg/day of methadone (Johnson et al. 1992; Strain et al. 1996) in reducing rates of opioid-positive urine samples and maintaining subjects in treatment. One study reported that thrice weekly dosing of buprenorphine (each dose was 16–32 mg of buprenorphine solution, which is approximately equal to 24–48 mg of the tablet formulation) may be as effective as 60–100 mg/day of methadone (Johnson et al. 2000). Several published reviews further detailing the clinical trials conducted with buprenorphine are available (Ling and Wesson 2003; Mattick et al. 2003; Strain 2006a).

CLINICAL USE OF BUPRENORPHINE IN AN OFFICE-BASED SETTING The clinical use of buprenorphine is relatively straightforward and physicians with limited substance abuse treatment experience have reported success treating this population (Galanter et al. 2003). The Substance Abuse and Mental Health Services Administration Center for Substance Abuse Treatment (SAMHSA/CSAT) has published a comprehensive Treatment Improvement Protocol titled Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction that outlines best-practice guidelines for buprenorphine use in OBOT (McNicholas 2004). The SAMHSA book is recommended for any physician or health care provider considering providing OBOT. (A free copy can be ordered online at http://www.kap.samhsa.gov/products /manuals/index.htm.) The following discussion highlights the major elements of OBOT.

Physician Requirements The DATA states that only qualified physicians can prescribe an opioid through OBOT. Table 21–1 lists the criteria necessary in order to be considered qualified. Once a physician has met these criteria he or she can apply to SAMHSA for a waiver, which allows the physician to prescribe a Schedule III, IV, or V opioid medication approved for the indication of opioid dependence treatment under the DATA. Most buprenorphine training courses will assist with this process, and more information about this process is online at http://www.fda.gov/cder/drug/infopage/subutex_suboxone/default.htm. Once the waiver is granted, the physician will receive a new U.S. Drug Enforcement Administration (DEA) number that begins with the letter X, which then allows the physician to begin prescribing buprenorphine. Legislation in 2007 allows a physician to treat up to 30 patients concurrently in the first year of practice, and after the first year, a physician can apply for an allowance to increase the number of patients concurrently in treatment up to 100.

Setting Up an Office-Based Practice Prior to starting OBOT, physicians are encouraged to determine the specifics of how their practice will function considering the anticipated patient population. Several important areas of consideration include developing patient selection criteria and referral resources for psychosocial services and common comorbid illnesses that the physician cannot treat on-site; making plans for dispensing medication and urine toxicology testing; educating staff; assuring reimbursement for treatment services; and developing a patient contract that

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outlines behavioral requirements and treatment expectations (Fiellin and Strain 2006). When considering patient selection criteria, the physician must determine whether he or she can safely and effectively provide OBOT to a patient who is also concurrently physically dependent on alcohol, benzodiazepines, and/or other sedative-hypnotics. If the answer is no, then the physician will need to refer the patient for treatment elsewhere, at least until the patient is no longer physically dependent on these other substances. While most clinical trials excluded volunteers with physical dependence on drugs requiring medical detoxification, many studies did safely and successfully treat opioid addiction among volunteers that frequently used benzodiazepines and cocaine. Another consideration is whether the treating psychiatrist will be able and willing to treat opioid-dependent patients with other major mental illnesses, such as bipolar disorder. If treatment services are available on-site for these common comorbid psychiatric illnesses, the dually diagnosed patient ideally should receive all psychiatric treatment services at the same location and with the same physician. One of the major hopes of OBOT, in addition to increasing access to treatment for patients with opioid addiction, is that more patients will have direct access to physicians so that comorbid illnesses that are within that physician's area of practice can be treated simultaneously. Off-site referrals for patients with addictions commonly result in lack of follow-up, which in turn leads to comorbid illnesses being untreated (Umbricht-Schneiter et al. 1994). It is important to offer accessible, affordable, and good quality counseling services either on-site or off-site; on-site is preferable to improve compliance. Counseling does not necessarily have to be individual counseling and can include group and/or family therapy. Psychosocial counseling services are integral to the treatment of patients with addiction and are associated with improved treatment outcomes (Galanter et al. 2004; McLellan et al. 1993). Physicians can dispense buprenorphine provided that they comply with the appropriate state law and DEA requirements for storage, receipt, and dispensing of controlled substances. Advantages of dispensing medication from the office include increased opportunities for therapeutic patient contact and decreased risk that the patient will fill a prescription for buprenorphine induction and take the medication before his or her scheduled induction date. Providing a prescription, however, certainly is acceptable. Urine drug testing is an integral feature of OBOT because it is one of the primary methods used to guide treatment and determine patients' progress in treatment. Arrangements for urine drug testing should be made prior to starting OBOT because urine toxicology testing can vary widely in the methods used, drugs tested, expense, and availability. For the purposes of OBOT, testing for the type of opioid abused as well as other commonly abused drugs in the patient population and geographic area is recommended. It is important to remember that if a patient is using prescription opioids, such as Oxycontin or Lortab, that the standard opiate toxicology screen, which is for morphine, may not be sensitive to these drugs and could result in a false negative test result. Testing specifically for oxycodone and hydrocodone may be necessary. Methadone and buprenorphine also will not be detected on an opiate-only urine drug screen. Qualitative urine drug testing is often sufficient (drug is present or absent); however, many commercial laboratories offer only quantitative testing that can be prohibitively expensive. There are many inexpensive and easy-to-use qualitative urine tests available for purchase so that urine testing can occur on-site if desired or needed (McNicholas 2004). Schedules for urine toxicology testing should also be considered. Ideally, random urine drug testing should occur, making it more difficult for patients to use illicit opioids on a schedule that allows their drug use to go undetected. Patients can either be called by office staff on the day that their random drug test is due or they can be instructed to call a phone number that gives a message with patient identification numbers (without personal information) scheduled for urine testing that day. Office staff and other medical professionals that will be in contact with potential patients should be educated about OBOT to the extent that they will be interacting with patients. Payment for services also should be determined because insurance coverage for substance abuse treatment varies widely, and it would be unfortunate for patients and the physician to start treatment only to discover that treatment services cannot be reimbursed. A treatment contract is an important element of addiction treatment and a sample contract is provided as Figure 21–2. A treatment contract typically outlines the expectations of patient behavior with the consequences of noncompliance (e.g., missed office visits) along with treatment requirements (e.g., urine

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toxicology testing and random pill counts). This contract should be available to the patient so that it can be explicitly reviewed and signed by patients before starting treatment. Modifications can be made to the standard contract throughout a patient's course of treatment so that it becomes tailored to the patient's progress and ongoing needs. FIGURE 21–2. Sample treatment contract.

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Initial Patient Evaluation

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Only opioid-dependent patients can receive buprenorphine treatment. Criteria used to diagnose opioid dependence are listed in Table 21–2. In addition to establishing the diagnosis of opioid dependence, a thorough evaluation should be completed that involves the same components as any other comprehensive medical evaluation (e.g., complete psychiatric and detailed substance abuse history, personal and family history, review of systems, physical exam, mental status exam, and screening laboratories). There are several purposes of this initial evaluation, including establishing diagnoses, appropriateness for treatment, initial treatment recommendations, and possible problems outside of opioid addiction that may need follow-up and continued assessment early in treatment. Baseline laboratories should be completed before treatment is initiated. Recommended tests include serum electrolytes, liver function tests (LFTs), hemogram, urine toxicology tests for opioids as well as other common drugs of abuse in the patient population, and a pregnancy test for females. Hepatitis B and C, rapid plasma reagin, and HIV testing as well as purified protein derivative placement should also be considered based on each patient's risk factors for these infectious diseases. For patients desiring OBOT that the clinician is not already familiar with, it can be helpful to contact an outside treatment provider or close family member or friend that can help gauge the suitability of the patient for OBOT, confirm the diagnosis of opioid dependence, and help ensure a successful induction on buprenorphine. For example, if a patient presents from a methadone maintenance clinic, it is important to contact the clinic and confirm the reason for transferring care and to find out if there were significant problems with clinic attendance, behavior, or nonadherence to treatment. If it is decided to accept a patient in OBOT from a methadone clinic, it is important that the methadone clinic arrange for a methadone dose taper to approximately 40 mg/day and know when the last dose of methadone should be given based on the scheduled buprenorphine induction date.

Dose Induction Induction is the initial phase of treatment with buprenorphine. The goals of induction are to engage the patient in treatment, begin buprenorphine dosing, alleviate opioid withdrawal, and initiate a process that will lead to abstinence from illicit opioid use. While abstinence from illicit opioid use is the ultimate goal of OBOT, it may not be achieved in the induction phase; however, abstinence is discussed with the patient with regard to the long-term treatment plan, and opioid use often begins to decrease during this phase. The initial evaluation and buprenorphine induction are typically completed on separate days. This allows baseline laboratories to be completed and any outside information to be gathered. If patients will be filling a prescription for buprenorphine and bringing it with them to use for induction, it is recommended that the physician write for a medication pick-up date no more than 1 day prior to scheduled induction. This decreases the likelihood the patient will start the medication on their own. Patients should be instructed to come for their induction appointment in mild opioid withdrawal. This will decrease the risk of buprenorphineprecipitated withdrawal and increase the likelihood of withdrawal suppression. Patients should also be told to expect to spend approximately 2 hours in the office during the induction day. This observation period allows for an initial dose of 4 mg to be given along with an additional 4-mg dose approximately 1–2 hours later if there is continued evidence of opioid withdrawal. The maximum dose recommended for the first day is 8 mg. Dose increases on subsequent days can occur at the doctor's office or patients can increase their dose on their own, provided they are given clear instructions on how to do so and are given ready access to the physician or nursing staff if they have questions. Over subsequent days, the dose may be increased with generally no more than an 8-mg/day increase (McNicholas 2004). Dose increases during the induction phase should be based on the presence of opioid withdrawal and craving.

Maintenance The maintenance phase of OBOT begins when there is evidence of significantly reduced illicit opioid use and when the patient no longer has evidence of significant signs of opioid withdrawal. The patient should progress steadily toward sustained opioid abstinence during this phase. Further dosage increases may occur during this phase based primarily on evidence of continued opioid use, particularly if the patient reports inadequate opioid blockade and is compliant with buprenorphine ingestion. The frequency of dosage increases may be decreased during the maintenance phase in order to determine if an increase produces a change in urine

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toxicology results. The final stabilization dosage may vary greatly among individuals but likely will range between 8 mg/day and 32 mg/day (Strain 2006a), with the majority of patients stabilizing in the range of 8–24 mg/day (McNicholas 2004). Continued opioid use in the context of repeated dosage increases and counseling may require referral to a more intensive treatment setting, such as a methadone maintenance clinic. Due to the long half-life of buprenorphine, less-than-daily dosing is possible during the maintenance phase (Johnson et al. 1995a, 2000). For example, buprenorphine dosing three times a week (e.g., Monday, Wednesday, and Friday) can be accomplished by multiplying the daily maintenance dose by two for Monday and Wednesday doses and by three for Friday doses to allow for the additional day over the weekend. Thus, if a patient is receiving 12 mg/day and conversion to dosing three times a week is desired, 24 mg would be taken on Monday and Wednesday, and 36 mg would be taken on Friday.

Treatment Monitoring The frequency of urine testing and office visits for counseling and medication prescription and dispensation has not been well established. Most clinical trials involved daily visits for medication dispensation and thriceweekly urine testing, which is not feasible or expected for OBOT. One study of patients receiving buprenorphine maintenance treatment (dose range 16–24 mg/day) in a primary care clinic demonstrated that frequent medication dispensation and counseling visits by a trained nurse (3 days/week with counseling sessions lasting 20–45 minutes) was not superior to once-weekly medication dispensation and counseling visits (20 minutes duration) for outcomes of decreased opioid use, increased opioid abstinence periods, or retention in treatment (Fiellin et al. 2006). In addition, patient satisfaction was higher for weekly visits than for thrice-weekly visits. The current recommendation is for patients to initially be seen weekly (McNicholas 2004). Less frequent visits may be possible and appropriate once the patient has progressed to the maintenance phase, has shown evidence of drug abstinence, and is deemed appropriate for less frequent monitoring based on treatment needs. However, physicians will need to determine on a case-by-case basis the appropriate frequency of visits when significant barriers to weekly visits arise, such as long driving distances (e.g., patients in rural areas) and child care and work responsibilities. Less-than-monthly visits or more than a 30-day prescription is not currently recommended. It is important to remember that the purpose of office visits is not only to assess drug use and deliver psychosocial and counseling services aimed at helping the patient achieve and maintain drug abstinence but also to help in the overall rehabilitation of the person. For example, it may become clear that the patient has an independent psychiatric disorder, such as a mood or anxiety disorder; has a newly diagnosed HIV or hepatitis C infection; lacks jobs skills or drug abstinence supports; or requires further physician and/or counselor assistance for these problems. In these cases, more frequent doctor and/or counselor visits may be appropriate. Although opioid agonist treatment is effective for the treatment of opioid addiction, continued opioid use can be a problem for some patients. For example, opioid-dependent patients in methadone maintenance treatment typically attend fewer than half of their prescribed counseling sessions (Kidorf and Stitzer 1999) and treatment retention was less than 50% in the OBOT study mentioned earlier by Fiellin et al. (2006). Addressing poor attendance and progress in treatment can be difficult; a comprehensive evaluation of the patient should determine the barriers to a patient's success. Even if barriers can be identified, it can be difficult to address them if the patient fails to attend appointments. One strategy that has had considerable success in motivating patients with illicit drug use disorders to decrease drug use and comply with treatment is contingency management (Higgins and Silverman 1999). Contingency management uses rewards to motivate patients to change their behavior. It may be possible to structure a treatment plan in OBOT using the number of medication doses (through a prescription or dispensing through the office) or frequency of office visits as a reward for treatment progress. For example, once the patient has remained on a stable maintenance dosage of buprenorphine for 2 weeks or more and has demonstrated urine tests that tested negative for illicit drug use consecutively for 2 weeks or more, the patient could earn 2 weeks of buprenorphine prescription (versus 1 week). When there is a lapse or noncompliance with treatment, the patient would be required to go back to weekly visits and weekly

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prescriptions with the opportunity of earning the reward again after documented drug abstinence. Evaluation of other treatment goals (e.g., having at least one outside drug-abstinent friend or family member supportive of the patient's treatment, obtaining work, or engaging in some other structured activity) may also be used as a reward to determine the frequency of visits or number of days of buprenorphine medication dispensed. The use of rewards and steps up and down in terms of treatment intensity has been successfully implemented in methadone maintenance clinics and is worthy of consideration for use in OBOT (Brooner et al. 2004).

Drug Safety and Side Effect Profile Respiratory depression Buprenorphine has an enhanced safety profile in contrast to full agonist opioids because of its ceiling effects on respiratory depression. However, when buprenorphine is misused and injected, especially if combined with other central nervous system depressants, such as a parenteral benzodiazepine, clinically significant respiratory depression can occur and result in death (Kintz 2001; Reynaud et al. 1998).

Liver function Moderate to severe hepatic pathology (i.e., jaundice, panlobular necrosis, and steatosis) has been reported among hepatitis C–positive patients who misused and injected high doses of buprenorphine and also reported use of other potentially hepatotoxic substances (e.g., alcohol and acetominophen) (Berson et al. 2001). However, when taken as prescribed, buprenorphine is generally well tolerated by the liver. A clinical trial of methadone- and buprenorphine-maintained volunteers found no significant differences between the two medications in the rate of development of abnormal LFTs or further elevation of LFTs among those volunteers with abnormal LFTs prior to treatment (Lofwall et al. 2005). One study reported small increases in aspartate transaminase (median increase of 9.5 U/L) and alanine transaminase (median increase of 8.5 U/L) among patients with hepatitis C infection receiving buprenorphine maintenance treatment, although there was no clear clinical significance associated with these increases (Petry et al. 2000). It is prudent to obtain baseline LFTs prior to buprenorphine induction and periodically during maintenance treatment with consideration of more frequent monitoring for patients with hepatitis C or pre-existing liver pathology. Elevated LFTs at baseline do not necessarily exclude a patient from buprenorphine maintenance treatment.

Other side effects Chronic dosing with buprenorphine is not associated with significant cognitive or psychomotor impairment (Mintzer et al. 2004) or electrocardiogram (ECG) QTc prolongation (Wedam et al. 2004). Buprenorphine produces a similar side effect profile as methadone. Commonly reported side effects include constipation, nausea, decreased interest in sex, headache, upset stomach, feeling groggy/sleepy after medication, and diarrhea; most side effects are mild in severity and decrease as time in treatment continues (Lange et al. 1990; Lofwall et al. 2005).

Duration of Treatment and Withdrawal From Buprenorphine There is no time requirement or restriction to the length of time patients can receive buprenorphine maintenance treatment. In general, relapse to illicit opioid use and treatment dropout is high during opioid detoxification (Resnick et al. 1992), such that opioid addiction is considered a chronic, relapsing disorder deserving of ongoing treatment and monitoring much like other chronic medical illnesses (e.g., diabetes mellitus) (McLellan et al. 2000). Patients receiving methadone maintenance treatment for up to 18 years have not suffered adverse medical consequences as a result (Novick et al. 1993). While patients may express worry about becoming addicted to buprenorphine and want to stop taking buprenorphine once they achieve opioid abstinence, it is important to remind the patient of the ultimate goal, which is to continue to not use illicit drugs and to achieve and maintain other life goals (e.g., employment, meaningful relationships, successful management of comorbid disorders). If it is decided that the patient should stop receiving buprenorphine, a gradual detoxification is recommended, based on data from methadone detoxifications showing that longer and more gradual dose reductions are associated with less opioid drug use and a less intense opioid withdrawal syndrome (Gossop et al. 1989; Senay et al. 1977). Buprenorphine withdrawal may be less severe and better tolerated by patients

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than methadone withdrawal because of its partial agonist activity (Kosten and Kleber 1988; Kosten et al. 1992). Urine drug testing should continue through the detoxification period and if illicit drug use resumes, there should be strong consideration for stopping the detoxification and resuming maintenance treatment. Once detoxification is complete, the patient's progress should be followed, urine test results should be monitored, and naltrexone treatment should be considered. This continuation of treatment, albeit without buprenorphine, allows for continued assessment, rehabilitation, and management of the patient's drug use disorder and related conditions. Recognition that opioid addiction as a chronic illness may require multiple courses of opioid maintenance treatment or chronic maintenance treatment will greatly improve the continuity and overall quality of care for these patients.

SPECIAL POPULATIONS Pregnant Opioid-Dependent Females Methadone is the standard of care for the treatment of opioid addiction during pregnancy. Given the limited availability of methadone treatment, having another effective pharmacotherapy for the treatment of pregnant opioid-dependent women would be useful, and buprenorphine is currently under investigation in a large, multisite, randomized clinical trial as a potential treatment for opioid addiction in this population. When buprenorphine is prescribed to pregnant women for off-label use, it is prescribed without naloxone. Several case reports and open-label studies of buprenorphine maintenance treatment during pregnancy have reported decreases in illicit opioid use among pregnant women with similar incidence of and possibly decreased severity of the neonatal abstinence syndrome among their newborns (Johnson et al. 2003). Neonatal abstinence syndrome is an important outcome in determining whether buprenorphine is safe and effective for use in this vulnerable population. It is characterized by multisystem dysfunction including autonomic, respiratory, and gastrointestinal distress, and it can be fatal to the newborn if left untreated. Two small randomized and controlled studies compared methadone and buprenorphine maintenance treatment in pregnant women and results supported earlier findings that buprenorphine appeared safe and effective. There were similar incidences of neonatal abstinence syndrome among newborns of buprenorphine-treated pregnant women compared with those receiving methadone maintenance treatment (Fischer et al. 2006; Jones et al. 2005). In addition, the study by Jones et al. (2006) reported that neonates born to pregnant women receiving buprenorphine maintenance treatment had shorter hospital stays compared with neonates born to pregnant women receiving methadone maintenance treatment, which resulted in significant cost savings.

Patients With HIV Integration of buprenorphine OBOT into HIV clinical care models can be an effective way to deliver both addiction and HIV treatment simultaneously, resulting in significant decreases in illicit drug use along with reductions in HIV viral load (Sullivan et al. 2006). There have been concerns about possible buprenorphine-HIV medication interactions, as many HIV medications interact with the cytochrome P450 3A4 system. However, studies to date have demonstrated an overall lack of clinically significant interactions (e.g., signs and symptoms of opioid excess or withdrawal, ECG QTc prolongation) that would require alteration of buprenorphine doses (Bruce et al. 2006). These studies have investigated buprenorphine in combination with the protease inhibitors nelfinavir, lopinavir/ritonavir, and ritonavir; the non-nucleoside reverse-transcriptase inhibitors efavirenz and delavirdine; and the nucleoside reverse-transcriptase inhibitor zidovudine (QTc prolongation not evaluated for zidovudine) (Baker et al. 2006; McCance-Katz et al. 2001, 2006a, 2006b). There is a report of a possible medication interaction between buprenorphine and atazanavir/ritonavir. A case report describes three HIV-positive patients developing clinically significant signs of opioid excess with buprenorphine and atazanavir/ritonavir, including sedation, feeling "doped up" and high, dizziness, and exhibiting "decreased mental functioning" (Bruce and Altice 2006). One patient had been maintained on 14 mg/day of buprenorphine when atazanavir/ritonavir was added to the existing HIV drug regimen, while the other two patients had been maintained on atazanavir/ritonavir and were then inducted on buprenorphine (8 mg/day). Buprenorphine dose reductions subsequently ameliorated the symptoms in all three patients. This potential drug interaction may be minimized during buprenorphine induction by using 4 mg as an initial dose, observing patients closely for signs of opioid excess, and by providing small dosage increases (2 mg) during

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the induction and maintenance phase. Providers should be aware of potential drug interactions with buprenorphine and monitor patients accordingly.

Patients Experiencing Pain The treatment of pain among opioid-addicted patients, particularly for those with chronic pain, with opioid analgesics is a controversial topic and the guidelines for the treatment for acute and chronic pain in subjects receiving buprenorphine maintenance treatment are limited (Alford et al. 2006; McNicholas 2004). For all buprenorphine-maintained patients with complaints of pain, it is preferable to continue buprenorphine maintenance treatment and attempt to manage the pain with non-opioid medications (e.g., acetaminophen and nonsteroidal anti-inflammatory drugs [NSAIDs]) and nonpharmacological interventions when possible. When these methods are not successful, it is helpful to distinguish between patients with acute pain and those with chronic pain.

Acute pain The possible treatment options for acute pain management include the following: Provide the patient with buprenorphine maintenance treatment, but divide the daily dose into four doses in attempt to maximize the analgesia from each individual dose. Buprenorphine was initially approved as an analgesic; however, when prescribed for analgesic purposes it is dosed multiple times per day. Add non-opioid analgesics if the divided doses are not adequate to determine if the combination can provide adequate pain relief. Provide the patient with buprenorphine maintenance treatment, but titrate a short-acting full

opioid

agonist to achieve adequate analgesia. Although the pharmacology of buprenorphine would make this seem like an ineffective analgesic plan because of its tight binding to the

opioid receptor and its

opioid blockade effects, a recent case report suggests otherwise. Two pregnant women participating in a randomized, controlled clinical trial of buprenorphine compared with methadone for opioiddependent pregnant women underwent cesarean section while continuing their blinded opioid maintenance medication. After the cesarean sections, both women were given access to a morphine patient-controlled analgesia (PCA) pump for 24 hours (maximum dosage of 180 mg in 24 hours) with subsequent oral oxycodone/acetaminophen on hospital discharge (maximum daily dose of oxycodone was 60 mg). The woman receiving buprenorphine (18 mg/day) reported a pain score of 0 (range 0–10) with the PCA pump and pain scores between 0–5 with the oxycodone/acetaminophen doses. The woman receiving methadone (80 mg/day) also reported a pain score of 0 with the PCA pump, but reported a pain score of 7 with oxycodone/acetaminophen and required the addition of an NSAID to assist with pain management (Jones et al. 2006). Discontinue buprenorphine maintenance treatment and start the patient on a short-acting full opioid agonist, which should be dosed adequately to avoid opioid withdrawal and titrated to desired analgesic effect. After the acute pain episode passes, the patient can be inducted back on buprenorphine (McNicholas 2004). Consider regional anesthesia, conscious sedation using a benzodiazepine, or general anesthesia for unanticipated acute severe pain that may require further medical or surgical intervention (e.g., trauma) when patients are in an appropriate medical setting for such care (e.g., emergency room).

Chronic pain It is important to thoroughly evaluate the chronic pain syndrome taking into account etiologies and possible psychiatric comorbidities that may exacerbate the pain. Strong consideration should be given to nonpharmacological treatments, and pain reduction and elimination should not be the sole treatment focus for patients experiencing chronic pain (Cohen and Jasser 2006). Methadone dosed multiple times per day can be helpful for chronic severe pain. If the person is receiving buprenorphine maintenance treatment but is not receiving adequate pain relief and is not able to achieve illicit opioid abstinence, a transfer to methadone maintenance treatment is recommended (McNicholas 2004).

Adolescents With the continued use of heroin and rapid rise in prescription opioid misuse within the United States, particularly among adolescents (Sung et al. 2005), there is a growing need to determine the best treatment

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practices and the appropriate role of opioid maintenance treatment for opioid addiction in this population. Buprenorphine is approved for use in adolescents age 16 years or older in OBOT, and there are no requirements of prior failed treatment in order to be eligible for buprenorphine OBOT, in contrast to methadone (U.S. Food and Drug Administration 2002). Studies of buprenorphine for pain in children and adolescents have shown it to be safe and effective (Girotra et al. 1993; Harcus et al. 1980); however, there is little research on the use of buprenorphine in this population for the treatment of opioid addiction. There has been one randomized, double-blind clinical trial of buprenorphine for opioid-dependent adolescents, although this was a detoxification study completed in an outpatient opioid treatment clinic (not an office-based setting) (Marsch et al. 2005). Thirty-six adolescents (average age 17 years; 13- to 18-year-olds were eligible) were randomly assigned to a 28-day detoxification regimen with either buprenorphine or clonidine. There were thrice-weekly individual counseling sessions and urine drug toxicology testing, daily medication dispensation, and monetary rewards for providing opioid-negative urine test results. Treatment retention (buprenorphine: 72%; clonidine: 39%), percentage of opioid urine test results that were negative (buprenorphine: 64%; clonidine: 32%), and medication liking were significantly higher for those adolescents taking buprenorphine compared with those taking clonidine. In addition, after completion of the 28-day detoxification, naltrexone maintenance treatment was accepted by a significantly higher proportion of adolescents in the buprenorphine (61%) versus clonidine condition (5%). There were no significant adverse effects reported or evidence of opioid intoxication associated with buprenorphine, and buprenorphine was well tolerated by all subjects. This study provides important information about the safety, tolerability, and short-term treatment outcomes among adolescents receiving buprenorphine detoxification in an outpatient opioid maintenance treatment setting with intensive nonpharmacological services. Future work will need to determine the effectiveness and role of buprenorphine maintenance for adolescents in less intensive treatment settings, such as OBOT.

CONCLUSION Buprenorphine is a partial opioid agonist used in the treatment of opioid addiction. It has been shown to effectively increase treatment retention and decrease opioid use, craving, and participation in illegal activities. Buprenorphine maintenance treatment is safe, relatively straightforward to prescribe, and generally well tolerated by patients. Treatment involves not only the prescription of buprenorphine and monitoring of urine drug test results but also the assessment, diagnosis, and treatment of comorbid illnesses and provision of nonpharmacological services aimed at the total rehabilitation of each patient. With the passage of the DATA in 2000 and the subsequent FDA approval of buprenorphine for the treatment of opioid dependence, buprenorphine currently is the only opioid agonist treatment available in the United States that can be prescribed in an office-based setting by qualified physicians. As such, buprenorphine maintenance treatment holds the promise of increasing the availability of opioid addiction treatment and increasing patient access to physicians. However, the ultimate success of buprenorphine treatment will depend largely on the number of physicians willing to provide buprenorphine maintenance treatment in an office-based setting.

KEY POINTS Buprenorphine is currently a Schedule III medication that is approved for opioid maintenance treatment and that can be used in an office-based setting. Buprenorphine can be prescribed by a qualified physician that obtains a waiver and X number from the U.S. Drug Enforcement Administration. Buprenorphine is a partial opioid agonist, which means that it stimulates the there is a limit (ceiling) to the degree of

opioid receptor, but that

opioid effects (e.g., respiratory depression) that it can produce,

thereby enhancing its safety profile. Naloxone is included in sublingual buprenorphine tablets to decrease the misuse and abuse of the drug; if tablets are tampered with and injected, the naloxone will precipitate opioid withdrawal among persons with opioid physical dependence. If tablets are taken as prescribed by the sublingual route there is little absorption of naloxone.

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Buprenorphine is metabolized by the liver cytochrome P450 3A4 enzyme system so inducers or inhibitors of P450 3A4 could interact with buprenorphine's metabolism. A comprehensive initial evaluation is required before beginning buprenorphine treatment, and treatment requirements (e.g., random urine toxicology screens and/or random pill counts) and expectations should be explicitly communicated between physician and patient prior to commencing treatment. Effective treatment includes addressing medical and psychiatric comorbidities and rehabilitation of the patient. Buprenorphine is not currently approved for the treatment of opioid dependence in pregnancy, but early research findings are promising for its use in this population. Office-based buprenorphine maintenance treatment has the potential to substantially increase the availability of treatment for opioid addiction, but buprenorphine's actual impact will be determined largely by the number of physicians willing to treat these patients.

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SUGGESTED READING Johnson RE, Strain EC, Amass L: Buprenorphine: how to use it right. Drug Alcohol Depend 70 (suppl 2): S59–S77, 2003 McNicholas L (ed): Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. TIP Series #40 (DHHS Publ No SMA-04-3939). Rockville, MD, U.S. Department of Health and Human Services, 2004. Available for free by calling the National Clearing House for Alcohol and Drug Information at (800) 487–4889 or on-line at http://www.kap.samhsa.gov/products/manuals/index.htm. Strain EC, Stitzer ML (eds): The Treatment of Opioid Dependence. Baltimore, MD, Johns Hopkins University Press, 2006, pp 213–276 U.S. Food and Drug Administration: Center for Drug Evaluation and Research: Drug information. 2002. Available at: http://www.fda.gov/cder/drug/infopage/subutex_suboxone/default.htm.

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Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 22. Antagonists of Opioids

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Charles O'Brien, Kyle M. Kampman: Chapter 22. Antagonists of Opioids, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.35 2692. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Antagonists of Opioids Charles O'Brien, M.D., Ph.D. Kyle M. Kampman, M.D.

ANTAGONISTS OF OPIOIDS: INTRODUCTION For the treatment of opioid dependence, agonist treatment with methadone and buprenorphine has had the greatest impact. These medications are agonists in that they have affinity for opiate receptors resulting in binding to the receptor and activating it. Agonists are effective for the treatment of opiate dependence mainly because they reduce opiate craving, reduce opiate withdrawal symptoms, and confer tolerance to opiates, thus reducing the euphoric effects of additional opiates, such as heroin. Methadone is a full agonist, whereas buprenorphine is a partial opiate agonist. Partial agonists bind to opiate receptors but activate them only in a limited way so that there is a ceiling to their agonist effects. Partial agonists may also prevent the occupation of receptors by full agonists with lesser affinity, thus blocking the euphoric effects of abused opiates. A partial agonist such as buprenorphine provides some opiate subjective effects and thus is more acceptable to most opiate addicts than an antagonist that binds to opiate receptors without activating them, thus producing no opiate effects. In overall clinical outcome, buprenorphine is comparable with methadone for the majority of opiate addicts who do not require a high maintenance dosage of opioid. There is another pharmacotherapy option available for the treatment of opioid dependence that takes advantage of different interactions between medications and opiate receptors. Opiate antagonists such as naloxone, naltrexone, and nalmefene occupy opiate receptors but do not activate them. These medications have high affinity for the opiate receptor, and thus they can prevent agonists with lower affinity, such as heroin, from binding with the receptor and thereby reduce or block the euphoric effects of abused opioids. If the agonist with lower affinity is already present at the receptor, as in an overdose, the antagonist can displace it. This produces recovery from the overdose and, depending on relative dosages, even a reversal from overdose to opiate withdrawal.

OPIOID ANTAGONISTS Naloxone and Nalmefene Opiate antagonists bind to opiate receptors, but they do not activate the receptor to initiate the chain of cellular events that produce so-called opiate effects. Naloxone is available as a parenteral form that can be given subcutaneously, intramuscularly, or intravenously to reverse opiate overdose. It can be used to reverse opiates used in operative anesthesia or to treat overdoses in the emergency department. The dosage depends on the amount of opiate taken and the potency of the opiate. Overdoses from fentanyl, a highly potent opiate, require large doses of naloxone given repeatedly until the patient's breathing improves. Nalmefene is also available in a parenteral form for reversal of overdose. The main difference is that nalmefene has a much longer duration of action than naloxone. The effects of naloxone can disappear in 20–30 minutes; therefore, in cases of overdose, the patient needs to be monitored and either given repeated doses of naloxone or given a continuous intravenous drip. Naloxone is also useful in the diagnosis of physical dependence. If the presence of physical dependence is in question, a small (0.2- to 0.8-mg) injection of naloxone can be given. In a dependent individual, an opiate withdrawal syndrome would occur immediately, but it would be short lived (i.e., 20–40 minutes).

Naltrexone

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Naltrexone is available in an oral form that was approved by the U.S. Food and Drug Administration (FDA) in 1984 for the treatment of opiate addiction. It is a relatively pure antagonist in that it produces little or no agonist activity at usual doses. Not only do pure antagonists fail to produce opiate effects, but their presence at the receptor also prevents opiate agonists from binding to the receptor and producing opiate effects. Because the antagonist competes for a binding site with the agonist, the degree of blockade depends on the relative concentrations of each and their relative affinity for the receptor site. Naltrexone has high receptor affinity, and thus it can block virtually all the effects of the usual doses of opioids and opiates such as heroin, including opiate-induced euphoria, respiratory depression, pupillary constriction, or any other opiate effect (O'Brien et al. 1975). Naltrexone differs from naloxone in several important ways. Naloxone is poorly absorbed from the gut; when given parenterally, it is effective but is metabolized rapidly. Naloxone, therefore, is useful when combined with buprenorphine because it antagonizes buprenorphine if the medication is injected, thus discouraging abuse. In contrast to naloxone, naltrexone is well absorbed orally, and it has a long duration of action. A long-acting drug such as naltrexone is ideal for use in preventing relapse to opioid use. In the presence of naltrexone, heroin self-administration is no longer rewarding, and under experimental conditions, addicted individuals stop taking heroin even when it is available. Although daily ingestion of naltrexone would provide the most secure protection against opioid effects, naltrexone can be given as infrequently as two or three times per week, with adequate protection against re-addiction to street heroin. The reduced frequency makes monitoring of the medication more practical over the long term. Tolerance to the antagonism of opioid effects does not appear to develop even after more than 1 year of regular naltrexone ingestion (Kleber et al. 1985). A depot preparation of naltrexone that is effective with monthly dosing was approved by the FDA for the treatment of alcoholism in 2006 (Garbutt et al. 2005). Of course this form of naltrexone is also effective against opiate injections (Bigelow et al. 2006). At the present time, use of depot naltrexone to treat opiate addiction is considered by the FDA to be an off-label use. This is ironic because naltrexone was developed in the 1970s for the treatment of opiate addiction, and it was not until 1983 that researchers at the Philadelphia Veterans Administration Medical Center began testing it in alcoholic individuals (Volpicelli et al. 1990, 1992), which led to FDA approval of the alcohol indication in 1994. Now, this medication, which is helpful for a subcategory of alcoholism but blocks all opiates, is used more in the treatment of alcoholism than of opiate addiction.

Benefits of naltrexone Naltrexone was approved by the FDA for the treatment of opiate addiction on the basis of its clear pharmacological activity as an opioid antagonist. Naltrexone is not effective when simply prescribed as a medication for street heroin–addicted patients in the absence of a structured rehabilitation program. Within a structured program, naltrexone appears to be effective, particularly with specific motivated populations. When tested in the usual manner with randomized, placebo-controlled clinical trials, the dropout rate was too large to detect a benefit (Hollister 1978). Patients with a history of recent employment and good educational backgrounds do well on naltrexone. Some patients avoid methadone because of the required daily clinic visits, especially at the beginning of treatment. Because naltrexone is not a controlled substance, greater flexibility is permitted, and it can be prescribed by any physician in their office. Although high-functioning patients may be strongly motivated to be drug free, they remain susceptible to impulsive drug use. Using naltrexone as a kind of "insurance" is often a very appealing idea. Health care professionals generally have done well in naltrexone treatment programs. For example, Ling and Wesson (1984) reported the use of naltrexone in the management of 60 health care professionals for an average of 8 months. Forty-seven (78%) were rated as "much improved" or "moderately improved" at follow-up. Washton et al. (1984) found that 74% of opioid-dependent physicians completed at least 6 months of treatment with naltrexone and were opioid free and practicing medicine at 1-year follow-up. More recently, Roth et al. (1997) reported on the use of naltrexone in a specialized treatment program for opiate-addicted health care professionals. This program combined

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supervised naltrexone administration and group therapy. In a sample of 18 subjects, 94% achieved long-term abstinence. These studies involved comprehensive treatment programs, with naltrexone providing a kind of structure around which psychotherapy was built. Washton et al. (1984) reported on the treatment with naltrexone in 114 businessmen dependent for at least 2 years on heroin, methadone, or prescription opioids. A critical feature of this group was that there was considerable external pressure for them to receive treatment, and almost half were in jeopardy of losing their jobs or facing legal consequences. Of the entire group, 64% were still opioid free at 12- to 18-month follow-up. Those patients who had stipulated pressure from their employers to get treatment did significantly better than the group without a clear-cut risk of job loss. Probationers and parolees with a history of opiate addiction constitute another population that has done well with naltrexone, probably because they face a return to prison if they relapse to opiate use. Cornish and colleagues (Cornish et al. 1997; O'Brien and Cornish 2006) conducted a random assignment study among federal probationers convicted of drug-related crimes in Philadelphia, Pennsylvania. The probationers all received the same amount of parole counseling, but half were randomly selected to receive naltrexone. At follow-up 6 months after leaving prison, the group randomly selected for naltrexone had approximately half the reincarceration rate of the control group.

How to use naltrexone in a comprehensive treatment program Various methods are available for beginning treatment with naltrexone. In all cases, there should be no residual physical dependence on opioid agonists. If the patient has been using a long-acting opioid such as methadone or buprenorphine, it may be necessary to wait up to 7–10 days after the last dose before initiating treatment with naltrexone. With dependence on short-acting drugs such as heroin or hydromorphone, the time between detoxification and starting naltrexone can be much shorter. If naltrexone is started too soon, precipitated withdrawal will occur. Even mild withdrawal, consisting of only abdominal cramps or periods of nausea, may be enough to discourage the patient from further treatment. The use of clonidine to reduce opiate withdrawal symptoms will make the patient more comfortable and increase the likelihood that early dropout will be avoided. Most clinicians who work with naltrexone have found it helpful to administer a naloxone test to determine whether the patient has any residual physical dependence before he or she is given the first dose of naltrexone. A positive test indicating physical dependence consists of symptoms of opioid withdrawal, such as perspiration, nausea, or cramps, that last for 20–40 minutes. A positive test indicates that the patient should wait at least another day before starting naltrexone. Naloxone can be given parenterally, 0.2–0.8 mg subcutaneously or intramuscularly. It can also be used intravenously if very rapid results are desired. When the naloxone challenge is negative, naltrexone can be started with an initial dose of 25 mg (one-half tablet). If no side effects occur within an hour, another 25 mg may be administered. The recommended dosage subsequently is 50 mg/day. After the first 1 or 2 weeks, it is usually possible to graduate the patient to three doses per week (e.g., 100 mg, 100 mg, and 150 mg given on Monday, Wednesday, and Friday, respectively). It is critical that psychotherapy sessions be initiated early in treatment and that these sessions involve family members and other significant figures in the patient's life. Oral naltrexone ingestion should be monitored. Confirmed dosing can occur in the clinic, but it is usually disruptive to the patient's rehabilitation to be required to come to the clinic for every dose. For this reason, it is important to involve significant figures in the patient's life to observe the ingestion of naltrexone and to report periodically to the therapist. Occasional doses can be taken in the physician's office. If a patient is pretending to take naltrexone and is using opioids, a dose in the office would precipitate a withdrawal reaction. Progress in treatment is determined by engagement in psychotherapy, performance on the job, and absence of drug abuse as confirmed by urine tests. The patient should be asked to agree to random urine tests. A slip should not be treated as a treatment

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failure but rather as a symptom to be examined in therapy (i.e., grist for the therapeutic mill). Of course, problems with medication adherence are much easier to deal with when the depot preparation is available. Although only approved for alcoholism, physicians have already begun using the depot to treat opiate addiction. In the treatment of parolees with a history of opioid addiction, a six-site collaborative study is currently under way. It is hoped that the depot formulation of naltrexone will soon be officially approved for opioid addiction. All indications are that this is the most effective delivery system for this medication. Although monthly injections are sufficient for medication coverage, more frequent psychotherapy sessions should still be planned, particularly during the early stages of treatment.

Adverse effects of naltrexone Naltrexone has few side effects. Side effects reported include nausea, headache, and mild anxiety. Because naltrexone blocks endogenous opioid peptides in addition to injected opioid drugs, one would expect to find multiple symptoms related to blockage of the wide-ranging functions of the endorphin systems. However, most formerly opioid-dependent patients do not report subjective effects that can be related to naltrexone. Changes in laboratory tests also have been examined in more than 2,000 patients involved in clinical trials with naltrexone (Pfohl et al. 1986). Although addicted individuals are often unhealthy to begin with, studies in addiction treatment programs have not identified significant laboratory abnormalities resulting from naltrexone treatment. Studies of patients given high-dose naltrexone for experimental treatment of conditions such as obesity have noted dose-related increments in transaminase levels that were all reversible when the drug was stopped. These subjects generally received 300 mg/day of naltrexone, or about six times the therapeutic dosage for prevention of addiction relapse (Arndt et al. 1986; Pfohl et al. 1986). Other studies of naltrexone for the treatment of addictions as well as other disorders showed no adverse effects on liver function (Arndt et al. 1986; Garbutt et al. 2005). Opioid-addicted individuals in liver failure should not be given naltrexone, although those with moderate abnormalities in liver function tests may receive the drug. Baseline laboratory tests must include a full battery of liver function studies, and monthly retesting should occur for the first 3 months. Caution should be exercised in administering naltrexone to patients whose serum chemistry results (aspartate aminotransferase and alanine aminotransferase) are five times or more above normal. A major impediment to the more widespread use of naltrexone is the early dropout rate and poor medication compliance when oral naltrexone is used. Patients are often ambivalent about treatment or forgetful, and a long-acting medication eliminates the need to remember to take a medication daily. One published randomized trial among heroin addicts has already demonstrated the utility of this formulation (Comer et al. 2006).

KEY POINTS Antagonist treatment is a useful option in the treatment of opioid addiction. Antagonists have an important role to play in treating overdose and in diagnosing physical dependence. The major obstacle in the use of oral naltrexone is the high dropout rate because patients either change their minds about treatment or decide they no longer need the medication. The long-acting depot preparation is a major improvement in maintaining medication adherence. Antagonists are particularly effective in selected populations such as medical personnel, white collar addicts, and parolees with a history of opioid addiction.

REFERENCES Arndt I, Cacciola JS, McLellan AT, et al: A re-evaluation of naltrexone toxicity in recovering opiate addicts, in Problems of Drug Dependence, 1985 (NIDA Research Monograph 67). Edited by Harris LS. Washington, DC, U.S. Government Printing Office, 1986, p 524

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Bigelow G, Preston K, Schmittner J, et al: A randomized, single-dose, opioid challenge study of extended-release naltrexone in opioid-using adults. Neuropsychopharmacology 31:S199, 2006 Comer SD, Sullivan MA, Yu E, et al: Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial. Arch Gen Psychiatry 63:210–218, 2006 [PubMed] Cornish J, Metzger D, Woody, GE, et al: Naltrexone pharmacotherapy for opioid dependent federal probationers. J Subst Abuse Treat 14:529–534, 1997 [PubMed] Garbutt JC, Kranzler H, O'Malley S, et al: Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized clinical trial. JAMA 293:1617–1625, 2005 [PubMed] Hollister L: Clinical evaluation of naltrexone treatment of opiate-dependent individuals. Arch Gen Psychiatry 35:335–340, 1978 Kleber HD, Kosten TR, Gaspari J, et al: Nontolerance to the opioid antagonism of naltrexone. Biol Psychiatry 20:66–72, 1985 Ling W, Wesson DR: Naltrexone treatment for addicted health-care professionals: a collaborative private practice experience. J Clin Psychiatry 45:46–48, 1984 [PubMed] O'Brien C, Cornish JW: Naltrexone for probationers and parolees. J Subst Abuse Treat 31:107–112, 2006 [PubMed] O'Brien C, Greenstein RA, Mintz J, et al: Clinical experience with naltrexone. Am J Drug Alcohol Abuse 2:365–377, 1975 [PubMed] Pfohl DN, Allen JI, Atkinson, RL, et al: Naltrexone hydrochloride (Trexan): a review of serum transaminase elevations at high dosage, in Problems of Drug Dependence, 1985 (NIDA Research Monograph 67). Edited by Harris LS. Washington, DC, U.S. Government Printing Office, 1986, pp 66–72 Roth A, Hogan I, Farren C, et al: Naltrexone plus group therapy for the treatment of opiate-abusing health-care professionals. J Subst Abuse Treat 14:19–22, 1997 [PubMed] Volpicelli JR, O'Brien CP, Alterman, AI, et al: Naltrexone and the treatment of alcohol dependence: initial observations, in Opioids, Bulimia, Alcohol Abuse and Alcoholism. Edited by Reid LB. New York, Springer-Verlag, 1990, pp 195–214 Volpicelli JR, Alterman AI, Hayashida M, et al: Naltrexone in the treatment of alcohol dependence. Arch Gen Psychiatry 49:876–880, 1992 [PubMed] Washton AM, Pottash AC, Gold MS: Naltrexone in addicted business executives and physicians. J Clin Psychiatry 45:4–6, 1984

SUGGESTED READING O'Brien CP: Drug addiction and drug abuse, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th Edition. Edited by Brunton LL, Lazo JS, Parker KL. New York, McGraw-Hill, 2006, pp 607–628 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 23. Psychodynamics

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Hallie A. Lightdale, Avram H. Mack, Richard J. Frances: Chapter 23. Psychodynamics, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.352765. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Psychodynamics Hallie A. Lightdale, M.D. Avram H. Mack, M.D. Richard J. Frances, M.D.

PSYCHODYNAMICS: INTRODUCTION Psychoanalysis and psychodynamic theory are fundamental to modern psychiatric practice, including addiction treatment. Although some investigators have argued that psychodynamic treatment has only a minor role in the treatment of substance abuse (Vaillant 1995), others have shown how psychodynamic understanding can add depth to work with individuals and groups, further the rehabilitation process (Dodes and Khantzian 2004; Frances et al. 1989; Khantzian 1997), and increase the usefulness of 12-step programs (Dodes 1988). As part of a transtheoretical integrated treatment model, sophisticated understanding of psychodynamic principles can be used by the therapist to help the addicted patient recognize that he or she has a problem and then to identify what might provide effective motivation for that individual to change. This approach helps patients in actualizing their wish to change by helping them move along the continuum from contemplation of a problem, such as smoking, to contemplation of the need for change, to taking action and then maintaining abstinence. In this chapter, we develop a rationale for the application of psychodynamic concepts in addiction treatment, examine their indications and contraindications, and explore how psychoanalytic theory can be used to enhance standard treatment techniques and deepen understanding of addiction treatment. Finally, we provide a psychodynamic approach to addiction that includes neurobiological findings.

PSYCHODYNAMIC THEORIES OF ADDICTION Classical and Early Psychoanalysis Psychoanalytic understanding of addiction derives from general psychodynamic theory. Psychodynamic treatment is based on Freud's work in discovering the importance of unconscious phenomena; the development of a theory of the relationship between id, ego, and superego, with an emphasis on resistance, defenses, and conflict; and the use of techniques such as free association, clarification, and interpretation. Freud (1905/1953), Abraham (1908/1960), and Radó (1984) each posited trauma-related developmental issues—including orality, regression toward infantile fixations, defenses against homosexuality, sexual and social inferiority, emotional immaturity, depressive tendencies, and insecurity—as psychopathological pathways leading to substance abuse (Lorand 1948). Freud (1930/1964) also connected the elation of intoxication, which he believed relaxed superego repression, to manic states. Glover (1932/1956) noted the important role of aggressive drives in substance abuse.

Modern Psychoanalysis and Psychodynamics As the focus of psychoanalytic theory has moved from drives to developmental and structural deficits and affective experience, psychoanalytic approaches to addictions have been redrawn as well. A number of theorists have contributed important ideas on the role of ego defenses, defense deficit, and affective experience in drug abuse and alcoholism. Affective regulation has been a major area of interest among those studying the psychodynamics of addiction. Krystal (1982–1983) emphasized a defective stimulus barrier resulting from early psychic

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trauma and the attempt to use substances to fortify against the onslaught of overwhelming affects. He described the inability of patients to label affects, which he called alexithymia, and the inability of addicted individuals to verbalize affective states. McDougall (1984) focused on drug use as a dispersion of affects into action. Lewis (1987) highlighted pathological shame, affecting one's core sense of self, as an affect associated with substance abuse. Dodes and Khantzian (2004) emphasized the addicted individual's sense of helplessness and powerlessness, often in the face of intolerable affects, and the drive to restore through drug use a sense of power and control to which the individual feels entitled. In this perspective, the goal of substance use is pharmacological control or change of one's affect state. Addictions have also been explained in terms of fixation or delay of psychosexual development. Krystal (1982–1983) described an inability in addicted individuals to take over the internal maternal functions associated with care of the self. Bean-Bayog (1988) described the addiction itself and the resultant loss of control as a sort of severe psychic trauma that leads to characteristic defensive patterns. Wurmser (1984) and Meissner (1986) emphasized narcissistic collapse as a cause of substance use: individuals use substances to compensate for a punctured grandiose or idealized self. According to Wurmser (1984), feelings of emptiness, boredom, rage, shame, depression, and guilt are symptoms of narcissistic wounds and superego regression, which prompt substance use. He further characterized addiction as self-medication for claustrophobia, a feeling of being trapped, with substance use becoming a means of escape. These authors stressed the severity of psychopathology underlying drug dependence. Silber (1974) emphasized the alcoholic individual's pathological identification with destructive or psychotic parents. Some authors have attempted to analyze the substance itself, framing alcohol as a fetish object (Keller 1992), or have described alcohol abuse in terms of falling in love with the reward state of intoxication (DuPont 1998). Both object relations and self-psychology perspectives have been applied to addictions. Kohut and Wolf (1978) considered substance problems as narcissistic behavior disorders in that the drugs serve as substitute idealized selfobjects for selfobjects missing developmentally in addicted individuals. Kernberg (1991) described addictive behavior as a reunion with a forgiving parent, an activation of "all good" self-object images, and a gratification of instinctual needs. Kernberg (1991) identified subsets of addicted individuals with malignant narcissism, which is associated with strong antisocial features. Although the questions of primary and secondary effects of alcoholism were originally raised by Hippocrates more than 2,000 years ago, they were raised again in 1911, when Bleuler (1911/1921) hypothesized that drinking was often the cause of neurotic disturbances and that clinicians should not be taken in by the "stupid excuses" of heavy drinkers. Ferenczi (1912/1916) and Freud and Ferenczi (1908–1914/1993), on the other hand, viewed alcoholism as an "escape into narcosis" from underlying psychodynamic causes. The self-medication hypothesis originated from this theory. The self-medication hypothesis has evolved over the past three decades and is based on observations of patients with dual diagnoses. Theorists such as Wieder and Kaplan (1969), Milkman and Frosch (1973), and Khantzian (1997) have discussed the importance of the specific effects of particular drugs on affect and the choice of a particular substance on the basis of specific sought-after effects. Khantzian (1997) highlighted this self-medication hypothesis in describing the use of opioids to assuage end-point feelings of rage and aggression and the use of cocaine to counter feelings of depressive anergic restlessness or to augment grandiosity. Alcohol has been related to deep-seated fears of closeness, dependence, and intimacy, with the effects of alcohol promoting the tolerance of loving or aggressive feelings. Moving the self-medication hypothesis beyond strict psychiatric diagnoses and toward underlying psychological states, Khantzian (1997) emphasized affect regulation, tolerance, self-regulation of affect, self-esteem, need satisfaction, relationships, and self-care. He also related psychodynamic concepts to the total care of addicted patients, providing a better understanding of how 12-step programs are helpful. He described substance-abusing individuals as lacking an internal, comforting sense of self-validation. These individuals also have difficulty obtaining nurturance and validation from others in a

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consistent, mature way. Self-care relates to the individual's developmental inability to anticipate danger or to worry about or consider the consequences of his or her actions, resulting in self-defeating and self-destructive behavior. Galanter (2002) emphasized the value of self-help groups and religious and social networks in providing a calming, soothing release of anxiety and a support for failing functions of the individual's ego and superego. Luborsky (1984) and Klerman et al. (1984) stressed the importance of clarifying the impact of drugs on the addicted individual's interpersonal relationships. Empirical research (using structured instruments) has failed to demonstrate high levels of dissociation among previously traumatized adults with substance use disorders, and the theory has been promoted that alcohol subsumes the expected dissociation (Langeland et al. 2002).

APPLICATION OF PSYCHODYNAMICS TO TREATMENT Applied psychodynamic theory must be distinguished from psychoanalysis. Whereas psychoanalysis is a specific form of therapy, psychodynamic principles can be used to inform individual and group therapies, rehabilitation, and other aspects of addiction treatment. Aspects of psychoanalysis as a treatment include seeing an analyst four or five times per week, with the analyst providing relatively little feedback, being quite neutral, and providing little reassurance in order to allow the patient to experience frustration and have regressive fantasies. The patient lies on a couch to facilitate regression and the therapist interprets the fantasies as they relate to the patient's childhood experiences. Psychoanalysis is not appropriate for most recovering addicted patients. Psychodynamic psychotherapy (also referred to as insight-oriented psychotherapy) is a modified form of such treatment: individual sessions usually occur one or two times per week, possibly in addition to other modalities, and the patient sits up, facing the therapist. (Use of a couch is generally avoided because it facilitates regression.) Abstinence from the addictive substance is essential for successful treatment. Vigilant efforts at relapse prevention and helping patients get back on track after relapse are very much part of psychodynamic psychotherapy with addicted patients. Psychodynamic psychotherapy and 12-step mutual self-help programs are compatible approaches for the maintenance of long-term abstinence. Today, the focus of psychodynamic approaches tends to be on current conflicts as they relate to the past rather than on dwelling on childhood experiences. Psychodynamic understanding takes into account the patient's childhood history; temperament; existing conflicts at the oral, anal, phallic, or genital levels; development of defenses; and ego and superego development, including object relations and relationships with parents, siblings, and friends (Khantzian 1997). With these insights, the therapist can help the patient to identify what motivates him or her for change. The therapist, aware of the patient's characteristic defenses and particular ego weaknesses and strengths, provides empathic interpretations and takes an active and supportive role. The therapist–patient relationship is discussed openly in order to work through resistance, and no effort is made to foster further regression. Psychodynamic techniques aimed at increased self-awareness, growth, and the working through of conflicts can be combined with cognitive approaches, case finding, relapse prevention, motivational techniques, suggestions, education, and provision of support and reassurance as indicated. Utilizing a transtheoretical treatment model, the therapist can help that particular patient to move along through the stages of change and recovery. A real danger in the history of psychoanalysis has been a reductionism in which attempts are made to apply one theory or approach to every situation. A broad and flexible use of psychodynamic thinking takes into account the total range of structural issues, including id, ego, and superego; developmental factors; conflict theory; self psychology; affect regulation; and cognitive deficits. Perry et al. (1987) clarified how three psychodynamic theoretical models—self psychology; object relations; and classical ego, id, and superego conflict theory—can be used to fit the metaphor that is most useful to a particular patient or psychodynamic history.

INDICATIONS AND RATIONALE FOR PSYCHODYNAMIC

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PSYCHOTHERAPY Psychodynamic principles are applicable throughout psychiatry and are relevant to addiction treatment. Insight-oriented therapy may be especially sought out by individuals for whom this kind of approach represents a particularly good fit. Individual psychodynamic psychotherapy may be the sole treatment or may be combined with group, family, psychopharmacological, self-help, and cognitive-behavioral therapy, as well as other treatment approaches. Individual psychodynamic psychotherapy may be reserved for treatment-resistant cases, or it may be the treatment of choice because of patient factors. Some patients refuse to participate in group or self-help programs and seek out individual psychodynamic therapy because of a wish for privacy, confidentiality, and insight. Patients with certain characteristics may especially seek out psychodynamic psychotherapy; positive characteristics of such patients may include high intelligence, interest, and insight; psychological mindedness; a wish to understand or find meaning in behavior; a capacity for intimacy; identification with a therapist; ample time; ample funds; and a wish to change aspects of self that are not acceptable. As with most forms of psychotherapy, positive prognostic indicators are higher socioeconomic status, marital stability, less severe psychopathology, and minimal sociopathy (Woody et al. 1986). Some relatively negative characteristics associated with other treatments are social phobia, avoidance, and fears, which make attendance at Alcoholics Anonymous (AA) and Narcotics Anonymous (NA) meetings difficult. Factors that may lead some individuals to consider psychodynamic psychotherapy instead of other treatments include initial reactions of distaste toward spirituality, as may occur in some atheists; strong negative reactions to groups in general; unwillingness to take medication when indicated; and a lack of a rational approach to the world (patients with such a lack might benefit from cognitive-behavioral treatment). Adolescents and young adults sorting out identity issues, problems regarding individuation, and a need for independence may especially benefit from an insight-oriented approach. For patients in whom denial, projection, splitting, and projective identifications are prominent defenses, consistent interpretation of defenses may be needed to form a working alliance that can be used to achieve sobriety and growth. Patients who continue to be anxious, depressed, and troubled after detoxification are more likely to seek out additional psychotherapy. In many ways, patients who benefit from psychodynamic psychotherapy and have abused substances are similar to those who benefit from such therapy and have not abused substances. At the same time, however, many patients who failed to respond to psychodynamic psychotherapy when they were drinking find that they do benefit from this form of treatment when they are sober. Insight-oriented psychotherapy may be used to achieve or maintain the benefits of abstinence and to prevent relapse. Those affected by disasters such as the Oklahoma City bombing or the September 11 terrorist attacks often turn to substances for relief of painful affects. Psychotherapy might prevent addiction or relapse in vulnerable individuals. Alcohol and substance use can increase vulnerability to posttraumatic stress disorder, and the disorder itself can increase alcohol and drug problems. In one study, alcohol use was decreased among victims of the Oklahoma City bombing, and alcohol did not alleviate symptoms but in fact increased functional impairment in these individuals (Pfefferbaum and Doughty 2001). Recovering addicted patients are often members of families with heavy addiction, and the danger of relapse is greater among patients who have conflicts about enjoying and enhancing their success. These patients may fear being more successful than an addicted parent or sibling, and insight into the sources of self-defeating behavior can be essential to preventing relapse. In the case of patients for whom self-care, self-destructiveness, suicidality, and masochism are major issues, an awareness of unconscious forces of self-destructive behavior can be useful to both patient and therapist. Many patients are not aware that their alcoholism may be what Menninger (1938) called "a slow form of suicide." Awareness of risk-taking aspects of behavior may lead the patient to take greater caution. Addiction and suicide are long-term solutions to what are often short-term problems, and the therapist's job is to help the patient realize this. The rationale for using psychodynamic principles is frequently based on an in-depth clinical understanding of a particular patient's life situation. There is good evidence that alcoholism is influenced

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by genetic and environmental factors. Biological factors, such as the dopamine reward pathways and the mesolimbic reward system, have also enhanced understanding of the brain basis of addiction (Koob and Le Moal 1997; Kreek and Koob 1998; Leshner 1997; O'Brien 1997a, 1997b; Volkow et al. 1997). Studies indicate that medications such as lithium and valproate may be neurotrophic for patients with bipolar disorder, and it will be interesting to see which forms of psychotherapy may also have neurotrophic effects (Manji et al. 2000). The study of temperament is leading to intriguing implications for psychiatric treatment, including treatment of addictions (Cloninger 1987). Psychodynamics are used to deepen the patient's understanding of the rehabilitation process and group psychotherapy and to help him or her understand how self-help groups work (Frances et al. 1989). Awareness of the importance of an unconscious wish to return to drinking, especially during periods of stress, is used in treatment. When unconscious factors have repeatedly led to relapse, exploratory psychotherapy may be particularly useful (Dodes and Khantzian 2004). For example, a patient's association of a "lost weekend," a drunk dream, or a planned vacation to a location where relapses frequently occurred in the past may be a warning sign of a possible relapse and can be used to help the patient to recognize that a craving still exists and should be addressed. An awareness of reasons not to drink and the strengthening of that side of the patient's internal conflict may help, along with increased insight into the sources of the internal struggle. The greatest focus of attention has been on how substances may be used to self-medicate for other psychiatric disorders or to self-regulate affect, and how their use may be a symptom of an underlying problem (Khantzian 1997). Abused substances may be used to push painful thoughts from one's consciousness and to numb feelings associated with painful knowledge, or they may be used to gain access to unconscious material and to facilitate the experience or expression of anger and other feelings that may be avoided during sobriety. For patients for whom affect regulation is an issue, psychodynamic psychotherapy may be especially valuable. A patient with an underlying dysthymia, depression, or affective disorder may need to understand how he or she has used substances to cope with unmanageable feelings. Given that alcohol or drugs invariably cause additional life difficulties, psychodynamic approaches may help the patient deal with the psychosocial effects associated with the toxic metabolic complications of substance use. The application of psychodynamic theory to the treatment of comorbid psychiatric problems such as Axis II personality disorders (including borderline, narcissistic, and avoidant personality disorders) is important, especially because alcoholism and drug abuse are overrepresented in these patients. The literature on comorbidity of Axis I and Axis II disorders is extensive, and a presentation of findings is beyond the scope of this chapter (for further discussion, see Kessler et al. 1997). It may be especially hard to identify the boundaries of temperament, acute substance-induced personality change, other Axis I disorders, secondary personality features, and independent personality disorders. Exploratory psychotherapy with patients with borderline personality disorder who have a history of addiction must be informed by a good knowledge of addiction psychiatry and an emphasis on structure and limit setting in treatment, including the vital parameter of abstinence. Kernberg (1991) discussed the deception and projection often seen in the initial therapeutic alliance with patients with borderline or narcissistic personality disorder, as well as the need to confront distorted views of reality in the therapeutic relationship. The use of insight in interpreting negative transference and acting out may deepen a positive transference and ultimately foster open expression. As a patient develops a clearer picture of his or her life through exploratory psychotherapy, the value of openness and honesty becomes apparent, and the tie to the therapist is cemented. Frequently, addicted patients have lied to themselves and others and are tired of feeling false and phony. The therapist's healthy ability to tolerate being conned by highly skilled, manipulative patients may minimize damaging countertransference reactions. If the therapist finds himself or herself doing something with a patient (either positive or negative) that is out of the ordinary, some examination of countertransference is always warranted. Early in treatment, it may be hard to tell whether a personality change is resulting from a gradual return to better function because of physical, social, and psychological recovery from addiction effects;

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whether the initial diagnosis of personality disorder was correct; or whether psychodynamic therapy and/or 12-step programs have effected personality change. Some patients experience a rebound high that is analogous to the practicing subphase of development in the second year of life, when there is a burst of autonomous development (Mahler et al. 1975). Many addicted patients who have narcissistic traits or personality disorder, and in whom the toxic effects of addiction heighten narcissism, feel a sense of specialness and entitlement, have no empathy for others, are unable to allow themselves gratification of dependence needs, and experience loneliness. For these patients, rehabilitation often involves acceptance of vulnerability and of being ordinary and similar to others with the same problem; a reaching out for help; and encouragement to develop a new humility. Whether this rehabilitation is achieved through 12-step programs, application of Beck's cognitive therapy (A. T. Beck et al. 1993; J. S. Beck et al. 2004), or psychodynamic exploration of the narcissistic vulnerability, these issues should be dealt with in this substantial subpopulation. Dodes (1996) suggested that addictions are in the same category as compulsions, and because compulsions have been seen as treatable with traditional psychodynamic psychotherapy, addictions should also be treatable by similar approaches. Evidence indicates that alcohol problems can either cause or result from anxiety disorders and that more often than not, agoraphobia, social phobia, and obsessive-compulsive disorder precede rather than follow an alcohol problem (Kushner et al. 1990). Although cognitive-behavioral and pharmacological approaches may be first-line treatments for panic disorder, agoraphobia, and social phobia, psychodynamic approaches are often used with patients whose conditions have been resistant to, or have only partially responded to, other psychotherapies and medications (Frances and Borg 1993).

CONTRAINDICATIONS FOR PSYCHODYNAMIC PSYCHOTHERAPY Contraindications for psychodynamic psychotherapy include active use of substances, severe organicity, psychosis, and, for the most part, antisocial personality disorder. Some patients who regress too readily in individual therapy, who develop psychotic transferences, or who develop negative therapeutic reactions benefit from the diffusion of transference that takes place in group therapy. If the principal problem is marital, family therapy is the treatment of choice.

INITIATION OF TREATMENT Some authors recommend waiting 6 months to 1 year before beginning psychodynamic psychotherapy with a patient (Bean-Bayog 1988). We believe that psychodynamic treatment can be initiated early; however, timing should be tailored to the patient. The greatest opportunity to develop a treatment alliance is often early, while the patient is in crisis. Supportive elements, such as confrontation, clarification, support of defenses, and building on ego strengths, may be more prominent early in treatment. The therapist should also take into account state-related problems of organicity, physical illness, and affective vulnerability, all of which can lead to an inability to utilize interpretations. In their work on initiating treatment, Prochaska et al. (1992) discussed the stages in which patients develop awareness of their addiction problems. Focusing on motivational aspects of treatment and confronting denial of a need for help are essential elements in initiating treatment. Promoting identification as a recovering person can boost self-esteem and provide stability. The psychodynamic psychotherapist needs to consider the effects of intoxication and withdrawal and the chronic organic effects of alcohol. However, during intoxication or withdrawal, there are patients for whom psychodynamic interpretations are indicated from the very outset of treatment, regardless of the stage of addiction. Interpretations may help the patient work through resistances to accepting help. They may also provide a meaningful explanation for destructive patterns, one that can inspire a wish for change. Timing of interpretations is crucial. A patient who may need to project blame and responsibility for his or her actions onto substances early in recovery may later be able to accept responsibility for those actions. For example, one patient admitted later in treatment that having an affair, embezzling money, and being abusive were things he wanted to do anyway and that he used alcohol and cocaine abuse as

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an excuse. The individual may not be ready to take full responsibility for his or her actions early in abstinence, but over time, these issues can be explored and pointed out, denial can be worked through, and acceptance of responsibility can be achieved. Defenses may need to be supported at first, including denial of affect related to some of the losses. Interpreting those defenses may be most effective when the patient is facing life challenges that offer a particular motivation for change. Consider, for example, the 67-year-old man who utilized the defenses of denial and displacement to avoid the grief he felt at how he had sabotaged his relationship with his children throughout their lives. When presented with the opportunity for a relationship with his grandchildren, he was more able to face his desperate wish to win back respect and love from his family. Confrontation should concentrate initially on denial surrounding addictive behaviors. Clarification, confrontation, and interpretation of denial, lying, splitting, and projective defenses in other areas ultimately need to be expanded. However, in selected cases, with repeated treatment failure, an initial intervention may require active, across-the-board confrontation and interpretation of inconsistencies and denial in order to help the patient accept a need for change. In patients with alexithymia or constricted affect, interpretations are aimed at increasing the patient's awareness of feeling states and helping him or her connect thoughts and feelings without the use of substances.

SESSION FREQUENCY, SETTING, AND GOALS Psychodynamic psychotherapy with alcoholic patients is usually conducted one to two times per week, is often combined with group psychotherapy, and includes a parameter of abstinence and a long-term goal of sobriety. It can be done during an inpatient stay or in an organized outpatient or office practice, and it can be time limited and focused or long-term. It is foolhardy for psychotherapists to promise that once underlying causes of a "symptom of drinking" are dealt with, the patient will be able to return to controlled drinking. Similarly, it is unwise to promise that once a patient is fully treated with psychoanalytically oriented psychotherapy, he or she will never need additional help through 12-step programs or additional psychotherapy. A treatment model that integrates multiple modalities is most likely to facilitate real change. For most alcoholic individuals, shifting from dependence on a chemical such as alcohol to dependence on a therapist, group, or spiritual belief or involvement with anything human is a major step in the direction of growth. Although issues of dependence may be worked through partially, an ongoing positive identification with a therapist, a sponsor, and/or recovering friends may be a major positive outcome of treatment. Active dialogue with the patient and an attitude of empathic concern and sharing on the part of the therapist are optimal. Issues of termination of individual therapy or graduation from phases of treatment may bring earlier conflicts back to the surface and trigger relapse. The goal of psychodynamic treatment for addicted patients is to help them maintain abstinence, provide them with a richer understanding of and control of their inner lives, and reduce psychological triggers for relapse. Achieving this goal helps improve patient self-esteem, self-care, and affect regulation (Khantzian 1997).

GENERAL TECHNICAL ASPECTS OF TREATMENT Advances in object relations theory, ego psychology, and modern psychodynamic understanding of conflicts and affect regulation can be applied to addiction treatment. Psychodynamic principles are applied in conjunction with an understanding of the clinical exigencies of addiction treatment. Techniques need to be modified, especially those related to attaining and sustaining abstinence, and the effects of regression should be monitored carefully. However, well-established techniques and principles of brief and long-term psychodynamic treatment are generally maintained. The therapist listens for themes relating to the patient's intrapsychic conflicts, developmental impairments, and defenses, paying special attention to how they may relate to substance abuse and relapse potential. The therapist has some important objectives: to obtain a careful developmental history of the patient, with attention to achievement of milestones of ego development; to evaluate temperament in the patient and significant caretakers; to examine the patient's capacity to identify with and to separate from important figures of identification, including parents, siblings, and admired peers; and to explore the patient's affect regulation, especially in relation to substance use. The therapist's tools include free

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association, "slips," and dreams, which are examined to find meaning in the unconscious derivatives of behavior (such as an unconscious wish to drink, expressed in a dream about being drunk). For example, a 45-year-old male patient described an ambivalent relationship with his father, who had failed in business and was devalued by the patient's overbearing mother. The patient expressed loving and sad feelings for his father. He had developed a pattern of sabotaging his own potential for success with alcoholic relapses. During an extended period of sobriety, he began to dream that he had killed his father and was drinking at his father's funeral. The interpretation of this dream helped the patient to begin to examine his unconscious need to fail so that he would not surpass his father, as well as suppressed rage at his father for his helplessness.

Treatment Parameters Treatment parameters for patients with addictions, such as structure, clear boundaries, and abstinence, are similar to those used effectively in treating borderline personality disorder. Structure and boundaries help the patient reestablish control and self-regulation and help him or her express feelings verbally rather than by acting them out. The conventional practice of psychodynamic psychotherapy with limit setting is generally helpful, although on rare occasions a more active approach may be needed. For example, a therapist may need to mobilize a family to bring a suicidal alcoholic patient to the emergency room or to the physician's office after a relapse. While the therapist works through the patient's resistance and defenses, he or she should be aware of how alcohol provides the patient with an escape, can numb or facilitate expression, and can itself alter defensive operations, especially in terms of heightening denial. The therapist should watch closely the interplay of ego function, feeling states, and chemical effects in the patient. Most therapists in the addiction field believe that abstinence is necessary for psychotherapy to be effective. Many think it is best to first develop a solid relationship with the patient and then aim for gradual achievement of abstinence (Dodes and Khantzian 2004). We believe that although flexibility is often needed for patients with severe psychiatric illness, psychiatric problems for the most part must be treated in synchrony with the addiction disorder, and abstinence is vital to this approach. Unfortunately, sometimes continuation of psychodynamic psychotherapy can enable the addicted patient to continue substance use. Psychodynamic psychotherapy can also raise conflicts that may lead to worsening of the addiction, and thus the treatment can be contraindicated. The following case illustrates such a situation: A 37-year-old successful journalist was in psychoanalysis 5 days per week for a severe alcohol addiction. He frequently arrived at sessions intoxicated or missed them altogether. During years of analysis, his addiction to alcohol progressed. His family tried to convince him to see an addiction psychiatrist. He protested that he had a good relationship with his analyst, thought that he was being helped, and used this as a rationale to avoid effective treatment. This patient achieved poor results in treatment because his psychoanalyst was not knowledgeable about addictions and was adhering to a technique that was wrong for the patient. The issue of abstinence was crucial here, but it was ignored.

Other Treatment Tools A combination of psychodynamic approaches, such as clarification, interpretation, and genetic reconstruction, may be used along with directive approaches, such as assertiveness training, social skills training, self-efficacy groups, modeling, positive reinforcement, cognitive awareness, and suggestion. A sophisticated familiarity with typical problems that occur in alcoholic or drug-abusing individuals and their families and the use of psychoeducation about these issues help the therapist establish a positive alliance with his or her patient. The literature on adult children of alcoholic patients can aid the therapist's understanding and be used in educating patients and their families. The following case illustrates the use of combined approaches: A 42-year-old recovering alcoholic woman with panic attacks and agoraphobia had special

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problems when flying. Psychodynamic psychotherapy was useful when added to desensitization, relaxation therapy, exposure to flying, and closely monitored medication for panic attacks (paroxetine and benzodiazepines taken 2 hours before airplane trips). The anxiety persisted at a significant level, frequently interfering with the patient's plans. Her fears of flying were related to childhood conflicts about having to take planes to visit her father after her parents divorced. She was the "apple of her father's eye" and had clearly won out over her mother, although she had considerable guilt over her especially favored position. Her oedipal guilt persisted, contributing to difficulty in reaching orgasm with her husband and feelings of guilt about enjoying her sexuality. At the time of treatment, the flights she feared most were those related to visits with her father and those involved in pleasure trips with her husband. Although none of the treatments totally allayed her fears, she was able to travel without drinking and was better able to understand and cope with her fears of flying, having gained enhanced insight into the roots of her fears. She was increasingly allowing herself to enjoy gradual steps toward success without relapsing (see Ballenger 1999 for a discussion of anxiety disorder treatments).

INITIAL FOCUS AND PHASES OF TREATMENT The phases of intervention include initial screening, evaluation and intervention, rehabilitation, and aftercare. The initial focus is often on conflicts related to the acceptance of addiction as a problem, the patient's reluctance to acknowledge dependence and the need for treatment, and conflicts resulting from the complications of alcoholism (including the loss of relationships, health, and jobs) and from missing alcohol itself. As emphasized above in "Treatment Parameters," the first goal is abstinence. More often than is usually the case in insight-oriented psychotherapy, the patient may initially be forced into the consultation by an employer, probation officer, family member, or physician. Especially when coercion has occurred, the therapist must make a considerable effort to develop trust and a working alliance with the patient. This is achieved through careful review of the patient's history and the ways in which addiction has interfered with work, family relationships, and other relationships or has caused legal problems, all of which have contributed to pain and the need to escape it. The therapist's integrity, adherence to confidentiality, and ability to be helpful all contribute to the establishment of trust. The patient is helped to accept a diagnosis and to accept the need for help, which may lead to positive transference. These steps are similar to the first two AA steps, in which patients admit their powerlessness over alcohol and accept their need for help or acknowledge their own dependence needs, which in AA is called "accepting a higher power." A psychodynamic perspective may aid in the confrontation of denial and other defenses, and through interpretations patients achieve a deeper understanding of certain destructive patterns that have led to the present problem. It is especially challenging to help the patient acknowledge dependence needs that have been channeled into the addiction. Therapy is a process in which a need for substances is shifted back into a need for people, including the therapist. Patients who abuse drugs often refuse to take medications because of fears of using them in compulsive ways, becoming dependent on drugs for relief, and becoming dependent on the therapist to obtain the medications. From early in treatment, issues of trust, dependence, separation, loss, disappointment, and truthfulness are frequent themes. In the later stages, the focus of exploratory psychotherapy should not be imposed from the outside—that is, it should not be based on purely theoretical considerations. Rather, the focus should be on the most pressing issue of the moment that may relate to the patient's drinking: a particular conflict; a relationship with a family member or employer; a problem with self-esteem, self-destructiveness, or self-medication for panic; or other painful affects. Other major themes include specific conflicts over assertiveness, handling of aggression, and issues of control and inhibition. The disinhibiting role of addiction, leading to risk-taking behavior (including increased sexual activity), may be an issue. Alternatively, alcohol may play a role in distancing the individual from sexual life, or drinking may substitute for sexual activity.

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RELAPSE Patients should be observed carefully for drinking or drug use behavior. Laboratory tests may be useful, and meeting with family and other sources of collateral information may be essential in order to get a true picture before confronting patients who dissimulate. As mentioned earlier in "Indications and Rationale for Psychodynamic Psychotherapy," psychodynamic therapy can help in relapse prevention. Consider the following case: A 47-year-old pediatric surgical nurse frequently relapsed in her addiction to diazepam on evenings after she had had to deal with families of children with disastrous surgical results. As a child, she had been traumatized by a younger sister's postoperative death due to a brain tumor. Her parents had tried to protect her by never discussing her sister's death, and she had always found this to be strange. Her relapses were triggered by unresolved conflicts and grief regarding her dead sister, whom she envied, loved, and, at self-destructive moments, wished to join in death. Her initial treatment plan involved detoxification, support, and an aim of abstinence. However, the effectiveness of relapse prevention was enhanced by psychodynamic treatment that helped her mourn her sister and eliminate an important trigger for relapse.

ACCEPTANCE OF SELF IN RECOVERY An important part of recovery is a change in self-awareness and self-perception. An enormous shift for the patient is the acceptance of a diagnosis of alcoholism as an illness. This entails not only shifting from a moral model (in which the patient sees himself or herself as weak, shameful, and bad for being alcoholic) but also being aware that a problem exists about which a great deal is known, that the problem is treatable, and that it does not have to lead to hopelessness and despair. Sometimes this awareness leads to reaction formation, in which the patient feels grateful for being alcoholic and turns a disability into an advantage. There may have been real advantages in terms of broadening of experience, overcoming a vulnerability, and developing a pride that can occur in any group that finds a way to overcome a stigma. The patient's feeling of relief after he or she is no longer experiencing the consequences of alcoholism and addiction often leads to a rebound after initial abstinence—a rebound that can approach euphoria. This euphoria is often followed by a letdown when awareness of the multitude of problems that the addiction caused occurs.

AN EGO PSYCHOLOGICAL MODEL OF REHABILITATION Assessment of ego function needs to include a search for strengths, talents, and positive qualities that can be used to help the patient. All too often, therapists miss opportunities to enhance self-esteem in patients whose self-criticism leads them to overlook real and potential opportunities for growth. One way to combine positive insight with support is to help patients recall periods in which their values were in place and to give them hope for a return to a higher level of function. Even very damaged, impaired individuals from deprived and disadvantaged backgrounds have dreams in their lives that they have buried. Rekindled dreams can foster renewed hope and improve self-esteem. The stigma of the illness can also be lessened by discussing positive role models, such as Betty Ford, who have struggled with the same illness and have worked hard at recovery. An ego psychological model can be applied to the biopsychosocial effects of addiction and to rehabilitation. Chemicals and psychosocial consequences have effects and may lead to regression and impairment of defenses, object relatedness, judgment, reality testing, and superego. It may take time and practice for good ego and superego function to return. The following case demonstrates recovery of function: A 47-year-old narcissistic man who had drunk heavily for 25 years had disuse atrophy of ego functions and was pushed to function better as part of rehabilitation. He thought of his wife only in terms of what she could do for him, as a part object or a need-satisfying object, and only with practice and with time sober could he relate to her in a more complex way as having needs of her own. He would idealize or devalue everyone and everything, and it took him a long time to relate to others as having both good and bad qualities. To develop friendships and break isolation, he had

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to practice relatedness in individual therapy, couples therapy, group therapy, and self-help groups. In this case, the superego had been dissolved in chemicals for years, and it took external structure and parameters to gradually awaken the sleeping policeman within—that is, for the superego to start working again. The program requirements and the external norms of the groups helped him regain structure. His superego was initially inconsistent and vacillated from a lack of restraint and self-indulgence to a primitive punitive masochistic rigidity. Cognitive impairment, especially in the nondominant hemisphere functions of spatial and temporal relationships, was present and improved over time with abstinence. The defenses initially encountered in treatment are usually the most primitive and include denial, rationalization, splitting, projection, and projective identification. With time and treatment, higher-level defenses such as intellectualization, reaction formation, repression, and sublimation may be more in the forefront. For example, instead of denying alcoholism and projecting poor self-esteem, a patient may feel grateful to have alcoholism and honored to be part of a group that initially was perceived as stigmatizing. Denial of alcohol's harmful effects on the liver, which can be addressed through psychoeducation, can be replaced with curiosity and intellectualization about how liver damage occurs. Use of reaction formation may also lead to noncompliance with psychiatric and other prescribed medications, with the rationale that they could have unknown negative effects on liver and other organ functions. Denial of losses related to addiction may be replaced with repression over time, after grieving over the losses has occurred.

APPLICATIONS OF PSYCHODYNAMICS TO GROUPS AND SELF-HELP The addition of group psychotherapy, AA, or NA is especially needed when individual therapy alone is not helping the patient maintain abstinence. Group treatments help diffuse some of the powerful negative transference that may be impossible to overcome early in treatment. Groups can focus on self-care, self-esteem, affect regulation, sharing, and exposure to feared social situations. They can provide social support and models for identification and coping skills, and they can help patients work through family problems. Groups can be targeted to specific additional diagnoses such as anxiety disorders or to specific subpopulations such as persons with chronic mental illness, those with medical complications, women, and adolescents. Groups can be homogeneous (e.g., recovering physicians with anxiety disorders) or heterogeneous (e.g., all patients in a detoxification unit). Khantzian (1997) described a model of modified psychodynamic group therapy for substance-abusing patients involving self-care, self-esteem, and affect regulation. Together the patient and the individual therapist can look at how the patient projects feelings toward other AA, NA, or group members who, for example, remind the patient of his or her alcoholic relatives. Character flaws can be actively worked on, with immediate and multiple feedback from group members. If the individual therapist is also the group therapist, the individual work may be used to encourage the patient to try a new behavior in the group; conversely, conflicts observed in the group can be worked on individually. Aspects of 12-step programs may readily lend themselves to integration with psychodynamic treatment. These aspects include accepting a diagnosis, accepting dependence needs, being aware that one cannot control drinking alone, taking a personal inventory (often discussed in terms of a higher power), working at change, dealing with sobriety one day at a time, accepting the structure of a treatment program, and enhancing self-esteem by helping others with the problem, thus living up to an ego ideal. The 12-step programs provide education, auxiliary ego and superego support, and powerful role models for positive identification. Steps in AA that involve taking a personal inventory and making amends can be used in conjunction with the psychotherapeutic process of self-exploration and insight aimed at behavioral change. The addition of AA is especially helpful during periods of relapse and during periods when the therapist is unavailable because either the patient or the therapist is away. Because alcoholism and drug abuse are often chronic relapsing illnesses, both the patient and the therapist must be prepared for the possibility of a relapse. The therapist should be both nonjudgmental and unafraid of confrontation.

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THE PATIENT–THERAPIST RELATIONSHIP Many problems related to working with addicted patients concern the challenge of establishing a positive therapeutic relationship between the patient and the therapist. Frequently, errors in treatment occur because of negative feelings and attitudes that therapists have toward addicted patients. Typical mistakes include providing inadequate empathy or overly identifying with patients. A major source of countertransference is the uncritical acceptance by a clinician of roles projected onto him or her in the patient's transference. In many cases, an understanding of the patient's specific transference that may either evoke countertransference problems or prevent compliance with treatment may be essential for good management and a successful alliance with the patient. Typical transference may result from growing up in a household in which the parents were addicted, inconsistent, and either overly harsh or indulgent. Children of alcoholic parents frequently have authority problems and will often trust siblings, peers, and other alcoholic individuals more readily than they will trust teachers, nurses, doctors, or police. When a patient describes a therapist as cold, neglectful, uninvolved, or detached, this may be transference to a parent who fits this description and may lead the therapist to unconsciously behave in this way. It is helpful for the therapist to be able to interpret negative transference and to know how to manage and appropriately use therapist's countertransference. Alcoholic patients frequently will try to evoke feelings of fear, anger, and despair in their therapists and will reenact relationships with alcoholic parents, siblings, and spouses through the transference. They may project critical attitudes onto the therapist and keep secrets out of fear that the therapist will respond like a parent. When the patient feels that the therapist is like a parent, sibling, or friend, this feeling may have been evoked for specific reasons. The greater the therapist's awareness of what is happening, the more this issue can be brought into the treatment in a constructive way. A second major source of countertransference in treating addicted patients is a therapist's weak knowledge base about addiction and its treatment. The more knowledgeable the therapist is about addiction psychiatry and about the patient, the less likely the therapist is to project his or her own problems onto the patient. Attitudinal problems on the part of the therapist can be reduced by good training and the experience of having worked through issues related to stigma. The more the therapist is in command of a treatment armamentarium, the less frightened he or she is in the face of what can be a dreadful disease. Ultimately, patients are the best teachers. By listening carefully, the therapist can learn about the addictive experience, addictive practices, and the street language of addiction. A third source of countertransference is based on a therapist's mostly unconscious transference, related to his or her past or present problems. Transference may relate to the therapist's attitudes about substances; present or past problems with addiction; or experience with a parent, spouse, or child with a substance use problem. The therapist's own envy, fear, hopes, and needs can adversely affect his or her prescribing practices and lead to overinvolvement, avoidance, hopelessness, jealousy, and burnout. Some clinicians who have chosen to work in the addiction field because of their wish to overcome personal problems related to addictions may have special difficulty dealing with patients' problems if they have not worked out their own. Frequent mistakes include excessive self-revelation of personal problems and a tendency not to see the specifics of patients' problems clearly because of a need to see everyone as similar to the self. A recovering clinician might consider a patient's problem minor compared with his or her own. Alternatively, some clinicians see every problem only in relation to addictive problems. This results in misdiagnosis and overdiagnosis. One extreme of overinvolvement is sexual or aggressive acting out with a vulnerable substance-abusing patient; this has disastrous consequences for both patient and therapist. Seeking out second opinions from or supervision by experienced practitioners is advisable when working with difficult patients. Thorough self-exploration by the therapist in personal therapy also helps. Clinicians with maturity, a good support system, and a secure personal life are better protected against countertransference problems. Additional protection is given by working in a team: team members can point out one another's blind spots and assist in improving one another's technique. Feedback from

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patients and their families can be another means of supervision for the clinician who listens carefully. A wise clinician admits his or her mistakes, learns from them, and tries to avoid future mistakes (Committee on Alcoholism and Addictions 1998).

MYTHS AND PITFALLS TO AVOID IN PSYCHODYNAMIC PSYCHOTHERAPY Clinical experience suggests that there are common misperceptions (myths) about the role of psychotherapy in treating addictions that can negatively affect treatment planning. There are also avoidable problems (pitfalls) that may arise in psychotherapies by even the most seasoned and well-meaning therapists. The following lists cannot be comprehensive, but they address some of the most frequent and relevant myths and pitfalls in psychodynamic psychotherapies with patients who have addictions.

Myths One can first develop a therapeutic relationship and then gradually wean the patient off substances. Substance use will disappear with understanding. Once conflicts have been resolved, the patient can safely return to drinking. If the problem is narcotic addiction, alcohol is safer and legal. Addiction is always a symptom, not a primary problem. Use of motivational interviewing, cognitive-behavioral techniques, group therapy, and 12-step programs cannot be integrated with insight-oriented therapy.

Pitfalls The therapist believes the patient's explanation for drinking, without awareness of rationalization and a patient's need to justify his or her behavior. The therapist does not check out the patient's story. The therapist conducts treatment as if psychodynamic interpretations were "golden" and other interventions less valuable. Treatment approaches and sequence should be selected on the basis of the patient's needs. The therapist does not have a healthy respect for the patient's dependence needs and has too-high expectations for resolving these needs. It is better for the patient to depend on therapists or on AA than on substances, and an endless relationship with AA is a desirable goal—not a compromise of a therapist's goal of self-reliance on the patient's part. The therapist is overinvolved or overly distant. Therapists in recovery themselves sometimes have blind spots or may share with the patient more than the patient needs to know. The therapist has a bias toward one or another form of treatment and lacks theoretical and practical flexibility. Even moderate biases of this type can be a disservice to the patient.

TREATMENT OUTCOME RESEARCH The state of the art in addiction treatment involves being aware of the results of treatment outcome studies but also selecting a combination of treatments that takes into account current knowledge and patient characteristics. Treatment recommendations depend on a wide range of considerations, and trial results are only one factor. The American Psychiatric Association (1995) developed practice guidelines for the treatment of substance use disorders based on reviews of the literature on treatment and outcomes. These guidelines recommend individualizing treatment planning and include treatment of comorbid conditions. Woody et al. (1986) showed meaningful differences in efficacy between supportive-expressive psychotherapy and drug counseling in patients receiving methadone maintenance treatment. Carroll et al. (1994) pointed out that there is a delayed emergence of effects of psychotherapy after cessation of short-term treatments in cocaine-dependent patients. O'Malley et al. (1996) compared psychotherapy with or without naltrexone therapy in alcoholic patients and found that the combined treatment had

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favorable results. With managed care entering the arena of health care, studies of cost-effectiveness and outcomes are becoming increasingly important. Humphreys and Moos (1996) found reduced substance-related health care costs in a study involving veterans participating in AA. O'Brien (1997a) found favorable efficacy when comparing specific treatment approaches for addictive disorders with other chronic disorders such as diabetes and asthma. O'Brien (1997b) also pointed to studies that have shown a cost saving of $4–$12 for every dollar spent on substance abuse treatment. It is too early in addiction outcome research to make hard-and-fast recommendations regarding treatments to be used. Treatment guidelines and the treatment outcome studies discussed in this volume provide useful information but are not definitive instructions to clinicians. Although clinicians agree on some points (e.g., the usefulness of abstinence as a goal, pharmacological treatment of comorbid disorders such as panic attacks, the value of adding education and cognitive and behavioral approaches), the value of 12-step programs and psychodynamic psychotherapy has not been strongly proved in controlled studies, although each treatment has a commonsense rationale. Where definite answers are still lacking, clinicians need to be aware of a growing literature of outcome study findings, of the methodological problems involved in conducting good studies, and of the problems in reliability and validity in applying these results. Uncertainties about the exact value of psychodynamic and combined treatments should not deter clinicians from using what has seemed useful, especially with patients who have specific favorable characteristics such as motivation and capacity for insight and who have destructive patterns amenable to interpretation. When definitive conclusions about the effectiveness of treatment components have been drawn, targeting of treatment will improve.

NEUROBIOLOGY Psychodynamics integrated with neurobiological models of addiction provide a deeper understanding of the patient and the factors that may help a particular patient to change. From a neurobiological perspective, psychotherapy can be understood as a controlled form of learning that occurs in the context of a therapeutic relationship (Etkin et al. 2005). And research into the plasticity of the brain has shown that once genes are activated by cellular developmental processes, the rate at which those genes are expressed is highly regulated by environmental signals (Gabbard 2000). The interplay of psychotherapy, abstinence, and pharmacotherapy in the treatment of addictions can be understood now more than ever as a learning process that may produce alterations of gene expression and thereby alter the strength of synaptic connections. Researchers have made great advances in recent years toward clarifying the biological factors that appear to modulate both the predisposition to addiction to illicit drugs and the risk for relapse. The neurobiology of pleasure and reward circuitry in the limbic system, which modulates the effects of substances of abuse and is fundamental to the process of addiction, involves dopaminergic and endogenous morphinergic signaling (Esch and Stefano 2004). Ongoing research explores genetic polymorphisms in these neuroendocrine pathways, including the mesolimbic system and the ventral tegmental area (Kreek 2000). The acute and chronic reinforcing effects of drug addiction lead to long-lasting neurobiological changes in the brain that undermine voluntary control (Volkow and Li 2004). Research into the positive and the negative reinforcing effects of drugs of abuse has demonstrated how the processes recruit numerous neurotransmitter systems, including dopamine, opioid peptides, serotonin, -aminobutyric acid (GABA), and glutamate- and corticotropin-releasing factor; the overall effect is a change in set point for drug reward that may represent prolonged functional dysregulation affecting vulnerability to relapse (Koob 2000). There is a growing body of evidence, particularly as demonstrated by neuroimaging studies, that psychotherapy influences biological activity in the brain. Although the evidence to date is limited, studies of basal brain metabolism and blood flow as well as studies of stimulus-response imaging have demonstrated that psychotherapy produces changes in the brains of patients who have been diagnosed with anxiety and mood disorders; some of these changes may be shared with those induced by

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pharmacotherapy and others may be modality specific (Etkin et al. 2005). Recent research into the neural bases of nondeclarative memory suggests how psychotherapy may work in the brain to modify pathological thought and behavior patterns by helping the brain to forget these patterns on a synaptic and molecular level. Long-term modifications of synaptic transmissions that underlie maladaptive memory trace encodings and present as compulsions, addictions, or anxiety, may be affected by two effects of psychotherapy: inhibition of memory consolidation/reconsolidation and extinction. Modification of implicit memory occurs both through reversing the plasticity associated with memory maintenance and through protein synthesis–dependent synaptic remodeling (Centonze et al. 2005). Psychological factors and a psychodynamic perspective clearly must be integrated with current scientific understanding of brain mechanisms in relation to the etiology and treatment of addictions. Further knowledge about the biology of conscious and unconscious processes will advance psychoanalytic understanding (Leshner 1997). Greater understanding of the process and psychology of addiction is achieved through psychodynamic psychotherapy. This understanding may add to the development of treatment methods, such as improved cognitive-behavioral techniques (A.T. Beck et al. 1993) that take into account not only complex human motivating factors but also the functional characteristics of that individual's brain. Sophisticated understanding of a patient's intrapsychic conflicts and motivations allows the therapist to help that patient move through the stages of change into recovery. For a patient with a dual diagnosis (a term most commonly used to indicate addiction plus another mental illness), an integrated approach geared toward treating both the mental illness and substance abuse yields better results. A psychodynamic understanding frequently enhances the treatment of anxiety disorders, depression, and personality disorders occurring with substance abuse.

IMPLICATIONS FOR RESEARCH New research is needed to identify the patients for whom psychodynamic treatment is appropriate. Specifically, investigators must determine which Axis I or Axis II disorders, which age group, what timing, and which patient characteristics are best suited for this approach, and they must determine which psychodynamic interventions should be used and combined with what other treatments. It is hard to find good databases of what is often clinically subjective material. Premature closure on any of these questions because of the challenge and expense of studying the particular area may lead to overly narrow, poorer-quality treatment approaches. It will take time, the pooling of large amounts of clinical data, and the collaboration of many clinical researchers to obtain these answers. Initially, nonrandomized, noncontrolled, and descriptive studies will be needed. Ultimately, randomized studies will best exclude even moderate biases, and with large samples, it will be possible to correct for both false positive and false negative results.

CONCLUSION Psychodynamic theory can play an important role in enriching and informing substance abuse treatment and improving the therapeutic relationship. However, rigid application of psychoanalytic technique is inappropriate in substance abuse treatment and can be counterproductive. Application of psychodynamic understanding—including attending to the unconscious, child development, ego function, affect regulation, and efforts to enhance self-esteem and deal with shame and other narcissistic vulnerability —widens the range of patients who can be treated. Greater academic and scientific attention are needed if progress is to be made in this area of the addictions. Currently, definitive outcome studies of psychodynamic psychotherapy in substance-abusing patients are rare. A rich descriptive clinical experience in this area will bring improved understanding of addicted patients in both theoretical and practical settings.

KEY POINTS Sophisticated, dynamic understanding of an individual's conflicts can help motivate patients to accept that they have a problem, help patients accept a need for change, aid in treatment, and be used to maintain progress.

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Psychodynamic understanding can be integrated with cognitive, behavioral, and pharmacological approaches to enhancing treatment. More research needs to be done on how influencing the mind can affect brain function, including addictive behavior.

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SUGGESTED READING Prochaska JO, DiClemente CC, Norcross JC: In search of how people change: applications to addictive behaviors. Am Psychol 47:1102–1114, 1992 Vaillant GE: The Natural History of Alcoholism Revisited. Cambridge, MA, Harvard University Press, 1995, pp 362–373 Volkow ND, Li TK: Drug addiction: the neurobiology of behaviour gone awry. Nat Rev Neurosci 5:963–970, 2004 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 24. Cognitive-Behavioral Therapies

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Kathleen M. Carroll: Chapter 24. Cognitive-Behavioral Therapies, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.353022. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Cognitive-Behavioral Therapies Kathleen M. Carroll, Ph.D.

COGNITIVE-BEHAVIORAL THERAPIES: INTRODUCTION Cognitive-behavioral treatments are among the most well-defined and rigorously studied psychotherapeutic interventions for substance use disorders. In contrast to the previous edition of this textbook (Galanter and Kleber 2004), behavioral, cognitive-behavioral, and motivational approaches are now covered in separate chapters, reflecting the increasing use of these strategies in clinical practice as well as their accumulating levels of empirical support. Thus, while this chapter will focus almost primarily on cognitive-behavioral approaches, it should be noted that cognitive-behavioral therapy (CBT) shares several features with these other empirically supported behavioral approaches. First, cognitive, behavioral, and motivational therapies are applicable across a broad range of substance use disorders; that is, well-controlled trials have supported their efficacy across alcohol-, stimulant-, marijuana-, and opioid-dependent populations. Second, these approaches were developed from well-founded theoretical traditions with established theories and principles of human behavior. Third, these approaches are highly flexible and can be implemented in a wide range of clinical modalities and settings. Moreover, they are compatible with a variety of pharmacotherapies and, in many cases, foster compliance and enhance the effects of pharmacotherapies, including methadone, naltrexone, and disulfiram treatment. Finally, these approaches are relatively short-term and highly focused approaches that emphasize rapid, targeted change in substance use and related problems. In this manner, they are very compatible in a health care environment that is increasingly influenced by managed care, best clinical practice models, and professional accountability. Support was provided by National Institute on Drug Abuse grants P50 DA09241, U10 DA13038 and K05-DA00457.

THEORETICAL BASIS Cognitive-behavioral treatments have their roots in classical behavioral theory and the pioneering work of Pavlov, Watson, Skinner, and Bandura (see reviews by Craighead et al. 1995; Rotgers 1996). Pavlov's work on classical conditioning demonstrated that a previously neutral stimulus could elicit a conditioned response after being paired repeatedly with an unconditioned stimulus. Furthermore, repeated exposure to the conditioned stimulus without the unconditioned stimulus would eventually lead to extinction of the conditioned response. The power of classical conditioning was demonstrated in drug abuse by Wikler (1973), who confirmed that opioid addicts exhibited conditioned withdrawal symptoms upon exposure to drug paraphernalia. Today, classical conditioning theory is the basis of several behavioral approaches to substance use treatment, such as cue exposure (Childress et al. 1999; Monti et al. 1993) and stimulus avoidance as an early component of many addiction counseling approaches. Skinner's work on operant conditioning demonstrated that behaviors that are positively reinforced are likely to be exhibited more frequently. The field of behavioral pharmacology, which has convincingly demonstrated the reinforcing properties of abused substances in both humans and animals (Aigner and Balster 1978; Bigelow et al. 1984; Thompson and Pickens 1971), is grounded in operant conditioning theory and principles. Behavior therapies assume that drug use and related behaviors are learned through their association with the positively reinforcing properties of the drugs themselves as well as their secondary association with other environmental stimuli. CBT attempts to disrupt this learned

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association between drug-related cues or stimuli and drug craving or use by understanding and changing these behavior patterns. A wide range of behavioral interventions, including those that seek to provide alternate reinforcers to drug use or reduce reinforcing aspects of abused substances, also are based on operant conditioning theory. Examples include the Community Reinforcement Approach (CRA) (Azrin 1976), the work of Stitzer et al. (1993), which has demonstrated that opioid-addicted individuals receiving methadone maintenance treatment will reduce illicit drug use when incentives such as take-home methadone are offered for abstinence, as well as contingency management voucher incentive systems (Budney and Higgins 1998; Higgins et al. 1991). CBT conceives substance abuse as a complex, multidetermined behavior, with a number of influences playing a role in the development or perpetuation of the disorder. These may include family history and genetic factors; the presence of comorbid psychopathology; personality traits such as sensation seeking or sociopathy; and a host of environmental factors, including substance availability and lack of countervailing influences and rewards. Though CBT primarily emphasizes the reinforcing properties of substances as central to the acquisition and maintenance of substance abuse and dependence, these etiological influences are seen as heightening risk for or vulnerability to the development of substance use problems. For example, some individuals may find substances unusually highly rewarding secondary to genetic vulnerability, comorbid depression, a high need for sensation seeking, and modeling of family and friends who use substances or environments devoid of alternative reinforcers (Carroll 1999). Cognitive-behavioral treatments also reflect the pioneering work of Ellis and Beck that emphasizes the importance of an individual's thoughts and feelings as determinants of behavior. CBT evolved in part from dissatisfaction with the extreme positions of radical behaviorism (i.e., emphasis on overt behaviors) and classical psychoanalysis (i.e., emphasis on unconscious conflicts or representations). CBT emphasizes how the individual perceives and interprets life events as important determinants of behavior (Meichenbaum 1995). An individual's conscious thoughts, feelings, and expectancies mediate his or her response to the environment. A key concept in CBT is reciprocal determinism, which emphasizes the interdependence of cognitive, affective, and behavioral processes. CBT also seeks to help patients become aware of maladaptive cognitions and "teach them how to notice, catch, monitor, and interrupt the cognitive-affective-behavioral chains and to produce more adaptive coping responses" (Meichenbaum 1995, p. 147).

EMPIRICAL SUPPORT CBT has been shown to be effective across a wide range of substance use disorders (Carroll 1996; Irvin et al. 1999), including alcohol dependence (Miller and Wilbourne 2002; Morgenstern and Longabaugh 2000), marijuana dependence (MTP Research Group 2004; Stephens et al. 2000), cocaine dependence (Carroll et al. 1994a; Carroll et al. 1998; McKay et al. 1997; Rohsenow et al. 2000), and nicotine dependence (Fiore et al. 1994; Hall et al. 1998; Patten et al. 1998). CBT has also been shown to be compatible with a number of other treatment approaches, including pharmacotherapy (Anton et al. 1999; O'Malley et al. 1992) and traditional counseling approaches (Morgenstern et al. 2001), and thus can be implemented in a wide range of settings. These findings are consistent with evidence supporting the effectiveness of CBT across a number of other psychiatric disorders as well, including depression, anxiety disorders, and eating disorders (DeRubeis and Crits-Christoph 1998; Roth and Fonagy 2005). For the past 15 years, my group at Yale has been involved in a programmatic series of studies on the effectiveness of CBT alone and in combination with pharmacotherapy. As our understanding of CBT has deepened over time, this series of studies has been marked by progressively larger effect sizes for CBT than for the control conditions. We believe this suggests that as our experience grows with this approach, we are developing a more potent form of CBT. For example, in our first randomized trial, we conducted a direct comparison of CBT with another active therapy, interpersonal psychotherapy (IPT; Rounsaville et al. 1985), adapted for cocaine users. Although CBT was not found to have a main effect over IPT in that trial, it was significantly more effective among the more severely dependent cocaine abusers (Carroll et al. 1991), suggesting that the higher levels of structure and emphasis on skills may have been particularly helpful for the more severely impaired cocaine users.

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Severity of cocaine dependence as a moderator of CBT effects was also replicated in our next study (Carroll et al. 1994a), which used a two-by-two factorial design, in which desipramine was compared with placebo and CBT was compared to supportive clinical management, a supportive psychotherapy control condition. This study was also the first to describe the "sleeper effect" phenomenon: after the study treatments were terminated, those who had been assigned to CBT continued to reduce the frequency of their cocaine use throughout the following year (Carroll et al. 1994b). Evidence of continued improvement associated with CBT in turn led to increasing interest in mechanisms that might underlie this effect, with skills training and behavioral practice through homework assignments as prime candidates, as described in more detail in later sections of this chapter. In our next study, which was the first to report a significant main effect for CBT over supportive clinical management (Carroll et al. 1998) and which replicated the sleeper effect for CBT over a 1-year follow-up (Carroll et al. 2000a), we evaluated the acquisition of coping skills in CBT and their relationship to outcome. We developed and validated a role-play task for assessing the acquisition of coping skills in CBT (Carroll et al. 1999) that involved the patient listening to a series of audiotaped high-risk situations (e.g., "What would you do if you found yourself at a party where you didn't think cocaine would be available, and then noticed a lot of people going in and out of a back room?" "What would you do if you started feeling really intense craving?"). The patient's responses were audiotaped and then rated for quality of response, type of coping response, and number of responses generated using a rating method demonstrated to be highly reliable. In this study, evaluation of the role-play task demonstrated the following: 1) coping skills increased significantly after CBT; 2) patients demonstrated increases in coping skills that were parallel to those taught in the treatment to which they had been assigned (i.e., differential acquisition of specific behavioral and cognitive coping strategies in CBT with respect to alternative behavioral therapies); and finally 3) greater acquisition of CBT-specific behavioral and cognitive coping skills was associated with significantly less cocaine use over the 1-year follow-up (Carroll et al. 2000a). In our most recently completed trial (Carroll et al. 2004), 121 cocaine-dependent individuals were randomized to one of four conditions in a two-by-two factorial design: 250 mg/day of disulfiram plus CBT; disulfiram plus IPT; placebo plus CBT; and placebo plus IPT. Across outcome measures and for the full intention-to-treat sample (as well as across all subsamples including treatment initiators and treatment completers), patients assigned to CBT reduced their cocaine use significantly more than those assigned to IPT, and patients assigned to disulfiram reduced their cocaine use significantly more than those assigned to placebo. Effects of CBT plus placebo were comparable to those of the CBT-disulfiram combination. This was our first trial to identify a significant main effect for CBT over another active behavioral therapy (IPT). Furthermore, although retention was a significant predictor of better drug use outcomes, the CBT by time effect remained statistically significant after controlling for retention. This series of trials has demonstrated increasingly strong effects for CBT over time, and our follow-up studies have consistently indicated high durability of CBT compared with other approaches. Similar results have been found by other research groups evaluating CBT across a range of substance use disorders; these will be briefly reviewed in the sections that follow.

Cocaine Dependence Maude-Griffin et al. (1998) randomized 128 cocaine users to either CBT or 12-step facilitation (TSF), a manualized disease model counseling approach (Nowinski et al. 1992), in order to test several a priori matching hypotheses. Treatment was delivered in both group and individual sessions and results suggested that CBT was more effective than TSF overall. In addition, several matching hypotheses were supported; for example, CBT was differentially effective for individuals with a history of depression, while TSF was more effective for participants with low levels of abstract reasoning skills. Monti et al. (1997) evaluated the effectiveness of adding individual sessions of coping skills training to treatment for 128 cocaine users who were enrolled in an inpatient program or an intensive partial hospitalization program. Compared with an attention placebo control condition (manualized meditation

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relaxation training), CBT was more effective in reducing the frequency of cocaine use and length of relapse episodes (when they occurred) through a 3-month follow-up. A 9-month follow-up study indicated that treatment effects on cocaine use were sustained through 6 months. McKay et al. (1997) evaluated the effectiveness of individualized relapse prevention as continuing care following completion of an intensive outpatient program. Ninety-eight cocaine-dependent patients were randomly assigned to either standard group counseling or relapse prevention. At the end of the 6-month trial, rates of complete abstinence were higher in the standard counseling condition than in relapse prevention, but for those who relapsed, the relapse prevention condition was associated with less severe relapses, particularly during the earlier months of the intervention. McKay et al. (1997) also evaluated a series of matching hypotheses with this group, and found that relapse prevention was associated with better outcomes for those individuals who did not maintain stable abstinence during the initial intensive outpatient program as well as for those individuals whose initial treatment goal was total abstinence. The latter effect was sustained through a 2-year follow-up (McKay et al. 1999). Another particularly exciting development in the field of treatment of drug dependence has been the very strong empirical support for contingency management (CM) approaches, in which participants receive incentives (e.g., vouchers redeemable for goods and services, chances to draw prizes from a bowl) that are contingent on demonstrating acquisition of treatment goals (e.g., submitting drug-free urine specimens, attending treatment sessions) (Higgins et al. 1991, 1994, 2003; Petry and Martin 2002; Silverman et al. 1996). Given that CM has strong immediate effects that tend to weaken after the contingencies are terminated, whereas CBT tends to have more modest effects initially but is comparatively durable, several investigators have begun to evaluate various combinations of CBT and CM, reasoning that the relative strengths and weaknesses of these may be offset by combining them. For example, Rawson et al. (2002) recently compared group CBT, voucher CM, and a CBT-CM combination in conjunction with standard methadone maintenance treatment for cocaine-using methadone maintenance patients. During the acute phase of treatment, the group assigned to CM had significantly better cocaine use outcomes. However, during the follow-up period, a CBT sleeper effect emerged again, where the group assigned to CBT essentially caught up to the other groups by the 52-week follow-up. Similar results were found for a parallel study conducted among a large sample (N = 171) of stimulant-dependent individuals treated as outpatients (Rawson et al. 2006), in which CM was associated with better retention and substance use outcomes during treatment, but outcomes for CBT and CM were comparable at 1 year. Epstein et al. (2003) conducted a similar study, again in the context of intensive methadone maintenance, in which participants were offered CM, group CBT, or a combination of the two, in addition to standard individual counseling. Results were largely parallel to the Rawson study in that the investigators reported large initial effects for CM, with a drop-off after the termination of the contingencies, and best 1-year outcomes for the CBT-CM combination.

Alcohol Dependence There is a very extensive and strong literature on the efficacy of CBT with alcohol use disorders (Irvin et al. 1999; Marlatt and Donovan 2005; Miller and Wilbourne 2002; Miller et al. 1995; Morgenstern and Longabaugh 2000) and hence the review below will be rather selective, highlighting just a few of the landmark studies in this area. In one of the earliest studies of CBT, Chaney et al. (1978) evaluated a CBT skills training approach as compared with a discussion control and no treatment condition for 40 alcohol-dependent inpatients. The CBT approach was associated with significant treatment effects for several, but not all, alcohol outcomes evaluated at a 1-year follow-up. Significant differences in acquisition of coping skills were seen posttreatment for groups receiving CBT versus the control group and groups receiving no treatment, with some degradation of skills seen at follow-up. Once the efficacy of CBT was established, several investigators began to evaluate what type of individual might have better or poorer response to CBT as compared with other treatments. Kadden et al. (1989) compared a cognitive-behavioral coping skills approach with an interactional approach for 96

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alcohol aftercare patients. This was explicitly a matching study, rather than a main effects "horse race" study. Thus, no main effects of study treatments were seen, but several of the investigators' a priori matching hypotheses were confirmed. That is, participants higher in sociopathy had better outcome (as measured by abstinent days or heavy drinking days) when treated with CBT, and patients lower in sociopathy had better outcome when treated with the interactional approach. For patients higher in psychopathology, CBT was superior. For patients higher in neuropsychological impairment, the interactional therapy was superior. A 2-year follow-up showed the matching effects were durable (Cooney et al. 1991). CBT was also evaluated in Project MATCH, a very large multisite trial that sought to identify patient– treatment matches for three individual therapies in a large sample of alcohol-dependent individuals (Project MATCH Research Group 1993). Although drinking outcomes were fairly good and sustained across all conditions, CBT was not associated with improved drinking outcomes with respect to the two treatments to which it was compared, TSF and motivational enhancement therapy (MET) (Project MATCH Research Group 1998a, 1998b). Furthermore, the multiple a priori hypotheses regarding the types of individuals who might respond better to CBT compared with TSF and MET were largely not supported. These findings, and the very sparse literature on support for mechanisms of action of CBT and other therapies (Morgenstern and Longabaugh 2000), have underlined both the need for more careful study of potential active ingredients of CBT as well as common factors associated with outcome (Longabaugh et al. 2005). Several investigators have also evaluated CBT in combination with the newly available medications for alcohol abuse and dependence. O'Malley et al. (1992) compared coping skills therapy, which included CBT skills, with supportive therapy in a two-by-two factorial design that also evaluated naltrexone versus placebo, for 97 alcohol-dependent patients. Naltrexone was found to be superior to placebo on several drinking-related outcomes, but significant main effects for the psychotherapy condition were not seen. However, there were significant psychotherapy–pharmacotherapy interactions, with the highest rates of complete abstinence seen in subjects who received the naltrexone–supportive therapy condition. However, significantly fewer drinks per day and fewer drinks per drinking occasion were reported for subjects who received the naltrexone–coping skills condition. A 6-month follow-up also indicated that subjects who had received the naltrexone–coping skills treatment were least likely to relapse, and once again, participants assigned to the CBT/placebo caught up to the other groups by the end of the follow-up in terms of reducing alcohol use (O'Malley et al. 1996).

Marijuana Dependence Despite increased demand for effective interventions for marijuana dependence, only a few randomized clinical trials evaluating well-defined treatments for individuals with a primary problem of marijuana dependence have been conducted to date, virtually all of which have included a CBT component. Stephens et al.'s (1994) comparison of a CBT group to a social support interactional group for 212 marijuana-dependent adults suggested that although both treatments were associated with significant and sustained reductions in reported marijuana use, there were no significant effects by treatment condition. The Marijuana Treatment Project, a large multisite trial, randomized 450 adult marijuanadependent individuals to a nine-session individual treatment that combined motivational interviewing and CBT, a two-session motivational intervention, or a delayed-treatment control condition. Participants assigned to the nine-session CBT intervention reduced their frequency of marijuana use and associated consequences significantly more than those assigned to the two-session intervention. Moreover, both interventions were associated with significantly greater reductions in marijuana use compared with the delayed-treatment control condition (MTP Research Group 2004; Stephens et al. 2002). Our group has also had very good results and has again seen continuing improvement associated with CBT by combining CBT and CM as a treatment strategy for young marijuana users involved with the criminal justice system (Carroll et al. 2006).

Individual Versus Group CBT

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Two trials have directly compared the delivery of relapse prevention in individual versus group format. Schmitz et al. (1997) compared outcomes following 12 sessions of either group or individually delivered relapse prevention as aftercare among 32 cocaine-dependent individuals after hospitalization. No significant differences were found in outcome through a 6-month follow-up. Given the small sample size, it should be noted that the groups were also small (3–7 members) and thus may have offered fairly substantial individual attention. In a larger study involving 155 both alcohol- and drug-using individuals, Marques and Formigoni (2001) also found no differences in outcome for group versus individually delivered CBT. While preliminary, these studies suggest that CBT can be effectively implemented in either group or individual formats.

COGNITIVE-BEHAVIORAL TECHNIQUES AND STRATEGIES Specific techniques vary widely with the type of cognitive-behavioral treatment used, and there are a variety of manuals, protocols, and training programs available that describe the techniques associated with each approach (Annis and Davis 1989; Carroll 1998; Kadden et al. 1992; Marlatt and Gordon 1985; Monti et al. 1989). Very simply put, however, most CBT approaches attempt to help individuals recognize the situations in which they are most likely to use, avoid those situations when appropriate, and cope more effectively with a range of problems and problematic behaviors associated with substance use by implementing a range of cognitive and behavioral coping strategies.

Defining Features of CBT Two key defining features of most cognitive-behavioral approaches for substance use disorders are 1) an emphasis on functional analysis of drug use (that is, understanding drug use with respect to its antecedents and consequences); and 2) emphasis on skills training. Cognitive-behavioral approaches involve a range of skills necessary to foster or maintain abstinence. These typically include strategies for 1) understanding the patterns that maintain drug use and developing strategies for changing these patterns (this often involves self-monitoring of thoughts and behaviors that take place before, during, and after high-risk situations or episodes of drug use); 2) fostering the resolution to stop substance use through exploring positive and negative consequences of continued use (also known as the decisional balance technique); 3) understanding craving and craving cues and developing skills for coping with craving when it occurs (these include a variety of affect regulation strategies, such as distraction, talking through a craving, "urge surfing" and so on); 4) recognizing and challenging the cognitions that accompany and maintain patterns of substance use; 5) increasing awareness of the consequences of even small decisions (e.g., which route to take home from work) and the identification of seemingly irrelevant decisions that can culminate in high-risk situations; 6) development of problem-solving skills and practicing the application of those skills to substance-related and more general problems; 7) planning for emergencies and unexpected problems and situations that can lead to high-risk situations; and 8) developing skills for assertively refusing offers of drugs, as well as reducing exposure to drugs and drug-related cues. These basic skills are useful in their application to helping patients control and stop substance use, but it is essential that therapists also point out how these same skills can be applied to a range of other problems. For example, functional analysis can be used to understand the determinants of a wide range of behavior patterns; skills used to cope with craving can easily be applied to other aspects of affect control; the principles used in the sessions on seemingly irrelevant decisions can easily be adapted to understanding a wide range of behavior chains; and substance use refusal skills can easily be transferred to more effective and assertive responding in a number of situations. We think it is essential that therapists who teach coping skills emphasize and demonstrate that those skills can be applied immediately to control substance use and also can be used as general strategies across a wide range of situations and problems the patient may encounter in the future. Broad-spectrum cognitive-behavioral approaches, such as those described by Monti et al. (1989) and adapted for use in Project MATCH (Kadden et al. 1992), expand to include interventions directed to other problems in the individual's life that are seen as functionally related to substance use. These

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interventions may include general problem-solving skills, assertiveness training, strategies for coping with negative affect, awareness of anger and anger management, coping with criticism, increasing pleasant activities, enhancing social support networks, and job-seeking skills, among others (Carroll 1999). In comparison to many other behavioral approaches, CBT is typically highly structured. That is, CBT is generally brief (12–24 weeks) and organized closely around well-specified treatment goals. An articulated agenda usually exists for each session and the clinical discussion remains focused around issues directly related to substance use. The therapist takes an active stance throughout treatment, and progress toward treatment goals is monitored closely and often, with frequent testing for substance use through urine toxicology screens. Generally sessions take place within a weekly scheduled therapy hour, and in broad-spectrum cognitive-behavioral approaches, they often are organized roughly in thirds (the 20/20/20 rule). The first third of the session is devoted to the assessment of the patient's substance use and general functioning in the past week and a report of current concerns and problems. The second third is more didactic and devoted to skills training and practice. The final third allows time for the therapist and the patient to plan for the week ahead and discuss how new skills will be implemented (Carroll 1998). The therapeutic relationship is seen as principally collaborative. Thus, the role of the therapist is one of consultant, educator, and guide who can lead the patient through a functional analysis of his or her substance use, aid in identifying and prioritizing target behaviors, and consult in selecting and implementing strategies to foster the desired behavioral changes. While structured and didactic, CBT is a highly individualized and flexible treatment. That is, rather than viewing CBT treatment as cookbook psychoeducation, the therapist carefully matches the content, timing, and nature of presentation of the material to the individual patient. The therapist attempts to provide skills training at the moments the patient is most in need of them. That is, the therapist does not belabor topics such as breaking ties with cocaine suppliers with a patient who is highly motivated and has been abstinent for several weeks. Similarly, the therapist does not race through material in an attempt to cover all of it in a few weeks; for some patients, it may take several weeks to master a basic skill.

Extra-Session Practice as a Possible Mediator of CBT In CBT, therapists encourage patients to practice new skills; such practice is a central and essential component of treatment. The degree to which the treatment is a skills training over merely a skills exposure approach has to do with the degree to which there is opportunity to practice and implement coping skills, making extra-session practice and homework all the more important. It is critical that patients have opportunities to try out new skills within the supportive context of treatment. Through first-hand experience, patients can learn what new approaches work or do not work for them, where they have difficulty or problems, and so on. There are many opportunities for practice within CBT, both during sessions and outside of them. During each session, there are opportunities for patients to rehearse and review ideas, raise concerns, and get feedback from the therapist. As noted earlier, there has been growing interest in understanding not only which treatments work, but how they work. Understanding the mechanisms of action of CBT and other empirically validated therapies has heretofore received very little attention in the literature (Kraemer et al. 2002; Morgenstern and Longabaugh 2000; Weisz et al. 2000), although it is an area of great importance. Understanding treatment mechanisms can not only advance the development of more effective treatment strategies but also result in more powerful, efficient, and ultimately less expensive treatments (Kraemer et al. 2002; Wilson et al. 2002). The converging evidence suggesting that CBT is a particularly durable approach has led to increased focus on unique or distinctive aspects of CBT that might account for its durability. Encouraging clients to implement and practice skills outside of sessions through homework assignments is one possible mechanism for this effect (Beck et al. 1979; Edelman and Chambliss 1995; Primakoff et al. 1986) and emphasis on extra-session practice assignments is a unique feature of CBT (Blagys and Hilsenroth

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2002). Moreover, investigators evaluating CBT in nonsubstance psychiatric disorders have noted the importance of homework in CBT's effectiveness. Some recent work suggests that homework compliance may have a causal effect on symptom reduction in CBT for depression (Addis and Jacobson 2000; Burns and Spangler 2000) and that ratings of the quality of the patient's homework predict outcome in CBT for panic disorder (Schmidt and Woolaway-Bickel 2000). The relationship of homework compliance, skills acquisition, and outcome in CBT has received very little attention in the substance abuse literature. Thus, in a recent trial (Carroll et al. 2005), we evaluated homework completion in detail, collecting data on the specific type of homework assigned and how well it was done (e.g., fully, partially, no attempt made) at every session. We found strong relationships between homework compliance and outcome. Compared with the participants assigned to CBT who did not do homework or who did it only rarely, the participants who did homework consistently stayed in treatment significantly longer, had more consecutive days of cocaine abstinence (a strong predictor of long-term outcome [Carroll et al. 1994b; Higgins et al. 2000]), had significantly more days of abstinence, and had fewer cocaine-positive urine screens during treatment. Similar effects were found for the subset of participants who completed treatment in this study, suggesting that the effects of homework compliance on better substance use outcomes were not completely accounted for by differential retention. In addition, we found strong relationships between homework compliance and acquisition of coping skills, as well as between homework completion and participants' ratings of their confidence in avoiding use in a variety of high-risk situations. Participants who completed homework had significant increases over time in their self-reported confidence in handling a variety of high-risk situations, while scores for the subgroup that did not do homework did not change over time. These findings have been partially supported by other groups (Gonzalez et al. 2006). Farabee et al. (2002) evaluated the extent to which cocaine users reported engaging in a series of specific drug avoidance activities (e.g., avoiding drug-using friends and places where cocaine would be available, exercising, using thought-stopping) after CBT as compared with alternative treatments (e.g., CM and a control condition). They found that, by the end of treatment, participants assigned to CBT reported more frequent engagement in drug avoidance activities than participants in the comparison treatments. Furthermore, the frequency of drug avoidance activities was strongly related to better cocaine use outcomes throughout the 1-year follow-up. Taken together, these two studies suggest that CBT interventions that foster the patients' engagement in active behavioral change may play a key role in CBT's comparative durability and should be pursued in future research.

TRAINING AND COMPETENCE IN CBT The growing evidence base for CBT and the increased emphasis on incorporating empirically supported therapies into clinical practice have also led to greater focus on training and dissemination. Although standard methods, such as intensive didactic workshop training plus structured feedback on supervised training cases, used to train clinicians to use CBT in clinical efficacy trials have generally been associated with high levels of treatment fidelity and comparatively small levels of variation in treatment delivery (Carroll 1998; Crits-Christoph 1998), these methods have not been empirically evaluated, nor are they commonly used to train clinicians to use novel approaches (Weissman et al. 2006). Thus, we have initiated a series of studies systematically evaluating different training strategies for clinicians wishing to learn empirically supported therapies such as CBT by randomizing clinicians working full-time in substance abuse treatment facilities to different training conditions. In our initial study of CBT training methods (Sholomskas et al. 2005), 78 clinicians were assigned to one of three training conditions: 1) review of the National Institute on Drug Abuse (NIDA) CBT manual only (Carroll 1998); 2) access to a Web-based training site (which included additional frequently asked questions, role plays, and practice exercises) plus the NIDA CBT manual; or 3) a 3-day didactic seminar plus up to three sessions of supervision from a CBT expert trainer based on actual session tapes submitted by the participants. Outcomes focused on clinician behavior and included between-group comparisons of the clinicians' ability to demonstrate key CBT techniques based on structured role-plays administered before and after training and scores on a CBT knowledge quiz. The videotaped role-plays were scored by

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independent raters, blind to the participants' training condition as well as time (e.g., pre- versus posttraining), and based on adherence/competence ratings of specific CBT techniques from the Yale Adherence and Competence Scale (YACS) (Carroll et al. 2000b). Although all groups demonstrated improved adherence and competence scores over time, the only training condition that reached levels of skill consistent with those required of clinicians participating in our CBT efficacy trials was the seminarplus-supervision condition, with intermediate ratings for the Web condition. The mean effect size for the seminar-plus-supervision condition compared with the manual-only condition was consistent with a large effect (.69), while the average effect size for the Web condition as compared with the manual only condition was consistent with a medium size effect (0.30). In addition, as shown in Figure 24–1, the seminar plus supervision condition was associated with significantly more clinicians reaching criterion levels for adequate fidelity than those assigned to the manual-only condition (54% versus 15%). FIGURE 24–1. Percentage of clinicians trained to criterion, by training condition.

These findings underscore the idea that merely making manuals available to clinicians has little enduring effect on clinicians' ability to implement new treatments. This has important implications for current efforts to disseminate new treatments. Our findings suggest that face-to-face training followed by direct supervision and credentialing may be essential for effective technology transfer and may raise questions regarding whether practitioners should feel competent (from an ethical perspective) to administer an empirically supported treatment on the basis of reading a manual alone. Finally, the findings suggest that standard strategies used to train clinicians in clinical trials can be effective for community-based clinicians and may be pursued as a strategy for future dissemination trials and bridging the gap between research and practice (Carroll and Rounsaville 2007).

LIMITATIONS OF CBT Despite CBT's emerging empirical support, future research is needed to address its limitations. CBT is a relatively complex approach in that it is comparatively complicated to train clinicians to use this approach or to implement it effectively in clinical practice. Potential strategies for addressing these issues include greater emphasis on understanding CBT's mechanisms of action, so that ineffective components of CBT can be removed and treatment delivery simplified and shortened, and perhaps even automated via delivery by computer or other means (Carroll and Rounsaville 2007). Another relative weakness of CBT may be the cognitive demands it places on patients, in that they are asked to learn a range of new concepts and skills, including monitoring and remembering cognitions and inner states, implementing new skills while in stressful situations, and so on. Recent data suggest that substance users with higher levels of cognitive impairment may have poorer outcome in CBT than those who are less impaired (Aharonovich et al. 2003; Kadden et al. 1989). This suggests that clinicians should

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monitor the cognitive skills of their patients, and in cases where the patients may have memory, attention, or impulse control problems, clinicians should adapt the implementation of CBT accordingly, with slower progression through concepts, frequent repetition of material and checking back with the patient to assess understanding, and providing more structure on extra-session assignments.

SUMMARY CBT is an empirically supported behavioral approach that has strong theoretical and empirical support with a variety of substance-abusing populations. In recent years, clinical researchers have emphasized moving these approaches more broadly into the clinical community, and thus a range of practical resources (e.g., books, videotapes, manuals, training resources and programs) for implementing them effectively in clinical practice are available. Moreover, these approaches can be combined and integrated effectively with a range of other empirically supported behavioral therapies (Barrowclough et al. 2001; Budney et al. 2000) as well as pharmacotherapies. Thus, they should be a component of all substance abuse clinicians' repertoire.

KEY POINTS Cognitive-behavioral therapy (CBT) has strong empirical support across a range of different substance use disorders as well as psychiatric syndromes that frequently co-occur with substance use disorders (e.g., depression, anxiety). CBT is highly compatible with available pharmacotherapies for addiction, and recent evidence suggests it can be delivered in a range of formats and settings. Key components of virtually all CBT approaches include functional analyses of substance use and individualized skills training with emphasis on cognitive and behavioral coping. Effects of CBT appear to be comparatively durable, with several studies reporting continuing improvement after patients leave treatment. Emphasis on skills training and practice may underlie this effect. A variety of manuals, videotapes, and other training materials for CBT may be available. However, specialized coaching and feedback, with structured supervision, may be needed for many clinicians to implement CBT effectively.

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[PubMed] Stephens RS, Roffman RA, Simpson EE: Treating adult marijuana dependence: a test of the relapse prevention model. J Consult Clin Psychol 62:92–99, 1994 [PubMed] Stephens RS, Roffman RA, Curtin L: Comparison of extended versus brief treatments for marijuana use. J Consult Clin Psychol 68:898–908, 2000 [PubMed] Stephens RS, Babor TF, Kadden R, et al: The Marijuana Treatment Project: rationale, design, and participant characteristics. Addiction 97:109–124, 2002 [PubMed] Stitzer ML, Iguchi MY, Kidorf M, et al: Contingency management in methadone treatment: the case for positive incentives, in Behavioral Treatments for Drug Abuse and Dependence. Edited by Onken LS, Blaine JD, Boren JJ. Rockville, MD, National Institute on Drug Abuse, 1993, pp 19–36 Thompson T, Pickens RW: Stimulus Properties of Drugs. New York, Appleton-Century-Crofts, 1971 Weissman MM, Verdeli H, Gameroff MJ, et al: National survey of psychotherapy training in psychiatry, psychology, and social work. Arch Gen Psychiatry 63:925–934, 2006 [PubMed] Weisz JR, Hawley KM, Pilkonis PA, et al: Stressing the (other) three Rs in the search for empirically supported treatments: review procedures, research quality, relevance to practice and the public interest. Clinical Psychology: Science and Practice 7:243–258, 2000 Wikler A: Dynamics of drug dependence: implications of a conditioning theory for research and treatment. Arch Gen Psychiatry 28:611–616, 1973 [PubMed] Wilson GT, Fairburn CG, Agras WS, et al: Cognitive-behavioral therapy for bulimia nervosa: time course and mechanisms of change. J Consult Clin Psychol 70:267–274, 2002 [PubMed]

SUGGESTED READING Marlatt GA, Donovan D: Relapse Prevention: Maintenance Strategies in the Treatment of Addictions, 2nd Edition. New York, Guilford, 2005 Marlatt GA, Gordon JR: Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors. New York, Guilford, 1985 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 25. Motivational Enhancement

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Carlo C. DiClemente, Miranda Garay, Leigh Gemmell: Chapter 25. Motivational Enhancem ent, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.353214. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Motivational Enhancement Carlo C. DiClemente, Ph.D., A.B.P.P. Miranda Garay, B.A. Leigh Gemmell, Ph.D.

MOTIVATIONAL ENHANCEMENT: INTRODUCTION Patient motivation is a necessary ingredient in substance abuse treatment and recovery. Because of the reinforcing nature of addictive substances and the physiological and psychological reliance they engender, individuals with problematic and dependent patterns of substance use often refuse to acknowledge problems or seek treatment. Even when substance abusers arrive at a treatment program, many are ambivalent about the need to modify their substance use and resist any notion that they need to reduce their use or abstain completely. Going to treatment is not a panacea that turns ambivalence and lack of readiness into commitment to change—a significant number of individuals who enter a treatment facility fail to complete the treatment and many drop out after intake or a single session (Simpson and Joe 1993; Wickizer et al. 1994). Engagement in substance and alcohol abuse treatment is sporadic. Even those who comply and complete treatment do not always achieve stated goals. Reluctance to seek help, attrition, and relapse are significant problems facing treatment providers as they try to help individuals who abuse drugs and alcohol along the path to recovery. All of these barriers are connected in some way to patient motivation. Earlier in the history of substance abuse treatment, motivation for recovery and treatment was viewed as the total responsibility of the patient. Treatment professionals believed that interventions would not work until the alcohol- or drug-dependent individual reached his or her personal "bottom" and brought the needed motivation to change with him or her into treatment. Little was done to help the unmotivated other than confronting them vigorously about their denial or waiting until they experienced sufficient losses or consequences to admit problems and seek help from treatment providers. Unmotivated individuals often were turned away from treatment or told to attend mutual help meetings (Alcoholics Anonymous, Narcotics Anonymous) in the hope that the testimony of peers would increase their motivation. Larger social systems became frustrated with this lack of motivation and began to use incarceration or mandated treatment to manage substance abuse problems (Loue 2003). Such coercion increased treatment attendance but not necessarily motivation to change. Since the late 1980s, there has been a significant shift in how society and the treatment community understand and address the problem of patient motivation in substance abuse. Public health approaches have encouraged aggressive screening of vulnerable populations (DiClemente 2005; Fleming et al. 2002). Courts, private companies, and professional sporting leagues have begun referring patients to treatment and seeking the collaboration of treatment providers in managing substance abuse (Turner et al. 2002). A more recent model of behavior change enumerated five stages of change and outlined specific tasks that occur even before individuals begin to take action (DiClemente 2003; Prochaska et al. 1992). More and more frequently, treatment providers are being asked to motivate and not just educate or medicate substance-abusing patients. Fortunately, demands on providers to become more involved in patient motivation have been accompanied by advances in treatment perspectives and strategies that focus on increasing patient motivation (Miller and Rollnick 2002; Petry 2006; Smith and Meyers 2004). Motivational considerations

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are now viewed as critical for engagement in treatment and modification of substance use (e.g., American Society of Addiction Medicine [ASAM] Patient Placement Criteria) and motivational enhancement approaches are becoming an integral part of most outreach, detoxification, and treatment programs. This chapter offers an overview of motivational considerations, highlights how motivational enhancement approaches are being used, and briefly reviews research regarding the application and efficacy of these approaches in the management and treatment of alcohol and drug abuse problems.

WHAT IS MOTIVATION? Motivation is a complex phenomenon and should not be compared to an on-off mechanism. Most patients are not unmotivated to quit their drug or alcohol use but are simply more motivated to engage in behaviors other than those desired by treatment providers. The challenge is to engage substance abusers in treatment and assist them in moving through a multidimensional process of change that leads to recovery. This process is described as the "stages of change" (DiClemente 2003) and involves five distinct steps that individuals take in order to create a sustainable behavioral change. The first stage is precontemplation, in which the individual is not interested in change and the therapist's task is to help the patient become interested and concerned about the need for change. Once interested, the individual moves through the contemplation stage by engaging in a risk-reward analysis that leads to a firm decision to change. This is followed by the preparation stage, in which the patient creates an effective and acceptable change plan while increasing commitment for implementing the plan. All of the mentioned tasks must be accomplished to some degree in order for a substance abuser to move through the stages of precontemplation, contemplation, and preparation before actually taking successful action to modify substance use. The action stage includes stopping the problematic pattern of behavior and beginning to establish a new pattern of abstinence or modified drinking or drug use behaviors, which is estimated to take 3–6 months. Maintenance, the final stage and task of the process, is when the new behavior is integrated into the lifestyle of the recovering substance abuser and maintained over time. Patient motivation involves the completion of all of these stages well enough to support and sustain successful recovery (Carbonari and DiClemente 2000). It is important to acknowledge that there are other perspectives on motivation. Some believe that individuals can engage in a behavior without being completely motivated or, "fake it until they make it." This can be a strategy to deal with ambivalence, but eventually, it seems reasonable to assume that the tasks of the change process need to be completed as the individual moves from faking to making the change (Fletcher 2001). A behavioral economics perspective uses contingency management techniques (rewarding drug-free urine tests) to get people to stop engaging in a behavior for a time and has been effective in helping patients achieve abstinence from drugs and alcohol (Vuchinich and Heather 2003). However, an individual must ultimately find or identify some personal contingencies or internal reasons to stop abusing substances in order to maintain abstinence once external contingencies are terminated (Petry 2006).

MOTIVATIONAL ENHANCEMENT INTERVENTIONS Motivational enhancement most specifically refers to the motivational interviewing strategies and approaches that focus on patient ambivalence, decision making, and commitment in order to stimulate movement through the initial stages of the patient process of change (Miller and Rollnick 2002). However, motivation is needed to sustain action and prevent relapse, as well as to move through the initial stages of making the decision to change, increasing commitment, and planning. Thus, motivational enhancement is probably best defined as employing strategies and approaches that enhance the ability of an individual to achieve key tasks of the stages of change and advance in the change process (DiClemente 2003). Although mental health care providers have to be ready to help problematic or unmotivated patients progress though each of the stages of change, they may not have to assist with every one of these tasks; many individuals accomplish some or all of the tasks on their own prior to, during, or following treatment, and at times even without the assistance of treatment (DiClemente 2006).

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A number of interventions and strategies that focus on internal and external dimensions of motivation have been developed and are designed to influence patient engagement in and movement through the process of recovery and change. The most well-known approach to addressing patient motivation is motivational interviewing (MI), developed by Miller and Rollnick (2002). MI encompasses a style of patient–provider interaction that includes strategies focused specifically on motivation, decision making, and resolving ambivalence. Initially, MI approaches were used in brief interventions that gave Feedback to patients about the problem, emphasized personal Responsibility, offered Advice and a Menu of options, used an Empathic approach, and supported the patient's sense of Self-efficacy or confidence that he or she could make the change (FRAMES). In interventions such as the drinker checkup program, for example, individuals with alcohol problems were evaluated and given feedback and advice over short periods of time or in one or two sessions of consultation (Bien et al. 1993; Miller et al. 1988). MI approaches have been incorporated into more formal intervention or treatment programs in a number of ways. Adaptations of MI include brief interventions in opportunistic settings, such as emergency departments (Longabaugh et al. 2001), developing treatment engagement strategies to be used prior to more extensive treatment (Carroll et al. 2006), and developing a motivational enhancement therapy (MET) that has been manualized and used in research projects and treatment programs. MET was first used in outpatient and aftercare settings in the large multisite alcoholism treatment trial called Project MATCH (Matching Alcoholism Treatment to Client Heterogeneity; Miller et al. 1992). Other researchers and clinicians have developed interventions that integrate MI approaches into stage-based approaches, thereby matching the interventions to stages of change (DiClemente et al. 1992; Substance Abuse and Mental Health Services Administration 1999; Velasquez et al. 2001). In an effort to incorporate family members into the process, Smith and Meyers (2004) have created familyand community-based approaches of MI to increase motivation and encourage treatment entry with patients in the early stages of change. Additionally, the ARISE approach (A Relational Intervention Sequence for Engagement; Landau et al. 2004) uses family members to assist in engaging patients in treatment and promoting change. Finally, contingency management approaches use monetary and other rewards to reinforce abstinence behaviors, thereby creating incentives for movement toward change and initiation of abstinence (Petry 2006; Vuchinich and Heather 2003). Although there are a number of ways to manipulate and increase patient motivation, this chapter will focus primarily on stimulating change through MI and stage-based approaches because these have become widespread among the treatment community and have been studied in a variety of intervention settings. We will use the term motivational enhancement to describe the various types of intervention and treatment strategies that use MI and stage-based approaches.

MOTIVATIONAL ENHANCEMENT IN ALCOHOL TREATMENT To date, there have been two very large, multisite, randomized controlled trials with alcohol-abusing and dependent participants that examined the effectiveness of MET compared with other nonpharmacological interventions. The first of these, Project MATCH, consisted of two parallel studies, each consisting of 12 weeks of treatment delivered as outpatient or aftercare, that were designed to examine the differential effects of three manualized treatments in alcohol-dependent or alcohol-abusing participants (Project MATCH Research Group 1997a). Participants were randomly assigned to receive 12 sessions of cognitive-behavioral therapy (CBT), 4 sessions of MET, or 12 sessions of an individual therapy called 12-step facilitation (TSF) delivered over 12 weeks. All participants were followed for 1 year posttreatment, and outpatients also received follow-up at 3 years posttreatment. Although there was little support for matching, which would have indicated differential effects of treatments based on participant characteristics, all three of these treatments improved alcohol-related outcomes at follow-up and there were no substantial differences between the treatments. With this alcohol-dependent population, a four-session MET intervention performed as well as the more comprehensive 12-session treatments in improving drinking outcomes, although patients in MET drank more during the treatment period. The second large, multisite, randomized controlled study was the United Kingdom Alcohol Treatment

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Trial (UKATT), which compared the effects of MET and social behavior and network therapy (SBNT) on alcohol-related outcomes in alcohol-dependent or alcohol-abusing participants (UKATT Research Team 2001). Treatment for the SBNT group consisted of eight sessions using cognitive-behavioral strategies and techniques to help participants create positive social support networks that were meant to help change drinking behaviors. The MET group received three sessions over an 8-week period. Participants were followed for 1 year. The results of this study indicated that both MET and SBNT were effective interventions in producing reductions in drinking and improving abstinence outcomes (UKATT Research Team 2005). The findings from Project MATCH and UKATT are consistent in demonstrating that participants who received three or four sessions of MET did as well as participants who received cognitive-behavioral or social support types of treatment for a longer period of time. MET consists of an assessment of alcohol history, patterns, problems, and consequences; provides objective feedback using empathy; engages the patient in a discussion of drinking and lifestyle using MI techniques (reflection, affirming, summarizing, rolling with resistance, and avoiding argumentation); and works with the patient to overcome ambivalence and to create a patient-driven change plan. This type and amount of support and direction appears to be sufficient to engage the change process and motivate modification of drinking behavior. It should be noted that this approach may be more helpful when patients are high in state/trait anger (hostility and anger control) and that patients with drinking-saturated environments may need more long-term support for sobriety from mutual help groups (Project MATCH 1997b, 1998). The role of motivation and the use of motivational enhancement strategies are being explored in alcohol-related pharmacotherapy trials as well (McCaul and Petry 2003). The COMBINE (Combining Medications and Behavioral Interventions) study was a randomized controlled trial that examined the independent and combined effects of medication and behavioral therapy on alcohol-related outcomes, such as abstinence from alcohol (Anton et al. 2006). The behavioral therapy component was called a combined behavioral intervention (CBI), and it included components of MI, CBT, and TSF. The results of this study indicated that CBI was a useful addition to medication management and naltrexone in improving drinking outcomes. Although this study did not examine the effects of MET alone, it provides initial support for the use of motivation-based interventions in conjunction with medication management to improve alcohol-related outcomes. Some brief adherence enhancement strategies that incorporate motivation-enhancing strategies are also being developed and used in some trials (Johnson et al. 2003; Volpicelli et al. 2001).

BRIEF MOTIVATIONAL INTERVENTIONS FOR ALCOHOL USE DISORDERS Brief interventions for individuals with alcohol problems have become respected and empirically supported strategies for reaching large numbers of individuals with hazardous, abusive, and dependent patterns of drinking. These interventions are generally conducted in a variety of settings, can occur in person or by telephone, and can be implemented in 10–15 minutes or extended to include several (e.g., two to four) sessions or contacts. Patients discuss their drinking, complete some assessment measures, and are given feedback and advice about their drinking (Miller et al. 1998), which is designed to be an incentive for altering problematic drinking (Babor et al. 2001; Holder et al. 2000). Although this type of proactive therapy has been used with a wide range of drinking patterns, from hazardous to dependent, most research has been done with individuals who abuse alcohol and have not yet developed a pattern reflecting alcohol dependence (U.S. Department of Health and Human Services 1997). Unlike more traditional treatments for problematic drinkers, this technique does not involve overtly confrontational tactics (Miller and Rollnick 2002). The lack of explicit confrontation is thought to reduce the defensiveness of targeted individuals who tend not to be self-referred and may not see any need for substance use treatment (Miller et al. 1998). Oftentimes, the goal of brief interventions is harm reduction rather than complete abstinence (U.S. Department of Health and Human Services 1997). Overall, brief interventions generally have been found to be effective (U.S. Department of Health and Human Services 1997). A meta-analysis of controlled studies comparing baseline with posttreatment

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alcohol measures found that brief interventions were quite effective and yielded high mean effect sizes (Cohen's d = 0.70–0.80) for problem drinkers (Bien et al. 1993). When brief interventions were compared with control groups that were assessed and advised, the effect size fell to 0.38, indicating that merely asking individuals about their drinking and related correlates may result in less drinking for some individuals (Bien et al. 1993). Moreover, this meta-analysis revealed that brief interventions were comparable to more extensive treatment in terms of treatment success. In fact, Miller et al. (1998) conducted a large meta-analysis of the effectiveness of treatments and found that brief motivational interventions had some of the best effect sizes in comparison with a large number of alternative treatments. Nevertheless, additional research is warranted to determine which individuals benefit most from these interventions, since there is some evidence that, for men, brief interventions may be more beneficial than merely screening for alcohol problems (this effect has not been found for women) (Babor and Grant 1992; Scott and Anderson 1991; U.S. Department of Health and Human Services 1997). A number of studies have examined brief interventions with problem drinkers, including drinkers with hazardous, binge, and abusive patterns of use. In much of the research on the "drinker checkup," a brief evaluation and consultation program for problem drinkers from the community, Miller et al. (1988) often excluded drinkers who met criteria for alcohol dependence and focused on problem drinkers. However, a more recent meta-analysis that evaluated high-quality, randomized controlled trials in primary care settings concluded that heavy drinkers had better outcomes with brief alcohol interventions than with no intervention, with an odds ratio of almost 2:1 (1.91) (Wilk et al. 1997). Some of the reviewed studies also suggested lower mortality and morbidity rates with brief interventions and decreases in health care costs (Edwards and Rollnick 1997; Miller et al. 1998). The success of brief interventions has led many groups to call for including them in many different health care settings—for example, the College of Surgeons is making screening and brief intervention for alcohol a part of the accreditation criterion for Level I trauma units (Committee on Trauma 2006), and other settings are recommending a stepped-care approach for working with problem drinkers who do not respond to brief interventions (Joseph et al. 1999). Brief interventions targeting vulnerable populations of drinkers require appropriate screening. One of the issues that must be addressed in implementing these programs is how to define the problem that would trigger the intervention. Problem drinking has been defined in a variety of ways in various settings and studies. Some use "at-risk drinking in the previous month or an alcohol use disorder in the past 12 months" as the screen (Taj et al. 1998), while others use screening instruments such as the CAGE Questionnaire or Alcohol Use Disorders Identification Test (AUDIT) either in part or in their entirety (for a review of instruments, see Fiellin et al. 2000). Taj et al. (1998) investigated the effectiveness of a single question, "On any single occasion during the past 3 months, have you had more than five drinks containing alcohol?" and compared the answer with responses to the AUDIT (Babor et al. 2001). Findings indicated that the question had a 74% positive predictive ability and an 88% negative predictive ability for problem drinking (sensitivity = 62%; specificity = 93%). Thus, this single question appears useful in screening for problem drinking but does not necessarily capture drinkers engaged in what are called hazardous drinking patterns as defined by daily or weekly levels of drinking (visit the National Institute on Alcohol Abuse and Alcoholism Web site for additional information: http://www.niaaa.nih.gov.ezproxy2.library.usyd.edu.au). A second concern and difficulty in studies examining brief interventions is whether they reach the population of individuals who need interventions the most. Edwards and Rollnick (1997), for instance, reviewed all published studies of brief interventions for drinking that were conducted in primary care settings and found that there were high levels of attrition in these studies. Although researchers rarely publish attrition analyses that describe how participants who dropped out or who were lost during study follow-up may differ from those who completed the study, this study found some evidence to suggest that the two groups are very different from each other: the former tended to be younger, less educated, and heavier drinkers.

MOTIVATIONAL ENHANCEMENT AND DRUG ABUSE

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Although there is less research exploring the use of MI and MET approaches to reduce drug use, there is a growing body of empirical studies that show them to be effective in motivating change and enhancing treatment entry and engagement with patients experiencing problems with substances other than alcohol, such as tobacco, marijuana, and cocaine. Much of the research that finds such positive effects suggests that when motivation-enhancing components precede more intense substance abuse treatment, retention in treatment increases (Martino et al. 2000; Saunders et al. 1995; Stotts et al. 2001; Swanson et al. 1999). A manual for implementing MET as a precursor to outpatient drug treatment is currently being tested in Clinical Trials Network studies of the National Institute on Drug Abuse (NIDA) (Carroll et al. 2002). This treatment consists of three sessions based on the study by Miller et al. (1992), which focus on problem identification and feedback, resolving ambivalence, and creating a change plan. Although some would argue that brief MET is as effective as a stand-alone treatment for substance use disorders, others object because of findings that link longer drug treatment to better outcomes (Simpson et al. 1997). However, MET is consistent with long-term treatment approaches; its philosophy can guide intervention and its techniques can be used during longer-term treatment, as long as treatment remains based on an individual's stage of change. Therefore, the Haight Ashbury Free Clinics have created and are testing a "higher dose motivational enhancement" manual (Polcin et al. 2004). The first three sessions are congruent with the ones mentioned as part of the NIDA study. The final eight sessions continue to employ motivational enhancement techniques and provide help in resolving continued ambivalence, reinforcing accomplishments and progress, addressing drug use and temptations to use, and allowing for revision of the change plan. Longer-term use of MET could be particularly beneficial if an individual does not quickly move from early (e.g., precontemplation) to later (e.g., action) stages of change.

Nicotine Although more research needs to be done in the area of nicotine addiction, there are a few studies that support the potential that MET has for reducing smoking. Home health care nurses have used MET with patients, which has led to more quit attempts and greater reductions in the number of cigarettes smoked daily than when patients received the standard care for smoking cessation (Borrelli et al. 2005). These benefits were maintained at 1 year posttreatment, and the percentage of individuals in the MET condition who quit smoking was double that of the standard care group. Other research compares adaptations of MI and MET—adapted motivational interviewing (AMI)—to the provision of authoritarian advice to quit smoking (Butler et al. 1999; Colby et al. 1998). Adults in an AMI group used fewer cigarettes in the 24 hours prior to assessment, increased the time between waking up and the first cigarette of the day, had more attempts to quit that lasted one week or more, and were more likely to move into a later stage of change (Butler et al. 1999). In an adolescent population, a 30-minute AMI session resulted in two-thirds of the sample attempting to quit smoking as well as significant reductions in smoking rate and dependence (Colby et al. 1998). Although AMI results were not significantly better than those following 5 minutes of brief advice, the effectiveness of AMI was supported. However, these types of interventions are not always effective with individuals with multiple problems (Velasquez et al. 2000), and even a four-session MET intervention with drug-abusing pregnant women was not found to be sufficient to motivate changes in smoking (Haug et al. 2004).

Marijuana The use of MET components has led to significant reductions in marijuana use for adults (Marijuana Treatment Project Research Group 2004; Sinha et al. 2003) and adolescents (Colby et al. 1998; Monti et al. 1999). In adults, MET and skills-based relapse prevention interventions both demonstrated decreases in marijuana-related problems and symptoms of dependence (Stephens et al. 2000). Although neither intervention outperforme the other, only 3 hours of MET was as effective as 28 hours of relapse prevention in increasing abstinence. The brevity of MET supports its use as a cost-effective alternative to more extensive care, particularly if an opportunity for lengthy care is not likely (e.g., with homeless populations not seeking treatment). Finally, a study comparing two sessions of MET, nine sessions of

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MET plus CBT, and a delayed-treatment control group showed that although the nine-session treatment performed the best, the two-session MET condition produced significant reductions in marijuana use among dependent adults and was as effective as MET plus CBT in increasing the use of coping skills (Litt et al. 2005). Findings in adolescent populations have not been as convincing but reflect that continued research is important and stronger effects may be found if more intensive treatment is provided (Melnick et al. 1997). A one-session MET intervention to address alcohol and marijuana use in homeless adolescents did not affect the use of these two substances, but the use of other illicit drugs at the 1-month follow-up decreased significantly (Peterson et al. 2006). A school-based study showed that adolescent marijuana users are willing to attend an intervention for use, even though significant decreases in marijuana use were observed in both the two-session MET intervention and a waitlist control group (Walker et al. 2006).

Cocaine Motivational enhancement is likely to be useful, particularly as a precursor to more intensive treatment, for individuals seeking help for cocaine misuse (DeLeon et al. 1997). Level of motivation has been found to influence success in treatment for cocaine abusers, suggesting that increasing motivation will increase success. In fact, those with low initial motivation to change who received MET reported lower rates of relapse to cocaine use and fewer days of cocaine use at the 1-year follow-up than those with high initial motivation (Rohsenow et al. 2004). This was the case despite lack of observable benefits at the 3- to 6-month follow-up periods, suggesting that even if immediate benefits of MET are not observed, effects may emerge up to 1 year posttreatment. In this study, MET was also predictive of decreased alcohol use and increased motivation, treatment expectations, perceived negative effects of cocaine, and self-efficacy to deal with high-risk situations. However, for individuals with high initial motivation to change, those receiving MET reported higher frequencies of cocaine use and more severe alcohol problems than did those with low motivation and those not receiving MET. Thus, it is possible that MET should only be used when motivation for change is low. This is reflective of the need to match intervention strategies to stage of change (DiClemente 2003). The type of change to which patients commit also has effects on treatment success. Specifically, those who commit to complete abstinence are less likely to relapse than those who commit to use reduction (Rohsenow et al. 2004). Thus, with cocaine users, it may be helpful not only to encourage change in MET but also to stress the importance of committing to complete abstinence.

Opiate and Polydrug Research on the effectiveness of MET for treating opiate and multiple drug addictions is lacking. Only one study was found that used an intervention for opiate addiction based on MI, and the intervention did not contain all of the components necessary to define it as MET (Saunders et al. 1995). Nevertheless, this study found that one intervention session plus one follow-up session resulted in decreased opiaterelated problems and greater compliance with treatment 6 months later. Significant reductions in actual use were not found. Individuals who injected multiple drugs were included in a study that provided either five 30-minute sessions of MET/AMI or risk-reduction sessions of equivalent intensity (Booth et al. 1998). The outcome, successfully completing the intake procedure for treatment entry, did not differ between the two groups. While MET/AMI has been shown to increase treatment entry in a number of drug use studies, strong support for the use of these methods has not been found in the area of opiates and multiple drug use, perhaps because of a lack of research. Although numerous studies have shown support for motivational techniques, some have not found effects on drug use outcomes (Booth et al. 1998; Donovan et al. 2001; Miller et al. 2003; Schneider et al. 2000). For example, Schneider et al. (2000) found that MI was no more effective in an employee assistance program than confrontational interviewing for substance abuse and thus concluded that both would afford similar benefits; however, motivational techniques provide an alternative for practitioners and patients who prefer to avoid a confrontational approach. Nonsignificant effects in these studies could

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be attributed to mismatching strategies with the patient's stage of change. When treatment is incongruent with where an individual is in the process of change (e.g., an individual is further along in the process of change than the intervention), resistance to treatment and change and/or dropout is more likely (Booth et al. 1998; Rollnick et al. 1992). Since stage status could be an important matching variable, it could also serve as an important outcome variable, since behavior change is not the only outcome one would expect from motivational enhancement approaches. Positive effects are seen even when interventions based on MET are provided by clinicians who are not substance abuse treatment specialists (Dunn et al. 2001). However, as with any other treatment, MET "must be provided with fidelity and skill" (Madson and Campbell 2006, p. 67). Clinicians planning to implement MET are encouraged to attend trainings and refer to primary sources of information about MET (Miller and Rollnick 2002; Miller et al. 1992); see also http://www.motivationalinterviewing.org). Integrating MET into the treatment plan of new patients entering treatment for any combination of drug problems is likely to demonstrate benefits, especially among those who report low motivation for change (Dunn et al. 2001) and are unready, unwilling, or unable to change (DiClemente 2003). Additionally, MET has been found to maintain its effects regardless of length of follow-up (Dunn et al. 2001) and effects can emerge at time points subsequent to initial posttreatment assessments.

MOTIVATIONAL ENHANCEMENT WITH DUALLY DIAGNOSED POPULATIONS Although there are concerns and skepticism regarding the severity of mental illness and cognitive impairment of individuals with substance abuse problems with whom MET would be used, there is a growing literature in this area. Motivational considerations and approaches are being recommended and tested with a variety of dually diagnosed individuals with different substances of abuse. Motivational enhancement interventions have often produced improved outcomes compared with control conditions in a range of alcohol and drug abuse patients, some of whom had coexisting psychiatric problems of varying degrees (Bien et al. 1993; Stotts et al. 2001). In a large, recent, multisite effectiveness study, Carroll et al. (2006) found that integrating MET into intake procedures increased retention but not short-term drug use outcomes. However, brief motivational interventions prior to treatment have not always improved treatment engagement and outcomes, particularly in populations of drug abusers who are poor, of minority status, less educated, and have multiple problems (Donovan et al. 2001; Miller et al. 2003). Motivational techniques based on MI principles have been viewed as promising in a systematic literature review of interventions for improving medication adherence and viewed as superior to more traditional psychoeducational approaches for dually diagnosed individuals (Ziedonis and Trudeau 1997; Zygmunt et al. 2002). Swanson et al. (1999) found that adding MI techniques to initial assessment increased the proportion of patients attending outpatient appointments overall and for a dually diagnosed group of patients. Others have found that MI and personalized feedback increased tobacco treatment engagement and attendance for individuals with serious mental illness (Steinberg et al. 2004). In a pilot study, Daley et al. (1998) found that a motivational intervention increased attendance and engagement and decreased rehospitalization among patients with depressive disorders and cocaine dependence. There are also some very innovative proactive programs reaching out to homeless, drug-abusing individuals with serious mental illness, where treatment providers go onto the streets and begin discussions on behavioral change using MI principles (Fisk et al. 2006). These findings are promising but much more needs to be done to evaluate how to use both brief interventions and motivational enhancement approaches with dually diagnosed individuals and, in particular, with individuals with serious mental illness and substance abuse. Nevertheless, initial findings indicate that it is possible to assess and intervene in order to motivate dually diagnosed individuals to move through the process of modifying substance use in ways that are similar to those described above, with some modifications and attention to the special needs of this population (DiClemente et al., in press).

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CONCLUSION Motivation is critical for making changes in substance-abusing behaviors. In order to overcome the common difficulties and barriers to the successful modification of problematic patterns of substance use and to recover from alcohol and drug dependence, individuals must negotiate a multidimensional path of change that requires decision making, choice, commitment, and coping activities. Motivation is needed to stimulate and negotiate accomplishment of these tasks. A number of very self-motivated individuals negotiate this path on their own without treatment. Others seem to benefit from brief motivational interventions to help them to activate the process. However, many others need treatment and assistance to consider, decide, plan, and commit to changing their problematic substance-using behaviors. Motivational enhancement approaches could be very helpful for all health care providers who treat problems that are related to substance abuse or who treat substance abuse directly. There are a number of ways that motivational enhancement techniques are being incorporated into interventions to assist individuals with problematic patterns of alcohol and drug use. Screening and brief interventions are being used to address problematic use more proactively in a variety of health care and opportunistic settings. This is particularly true for alcohol abuse; screening and brief motivational interventions are being offered in primary care offices, emergency departments, trauma centers, college health and student services, employee assistance programs, and other venues. At the same time, substance abuse treatment providers are developing pretreatment motivational enhancement approaches to prepare patients for treatment, increase engagement, and accelerate movement through the process of change, both in individual and group formats. Some treatment programs are using MET as one of the options that are given to patients, either as stand-alone treatment or as part of a more comprehensive, multicomponent treatment delivered as a package or in a stepped-care manner (offering more extensive treatments to individuals unable to change with less intensive, motivational approaches). Clearly, there are many ways to incorporate motivational enhancement and MI approaches into substance abuse interventions (Wagner and Conners 2007). It is also important to note that there are two key components of motivational enhancement approaches. The first represents a style or way of interacting with the patient that is patient-centered, nonconfrontational, empathic, respectful, and reflective in its advice giving (Miller et al. 1993). The second component consists of the techniques and strategies that are designed to influence motivation, resolve ambivalence, and elicit self-motivational statements and activities. These techniques include complex reflections, use of summaries to frame motivational messages, techniques to manage and roll with resistance, offering advice with permission, maximizing opportunities to affirm and build the patient's sense of efficacy to be able to implement change, and assisting the patient to create a realistic change plan rather than attempting to control the patient change process. Although the techniques are focused on the tasks that generally occur in the earlier stages of change, the style of MI and MET can be integrated into most treatment approaches and is compatible with use of pharmacotherapy, mutual help, and intensive psychosocial treatments. Over the past 15 years, there have been major advances in treatment options for patients with alcohol and drug abuse problems. Motivational enhancement approaches represent one of these advances that have extended the reach and effectiveness of existing interventions. The reach and impact of motivational enhancement approaches are only beginning to make a difference in the behaviors of substance abuse treatment providers.

KEY POINTS Motivation is a multidimensional concept that is critical to understanding recovery and providing substance abuse treatment. Motivation consists of the patient's readiness to change and engagement in the multiple tasks needed to successfully achieve and maintain sobriety, often identified by the stages of change.

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Motivational enhancement strategies can include brief interventions in opportunistic settings (e.g., emergency department, primary care, substance abuse testing or screening) and more extensive multisession treatment protocols. Motivational interviewing developed by Miller and Rollnick is both a style of interacting and a set of techniques that addresses patient ambivalence and lack of motivation. Although more research is needed (especially with more severe cases and in individuals with multiple diagnoses), studies generally support use of motivational interviewing and motivational enhancement for individuals with a broad range of substance abuse problems. More extensive research on motivational enhancement approaches has been done with alcohol problems followed by studies of nicotine and marijuana and fewer studies involving cocaine and opiates.

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main effects and matching effects on drinking during treatment. J Stud Alcohol 59:631–639, 1998 Rohsenow DJ, Monti PM, Martin RA, et al: Motivational enhancement and coping skills training for cocaine abusers: effects on substance use outcomes. Addiction 99:862–874, 2004 [PubMed] Rollnick S, Heather N, Bell A: Negotiating behaviour change in medical settings: the development of brief motivational interviewing. Journal of Mental Health 1:25–37, 1992 Saunders B, Wilkinson C, Phillips M: The impact of a brief motivational intervention with opiate users attending a methadone programme. Addiction 90:415–424, 1995 [PubMed] Schneider RJ, Casey J, Kohn R: Motivational versus confrontational interviewing: a comparison of substance abuse assessment practices at employee assistance programs. J Behav Health Serv Res 27:60–74, 2000 [PubMed] Scott E, Anderson P: Randomized controlled trial of general practitioner intervention in women with excessive alcohol consumption. Drug Alcohol Rev 10:313–321, 1991 [PubMed] Simpson DD, Joe GW: Motivation as a predictor of early dropout from drug abuse treatment. Psychotherapy 30:357–368, 1993 Simpson DD, Brown BS, Joe GW: Treatment retention and follow-up outcomes in the Drug Abuse Treatment Outcome Study (DATOS). Psychol Addict Behav 11:294–307, 1997 Sinha R, Easton C, Renee-Aubin L, et al: Engaging young probation-referred marijuana-abusing individuals in treatment: a pilot trial. Am J Addict 12:314–323, 2003 [PubMed] Smith JE, Meyers RJ: Motivating Substance Abusers to Enter Treatment: Working With Family Members. New York, Guilford, 2004 Steinberg ML, Ziedonis DM, Krejci JA, et al: Motivational interviewing with personalized feedback: a brief intervention for motivating smokers with schizophrenia to seek treatment for tobacco dependence. J Consult Clin Psychol 72:723–728, 2004 [PubMed] Stephens RS, Roffman RA, Curtain L: Comparison of extended versus brief treatments for marijuana use. J Consult Clin Psychol 68:898–908, 2000 [PubMed] Stotts A, Schmitz JM, Rhoades HM, et al: Motivational interviewing with cocaine dependent patients: a pilot study. J Consult Clin Psychol 69:858–862, 2001 [PubMed] Substance Abuse and Mental Health Services Administration (SAMHSA), Center for Substance Abuse Treatment: Enhancing motivation for change in substance abuse treatment, TIPS #35 (DHHS Publ No SMA-99-3354). Rockville, MD, U.S. Department of Health and Human Services, 1999 Swanson AJ, Pantalon MV, Cohen KR: Motivational interviewing and treatment adherence among psychiatric and dually diagnosed patients. J Nerv Ment Dis 187:630–635, 1999 [PubMed] Taj N, Devera-Sales A, Vinson DC: Screening for problem drinking: does a single question work? J Fam Pract 46:328–335, 1998 [PubMed] Turner S, Longshore D, Wenzel S, et al: A decade of drug treatment court research. Subst Use Misuse 37:1489–1528, 2002 [PubMed] UKATT Research Team: United Kingdom Alcohol Treatment Trial (UKATT): hypotheses, design, and methods. Alcohol Alcohol 36:11–21, 2001 UKATT Research Team: Effectiveness of treatment for alcohol problems: findings of the randomized UK alcohol treatment trial (UKATT). BMJ 331:541, 2005 U.S. Department of Health and Human Services: Ninth Special Report to the U.S. Congress on Alcohol and Health (NIH Publ No 97-4017). Bethesda, MD, National Institutes of Health, 1997

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Velasquez MM, Hecht J, Quinn VP, et al: Application of motivational interviewing to prenatal smoking cessation: training and implementation issues. Tob Control 9(suppl):36–40, 2000 Velasquez MM, Maurer GG, Crouch C, et al: Group Treatment for Substance Abuse: A Stage of Change Manual. New York, Guilford, 2001 Volpicelli JR, Pettinati HM, McClellan AT, et al: Combining Medication and Psychosocial Treatments for Addictions: the BRENDA Approach. New York, Guilford, 2001 Vuchinich RE, Heather N (eds): Choice, behavioural economics and addiction. New York, Pergamon, 2003 Wagner CC, Conners W: Motivational interviewing: resources for clinicians, researchers, and trainers. 2007. Available at: http://www.motivationalinterviewing.org. Accessed January 2, 2008. Walker DD, Roffman RA, Stephens RS, et al: Motivational enhancement therapy for adolescent marijuana users: a preliminary randomized controlled trial. J Consult Clin Psychol 74:628–632, 2006 [PubMed] Wickizer T, Maynard M, Atherly A, et al: Completion rates of clients discharged from drug and alcohol treatment programs in Washington State. Am J Public Health 84:215–221, 1994 [PubMed] Wilk AI, Jensen NM, Havighurst TC: Meta-analysis of randomized control trials addressing brief interventions in heavy alcohol drinkers. J Gen Intern Med 12:274–283, 1997 [PubMed] Ziedonis DM, Trudeau K: Motivation to quit using substances among individuals with schizophrenia: implications for a motivation-based treatment model. Schizophr Bull 23:229–238, 1997 [PubMed] Zygmunt A, Olfson M, Boyer CA, et al: Interventions to improve medication adherence in schizophrenia. Am J Psychiatry 159:1653–1664, 2002 [Full Text] [PubMed]

SUGGESTED READING Arkowitz H, Westra HA, Miller WR, et al: Motivational Interviewing in the Treatment of Psychological Problems. New York, The Guilford Press, 2007 Miller WR, Rollnick S: Motivational Interviewing: Preparing People for Change, Second Edition. New York, Guilford, 2002 Miller WR, Zweben A, DiClemente CC, et al: Motivational enhancement therapy manual: a clinical research guide for therapists treating individuals with alcohol abuse and dependence. Project MATCH Monograph Series, 2 (SHHA Publ No ADM-92-1884). Rockville, MD, National Institute on Alcohol Abuse and Alcoholism, 1992 Rollnick S, Miller WR, Butler CC: Motivational Interviewing in Health Care. New York: Guilford Press, 2007 Velasquez MM, Maurer GG, Crouch C, et al: Group Treatment for Substance Abuse: A Stage of Change Manual. New York, Guilford, 2001 Wagner CC, Conners W: Motivational interviewing: resources for clinicians, researchers, and trainers. 2007. Available at: http://www.motivationalinterviewing.org. Accessed January 2, 2008. Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 26. Twelve-Step Facilitation: An Adaptation for Psy...

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Richard K. Ries, Marc Galanter, J. Scott Tonigan: Chapter 26. Twelve-Step Facilitation: An Adaptation for Psychiatric Practitioners and Patients, in The American Psychiatric Publishing Textb ook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.353395. Printed 10/7/2011 from www.psychi atryonline.com Textbook of Substance Abuse Treatment >

Twelve-Step Facilitation An Adaptation for Psychiatric Practitioners and Patients Richard K. Ries, M.D. Marc Galanter, M.D. J. Scott Tonigan, Ph.D.

TWELVE-STEP FACILITATION: INTRODUCTION The goal of this chapter is to help clinicians better engage and support patients who have co-occurring or primary alcohol or drug problems through use of 12-step programs to enhance treatment outcomes and recovery. Twelve-step facilitation (TSF) is an evidence-based practice with a large research base, a therapy manual (Nowinski et al. 1995), and a Web-based training site (Sholomskas and Carroll 2006). It is a valuable technique easily available to the practicing psychiatrist and other mental health professionals. The research base of TSF is reviewed in other chapters of this book. This chapter is a condensed presentation of some of the key techniques and concepts of TSF, with some special adaptations for psychiatric practice. An important concept to recognize at the outset is that TSF is a therapist's technique to help patients engage in and maximize their response to 12-step meetings, such as Alcoholics Anonymous (AA). (TSF is not AA, nor is it, as far as we know, officially endorsed by AA or other 12-step programs.) TSF can also be applied to treat individuals who are dependent on substances other than alcohol, such as narcotics. Such individuals can be encouraged to go to Narcotics Anonymous (NA) meetings, where the 12 steps are applied as well. It should be noted that there are many approaches to self-help that clinicians can promote through TSF that have parallels to group mutual help. Norcross (2006), for example, describes a variety of self-help techniques and available resources, including meditation, readings, and film. This chapter was developed in conjunction with the American Academy of Addiction Psychiatry at their December 2006 annual meeting. Support for the workshop was provided by the National Institute on Alcohol Abuse and Alcoholism and the National Institute on Drug Abuse.

DEFINING THE PROBLEM Why should one be interested in this technique? Fifteen percent of the general population may be diagnosed with a substance use disorder (13% with alcohol abuse, with or without other drug abuse) at some time in their lives (Kessler et al. 2005), and somewhere between 20% and 50% of typical psychiatric inpatients or outpatients will have a current, episodic, or past history of a substance use disorder (Center for Substance Abuse Treatment 2005). For example, approximately 50% of patients with bipolar disorder will experience alcohol or drug problems, and research has shown that those with active substance use are more likely to be medication nonadherent and experience a wide variety of other problems, including suicide attempts and more frequent decompensations (Comtois et al. 2004). Other research shows that these problems improve with sobriety (Weiss et al. 2005). When treating a patient with bipolar disorder who has relapsed to or developed substance dependence, the clinician is faced with several options: try to manage the patient on his or her own, refer the patient for outside substance use treatment while continuing to treat him or her, or refer the patient to another service or an addiction specialist for management of both the bipolar disorder and substance use problems. In our experience, many clinicians would rather continue with most of their patients; however, many assess

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their weekly, biweekly, or monthly visits as just not potent enough to deal with active addiction as well as the bipolar issues. For patients who have developed major addiction, have lost control, and are at serious risk for adverse consequences, referral to a specialized inpatient or outpatient program may be the best choice. However, many patients may not be so out of control, or they may not want addiction treatment to show up on their insurance or health records. Furthermore, participating in concurrent, outside professional treatment may present other problems, including problems with cost, location, transportation, time, and potentially conflicting treatment messages. Even if outside referral is made but the patient returns when stable, there is a good chance that 12-step programs will be part of his or her ongoing treatment plan. In any case, almost all residential treatment programs in the United States have a strong 12-step orientation and are oriented to continuation with 12-step attendance after discharge. Thus, knowing about TSF would likely be helpful.

ADDING TSF TO ONGOING TREATMENT A typical treatment plan would be to integrate the patient's usual therapy and medications with the principles, content, and support offered in 12-step meetings. TSF is a method for helping the patient both get to and productively use 12-step meetings, as well as a method for the clinician to learn and utilize key concepts about 12-step meetings as part of overall therapy. This integrated treatment plan, though not indicated or possible for all patients, has some significant advantages in terms of its addictions impact: no or low cost, ready availability in most communities, anonymity to insurance and others, long-term support that will not go away with a change or end in insurance benefits, and importantly, the ongoing relationship of the treating clinician. Patients with alcohol dependence and psychiatric disorders may have become socially isolated and will benefit from 12-step meetings' social support, particularly support that does not endorse substance use. For example, research has shown that nondrinking support from other 12-step meeting participants is associated with abstinence over three times more than support from the patient's own family (Kaskutas et al. 2002). Addiction treatment programs that are 12-step based have been shown to yield reduced cost in continuing care (Humphreys and Moos 2007). Further evidence of the benefit of 12-step–oriented approaches in treatment programs was provided by Morgenstern (2004) who found that promotion of a 12-step orientation was associated with a greater decrease in substance use at 6 months posttreatment than was the orientation of cognitive-behavioral therapy. Furthermore, 12-step programs endorse personal responsibility for recovery behavior, loss of denial of illness (denial of illness also occurs for many psychiatric disorders), and helping others to recover (thus developing both empathy and self-esteem). These elements of 12-step recovery are applicable to the treatment of and recovery from psychiatric disorders, in addition to addiction recovery (Minkoff 1989). Nevertheless, patients and physicians may resist this approach due to some common misperceptions, such as that 12-step programs are antimedication and require certain religious beliefs. These issues will be addressed in later sections. AA is most appropriate for alcohol-dependent individuals, not alcohol abusers. That is to say, many people who meet DSM-IV-TR criteria (American Psychiatric Association 2000) for alcohol abuse (not dependence) can learn to drink in a controlled manner. For such individuals, alcohol may be associated with certain social situations or even mood states and can be limited; such people may be managed in a psychotherapy situation where they learn to moderate their drinking. It should be noted, however, that most alcoholics can stop drinking for a period of time before they fall into problematic use again; what they cannot do is moderate their consumption in a consistent manner over the long term. Clinicians must therefore clarify the distinction between the two patterns of consumption in deciding whether AA membership is indicated.

THE BACKGROUND OF TSF Just as with most manualized, evidence-based practices for psychotherapies, the elements of TSF come from good clinicians working with astute academics to put together a manual that is based on their

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experiences with 12-step treatment. In this case, Kathleen Carroll, Ph.D., from Yale worked with two talented addictions counselors, Joseph Nowinski, Ph.D., and Stuart Baker, M.A., to develop a manual for use as a treatment condition in Project MATCH (Mattson et al. 1998), the largest addictions treatment trial of the early 1990s, which compared outcomes of motivational interviewing, cognitive-behavioral therapy, and TSF. What follows is based on this manual but has substantial input from several other sources, including clinician focus groups organized by the American Academy of Addiction Psychiatry and other referenced sources. We also write from experience teaching psychiatry residents to do a psychiatric version of TSF with patients, using the TSF manual as a basis.

STARTING OUT The first step in helping your patients go to 12-step meetings is to work on a simple program to enhance your own familiarity with meetings as well as 12-step content. There are three easy ways to do this: 1. Read AA material. First, go to the AA Web site (http://www.alcoholics-anonymous.org) and read through the introductory material, or read printed material. You will be in a much stronger position with your patients in referring them to AA, and to this site, if you can talk to them about your actual experience with this material and with this site. Basic orientation requires 15–30 minutes. Other material is on the Web site, including Alcoholics Anonymous, the "big book" of AA. Printed materials can be obtained by calling your local AA phone number. This same approach applies to NA materials (http://www.na.org/). An additional resource is available in a brief course on AA on the Web site http://www.med.nyu.edu. 2. Read the TSF manual. This manual can be obtained in print from the National Institute on Alcohol Abuse and Alcoholism, Publications Distribution Center, P.O. Box 10686, Rockville, MD, 20849-0686. The manual is about 120 pages long. 3. Go to a meeting as a professional guest. There is no better way to learn about AA than by going to an actual AA (or other 12-step) meeting as a professional guest. This can be easily accomplished by calling the AA phone number in virtually any directory throughout the United States (and many other countries) and identifying yourself as a doctor or other health care provider who would like a guide to take him or her to a local AA meeting as a professional guest. Most AA communities have standing committees of members whose job it is to do this, and not uncommonly some of them are recovering health care professionals themselves. It works best to meet with one or two of these guides for half an hour before the meeting to hear their views and get oriented to what happens in meetings. Attend the meeting (an open meeting is one where guests [i.e., nonalcoholic individuals] are allowed), then meet with the guides afterward to talk about what you heard and ask questions you may have about what went on. Meetings typically run for an hour or an hour and a half. If you find this meeting interesting and helpful, you might want to talk to your guides about attending a meeting of a different socioeconomic, cultural, racial, or other group—AA meetings reflect the general communities from which they spring. Matching patients to the right AA meeting, where they feel more familiar with others, is often key to their becoming regular members. It is hard to appreciate these differences without experiencing them. It also substantially strengthens your suggestion to your patients to attend if you can invoke your experience with attending AA meetings as a professional guest, and, therefore, you know that one meeting can feel quite different from another.

CORE ELEMENTS OF THE TSF MANUAL All of the exerpts that follow are quoted from the TSF manual (Nowinski et al. 1995, pp. ix –18); however, because of space limitations, this chapter does not review the manual in full. What is offered might be considered a primer for the manual, with editorial comments and additions for psychiatrists regarding treating patients with co-occurring psychiatric issues. In Project MATCH, TSF was designed to be accomplished in 12 sequential sessions over about 3 months. However, for the practicing clinician, it is more likely that real-world TSF will occur off and on over the course of treatment, which for some may be weeks or months and for others could be many years.

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The following material set in block text is direct or paraphrased copy from the Project MATCH Twelve-Step Facilitation Therapy Manual and is primarily from the introductory material and therapist guidelines. The text set in italics is our edits to this material, with our discussion about TSF materials and our edits in regular paragraph type. Our comments may help the psychiatrist starting out with TSF by adding material and approaches that harmonize with psychiatric practice and psychiatric patients. For the sake of brevity, we have used the psychiatric example of bipolar disorder in most cases, rather than invoking many different diagnostic examples.

TSF Treatment Goals Acceptance Acceptance by patients that they suffer from the chronic and progressive illness of alcoholism It is very important that clinicians who refer patients to AA or other 12-step programs make sure that the message given to patients about their addictions harmonizes with what patients hear at 12-step meetings, because receiving conflicting information is not a good way to make a productive integration. A pharmacological analogy would be that one should not prescribe medications that negatively interact. Some clinicians will have a hard time swallowing the acceptance phrase above as it is written; however, if you add at the end, if they continue to drink abusively, and do not participate in recovery activities, then most clinicians can endorse this. The corollary for psychiatric patients can be useful: for example, in the case of bipolar disorder it would read, acceptance by patients that they suffer from bipolar disorder and that their disease will likely become chronic and progressive if they do not take their medications or participate in recovery (therapeutic) activities. Dual Recovery Anonymous (DRA), or "Double Trouble," is a 12-step program created by persons with both psychiatric and addiction disorders (see http://www.draonline.org/dra_steps.html). The first of DRA's 12 steps is "We admitted we were powerless over our dual illness of chemical dependency and emotional or psychiatric illness—that our lives had become unmanageable." Importantly, this means that individuals are Powerless over being born with the illnesses or managing them without help, and Powerless to predict behavior once drinking, in a manic episode, or both; but Not powerless to get to meetings or therapy appointments; Not powerless to take medications regularly and avoid bars; and Not powerless to participate in recovery from both disorders. Acceptance by patients that they have lost the ability to control their drinking Research has shown that persons with more severe dependence do better in AA than those with episodic abuse (Tonigan et al. 2006) because of the concept of loss of control stated above, as well as other issues. This means that if your patient has only mild abuse and can control his or her drinking most of the time with your support, then he or she is probably not the most likely AA candidate. In terms of bipolar behavior, the correlate would be acceptance by patients that they have lost the ability to control their behavior when manic or severely depressed. In talking to patients about this concept or phrase excerpted above, one can add the word reliably just before "control their drinking." For example, with the alcohol-dependent bipolar patient the clinician would ask, "Can you reliably control your drinking well enough that you are willing to take the risk of decompensating with both your alcohol and manic behavior and ending up in the hospital, jail, or both again? Can you reliably control your manic behavior (if you stop your medications) such that you are willing to take the risk of decompensating, or going back to drinking, or both?" Acceptance by patients that since there is no effective cure for alcoholism, the only viable alternative is complete abstinence from the use of alcohol If patients with major mental illness can reliably control their drinking to one small glass of wine a day,

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then by definition, they do not have dependence and TSF is not for them. However, if they do have dependence with episodic or regular dyscontrol if they drink, it is much easier for them to not drink at all than to prime the pump with attempts at controlled drinking. The analogy here is acceptance by patients that since there is no effective cure for bipolar or schizophrenic disorder, the only viable alternative is to take daily medications and participate in healthy recovery behaviors (such as seeing their psychiatrist and attending 12-step meetings if they have substance dependence).

Surrender Acknowledgment on the part of the patient that there is hope for recovery, but only through accepting the reality of loss of control (from alcohol dependence/major mental illness) and by having faith that some higher power (AA meetings, the psychiatrist, medications, support groups for the mentally ill, a spiritual higher power) can help the individual whose own willpower has been defeated by alcohol/major mental illness Most psychiatrists are unfortunately familiar with the mentally ill patient who understands his or her disorder one month, accepts it, and does everything in his or her power to stay well, but over time comes to believe that he or she no longer has a disorder and then decreases or stops taking medications and receiving therapy and decompensates to depression or mania. The same process can hold for addictions. Clinical experience shows that relapsing back into denial of illness happens for both psychiatric and addiction disorders and is not something that is dealt with once and for all. Quite often denial can creep back intermittently and lead to serious problems. By continually concentrating on acceptance of illness, 12-step members reinoculate themselves against denial. For example, each time AA, DRA, or other 12-step program members speak in meetings, they introduce themselves by saying, "Hi, my name is Rick, and I am a recovering alcoholic." In dual disorder AA or DRA meetings, the speaker might say, "Hi, my name is Rick, and I am a recovering bipolar alcoholic." The power in this phrase is the direct challenge to denial; 12-step meetings strongly promote that denial can reemerge if it is not actively and regularly challenged. Acknowledgment by the patient that the fellowship of AA has helped millions of alcoholics to sustain their sobriety and that the patient's best chances for success are to follow the AA path. Furthermore, the 12-step approach can be a valuable approach to dealing with any other potentially chronic and relapsing condition, such as most psychiatric disorders. There are two key issues here. First, by merely examining a schedule book of meetings in any community and going to a meeting or two, it becomes clear that many, many people go to AA meetings. For example, in Seattle there are about 1,200 meetings per week, and an average meeting has 15–100 attendees. Observing this mass of people all going in the same healthy direction has a potency that cannot be captured by the academic discussion of a research finding. Second, sustain is a key word in the excerpt above. That is, while our research shows that most psychiatric and addiction disorders are chronic and relapsing in nature, most treatment structures are short-term or episodic (e.g., limits on study lengths, limits on payment for an episode of treatment, managed care limits on number of sessions). Twelve-step meetings are available without cost, without end, and almost without boundary, as they are now easily available almost anywhere in the United States and are becoming more available throughout much of the world. As Mark Twain reportedly said, "Stopping smoking is easy. I've done it hundreds of times." In this regard, it is useful to explain to the patient how the speakers' presentations ("qualifications") are useful in putting the illness into context. It is increasingly understood that the narratives and personal stories that one hears at meetings have an important psychological role in promoting both the speakers' and listeners' recovery (Mankowski et al. 2001). But their relevance often needs to be clarified for the new attendee.

Objectives

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The two major treatment goals of acceptance and surrender are reflected in a series of specific objectives that are congruent with the AA view of individuals with alcoholism. These specific objectives are cognitive, emotional, behavioral, social, and spiritual in nature.

Cognitive Patients need to understand some of the ways in which their thinking has been affected by alcohol, other drugs, or mental disorders. Clinicians who conclude that TSF might be helpful to their patients are likely driven by observing behaviors and negative consequences due to alcohol or drug use. At times the patients themselves may conclude they have an addiction problem, but it is more likely that it is the clinician who will be led to such a conclusion based on the patient's substance-related problems and consequences. In such cases, although the patient may have sought treatment for a psychiatric problem alone, the clinician may decide that the patient also has a co-occurring problem with addiction, which needs clinical focus. Patients need to understand how their thinking may reflect denial and thereby contribute to continued drinking (or psychiatric relapse) and resistance to acceptance (Step 1), which can lead to decompensation of addiction, psychiatric, or both conditions. The therapist remains vigilant for signs of denial of either disorder, patient accounts of slips, and medication nonadherence or missing appointments, and explains these slips in terms of denial. The therapist suggests recovery tasks that will enhance patient's understanding of addiction and his or her psychiatric disorder, as well as how both of these can benefit from the fellowship of AA. Denial of illness in a previously substance-dependent person usually leads to experimentation, which may then lead to increased use (in an effort to match previous effects as tolerance to the substance builds), which may lead fairly rapidly to problematic and dependent use. In the case of relapse, this process may start with a drop-off in attendance at 12-step meetings, even before the actual substance use begins. The clinician should therefore be attentive to a patient's attendance at 12-step meetings and view a decline in attendance as an indication both to encourage renewed attendance on the part of the patient and to look for circumstances potentially associated with relapse. For individuals with a psychiatric disorder, denial of illness may lead to a refusal to initiate treatment. Similarly, individuals in denial of their relapse to substance use may begin canceling treatment appointments or decreasing or stopping medications—either of which may occur before recurrence of major psychiatric symptoms. Certain psychiatric conditions display denial in different manners. For example, grandiosity in mania leads the patient to believe that he or she knows better and can handle anything; nihilism in depression leads the patient to believe that he or she is not worth treatment and nothing matters anyway; posttraumatic stress disorder leads the patient to believe that his or her symptoms are worse than they actually may be because he or she is seeing a specialist and concentrating on the memories; delusions in schizophrenia may tell the patient that it is the medications that are causing, for example, electric rays from the sky that torture him or her. Patients need to see the connection between their alcohol abuse and negative consequences that result. . .which may be physical, social, legal, psychological, financial, or spiritual; and, further, patients need to analyze in detail how their co-occurring psychiatric problems have been affected by their addictions and vice versa. Common problems include aggravated symptoms, decompensations, medication adherence problems, suicide attempts, monetary problems, and the other problems named above.

Emotional

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Patients need to understand the AA view of emotions and how certain emotional states (e.g., anger and loneliness) or a relapsing psychiatric disorder can lead to drinking. A version of the AA view of emotions and how to deal with them is described in Topic 8 of the Twelve-Step Facilitation Therapy Manual (p. 79) but is too lengthy to fully review here. It may be surprising to the reader to find that many elements of Marlatt's relapse prevention (Marlatt and Gordon 1985) and Linehan's dialectical behavioral therapy (Linehan 1993) have a good deal of overlap with AA content and principles, in terms of analyzing how certain emotions lead to certain behaviors and how to handle them. HALT (Hungry, Angry, Lonely, Tired) is an AA mnemonic and slogan that not only captures common emotional relapse states but suggests action, as in "HALT before you do something you do not really want to do." Interestingly, this model is quite compatible with the cognitive-behavioral approach that many therapists apply in treating addictive disorders. Feelings such as anxiety and depression may regularly lead to the self-administration of a drug of abuse; these feelings may then become conditioned stimuli that produce a response experienced as craving, thereby precipitating drug taking without a conscious decision on the part of the addict. The same is true for a particular setting in which alcohol or drugs were repeatedly taken; it may become a conditioned stimulus for drug-seeking behavior on subsequent occasions of exposure. For this reason, the recovering alcoholic individual is warned in 12-step groups to watch out for negative feelings and avoid bars and drug-related social situations; these have become conditioned stimuli for alcohol-seeking behavior, leaving the alcoholic person more vulnerable to "needing" a drink. When reviewing psychiatric symptoms or substance use or craving since the last visit, the psychiatrist might integrate TSF by asking, "Have there been any episodes of feeling hungry, angry, lonely, or tired since your last visit, and if so, how did you handle them?" By using the AA verbiage, the psychiatrist is telling the patient that he or she supports AA and that the psychiatrist's therapy is meant to be integrated with what the patient is getting through AA. Patients need to be informed regarding some of the practical ways AA suggests for dealing with emotions so as to minimize the risks of drinking. The most common and obvious way for a patient to become informed of these methods is to attend AA meetings. In fact, the methods by which a patient learns how to deal with emotions are so numerous that they are included in almost every story, vignette, step description, or other literature that AA publishes (Topic 8 [pp. 79–86] from the Twelve-Step Facilitation Therapy Manual has very practical materials in a workbook format). For individuals who are seeing a therapist, AA methods present a way to deal with problematic emotions other than taking medication.

Behavioral Patients need to understand how the powerful and cunning illness of alcoholism has affected their whole lives and how many of their existing or old habits have supported their continued drinking. They further need to understand how their addiction and psychiatric conditions have interacted and adversely affected each other. The behavioral approach associated with conditioned stimuli is a useful cognitive-behavioral technique for addiction treatment to frame changes in the activities associated with drug use (Carroll 2004). The issue of self-medication may emerge and has the potential to confuse both the psychiatrist and the patient. Virtually all research conducted on the matter shows that dependent use of substances makes major psychiatric disorders worse, resulting in increased symptoms, decompensations, emergency room visits, homelessness, and suicide, among other problems (Center for Substance Abuse Treatment 2005). Furthermore, patients who invoke the term self-medication have an increased likelihood of suicidal

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ideation and suicide attempts (Bolton et al. 2006). To equate this with what our medications are supposed to do is like equating electricity used for home heating to electricity in a lightning bolt that destroys someone's house. Research has shown that when an individual with bipolar disorder who is in a manic state claims to be self-medicating, he or she is most likely aiming to get even more euphoric, and that patients who use the term self-medication have worse prognoses for recovery (Weiss 2004). Using the term self-medication when addiction or abuse of substances is more accurately meant can be confusing to both the patient and psychiatrist. Such use allows concrete-thinking patients to think, "Well, the psychiatrist said I self-medicated, so I guess I will take his medications [lithium, antipsychotics, etc.] on Monday through Friday and my medications [crack and alcohol] on the weekend. After all, it's all medication." We will deal with this topic more below when giving concrete examples of how to talk to patients about meetings.

Social Patients need to turn to the fellowship of AA and make use of its resources and practical wisdom in order to change their alcohol behavior. Patients need to "get active" in AA as a means of sustaining their sobriety. Patients need to attend and participate regularly in meetings of various kinds, including AA-sponsored social activities. Patients need to obtain and develop a relationship with an AA sponsor. Patients need to access AA whenever they experience the urge to drink or suffer a relapse. Patients need to reevaluate their relationships with "enablers" and fellow alcoholics. It is easy to understand the need for an individual who is trying to stay sober to avoid spending time with friends who are still drinking/using substances. This type of reasoning is also applicable to individuals who are receiving treatment for psychiatric disorders—it is not unusual for a well-meaning but uninformed friend or relative to suggest that a patient stop taking his or her medications because they are chemicals and not natural. Identifying persons who are supportive of recovery and avoiding or working to change those who are not are important elements of TSF. This is especially important in choosing certain AA meetings that may be more supportive of co-occurring issues and in choosing a sponsor. The sponsor should either have co-occurring disorders him- or herself or should be supportive and understanding of these issues.

Spiritual Patients need to experience hope that they can arrest their alcoholism and manage and recover from their psychiatric disorder(s). Patients need to develop a belief and trust in a power greater than their own willpower. The above statements hold for both addictions and psychiatric disorders. If the willpower of the individual seeking treatment were adequate, he or she would not need to see the psychiatrist, take medications, or use the 12-step programs. These types of "power greater than oneself" are pretty concrete; however, what about the role of spirituality or God?

The issue of God in TSF Spirituality has been defined as "that which gives people meaning and purpose in life" (Puchalski et al. 2004, p. 689). The element of spirituality is what distinguishes AA from orientations that approach addiction recovery on the basis of physical and behavioral consequences of disease alone as well as from formal religious practices. Alcoholics Anonymous repeatedly mentions a "program of recovery" and associates it with terms such as spiritual experience and spiritual awakening (Alcoholics Anonymous

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1976). A spiritual orientation is inherent in four of the steps, which include the word God. However, both key AA texts (Alcoholics Anonymous 1976, 1984) dedicate great effort to differentiating traditional concepts of God from the AA spiritual concept of a higher power. Both spirituality and God can have many different meanings, and a patient who balks at interpretation of these terms might be open to working under another interpretation—either word can attract or repel individuals, depending on their associations. During discussions of previous experiences with 12-step programs with a patient (or simply what he or she might have heard about them), the issue of the spiritual element in these programs is raised quickly. (Special care needs to be taken here for psychotic patients with religious delusions.) One should try to explore the person's associations to key words with open questions. What do you know or think about the term spirituality? How do you think it is used in AA [or another 12-step program the individual may have attended or heard about]? How about the term higher power? Was this concept helpful to you? If not, let's see if we can figure out how it might be. Your dependence on alcohol/drugs, by definition, is clearly stronger than your own willpower. Do you recognize your dependence as a power greater than yourself? If so, then what are some examples of this? Recovery from this dependence can also be seen as greater than yourself; what does this mean to you? The wisdom and experience from those in 12-step meetings with successful long-term recovery are clearly greater than your own; are you willing to use this help? How do you feel about the term God? What does this term mean to you? When speaking with an individual who seems resistant to discuss God, one may find it helpful to explain that the use of this term is not a requirement for membership in AA or other 12-step programs and that others prefer the terms my higher power or the power of my AA group. Most larger AA communities even have agnostic and atheist groups, for those for whom hearing the term God is too disruptive. In the context of the 12-step process, spirituality can be thought of as the willingness to change. It can also be defined as connectedness with other people and what is meaningful in someone's life. How is the discomfort with the use of God addressed in AA? First, the issue of God is qualified (Alcoholics Anonymous 1976, pp. 44–57; 1984, pp. 25–33, 34–41) with "as we understood him." Second, flexibility on the concept of God is made clear in one chapter of Alcoholics Anonymous that addresses any alcoholic person "who feels he is an atheist or agnostic," encouraging his or her membership. The text points out for these potential members that "We Agnostics. . .had to face the fact that we must find a spiritual basis for life" in order to achieve recovery, thereby implying AA's distinction between spirituality and theistic religion.

Universality of spirituality All people across cultures have had exposure to spirituality. Encourage patients to reflect on past spiritual experiences and to build on them. Also, encourage patients to find comfort in spiritual experiences.

Resistance to religion or spirituality For patients who express resistance to religion or spirituality, talk to them after they have been to a few 12-step meetings in order to determine if there is anything they can connect with.

Spirituality from a different perspective For patients who are not inclined to look at the spiritual aspects of AA, the doctor can suggest that they do some other things that have similar spiritual foundations. For example, patients can volunteer for the Salvation Army to experience spirituality from another perspective.

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Spirituality and morality Patients need to acknowledge character defects including specific immoral or unethical acts, and harm done to others as a result of the patients' alcoholism or psychiatric disorders. The moral tone of this statement may cause discomfort for many psychiatrists; however, looking at the "wreckage of the past"—a typical AA phrase—is something that should be done as part of taking any good history. This task helps to challenge denial. While it is clear that the cocaine-abusing patient who sold his or her parents' television should acknowledge substance use problems and make restitution, what about the manic patient who by choice cuts down medications to "get an edge," then spends the entire limit of the family's credit cards on unnecessary, impulsive items? Is this an illness issue, a moral issue, or both? The AA approach says that although an individual may not be responsible for having the illness, he or she is very responsible for managing its recovery. Facing up to the wreckage of the past, whether from addictions, psychiatric illness, or both, is a basic part of recovery. While restitution of money or other concrete objects can be made, self-forgiveness for hurting others, such as in the examples above, is more difficult. Both the individual and the therapist must work together on this task.

ROLE OF THE THERAPIST The primary role of the therapist is as a facilitator of patients' acceptance of their alcoholism and of a commitment to the fellowship of Alcoholics Anonymous as the preferred path of recovery. However, when the facilitator is also a pyschiatric practitioner (and often a prescriber), explaining the nature of co-occurring psychiatric illnesses, medications, and other therapies are also key facilitation issues.

Education The therapist acts as a resource and advocate of the 12-step approach to recovery. The 12-step therapist explains the AA view of alcoholism and interprets slips and resistance to AA in terms of the power of alcoholism and the dynamics of denial. The 12-step therapist introduces several of the 12 steps and their related concepts and helps the patient to understand key AA themes and concepts (e.g., denial, powerlessness) by identifying the patient's personal experiences that illustrate them. And for those with comorbid disorders, the therapist adds the context of the patient's psychiatric disorder to these same conditions (for example, the role of denial in bipolar illness; how a slip with drinking and psychiatric medication nonadherence might be similar). Introduction of steps is probably best done in actual meetings or by the patient's sponsor, unless the psychiatrist wants to get much more involved. Table 26–1 lists the DRA steps. Introduces, explains, and advocates reliance on the fellowship of AA as the foundation for recovery, which should be thought of as an ongoing process of "arrest" (as opposed to cure). The concepts of arrest and recovery versus cure hold for most psychiatric disorders. In the clinical context, recovery is based on an individual's behavior and medical status, which can be assessed by recourse to diagnostic criteria in DSM-IV-TR. Some of these criteria are also given in the items listed in the Addiction Severity Index (McLellan et al. 1992), which is used widely in research to evaluate recovery. Behavior and medical status can be assessed relatively easily because they are premised on observable behavior or symptoms described by the patient, family member, or clinician. But a spiritually grounded definition of recovery can be useful as well. A different set of criteria can be used to diagnose addiction and describe the spiritual aspects of recovery associated with the 12-step experience, such as relief of guilt and shame, expression of gratitude, and finding purpose in life (Galanter 2007). These are particularly relevant in helping the patient understand what is meant by

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recovery from the broader perspective of the 12-step experience. Explains the role of a sponsor and helps patients identify what they would most benefit from in a sponsor. Answers questions about material found in the Big Book, The Twelve and Twelve, and other readings. Again, it is possible for a psychiatrist to help his or her patients to attend AA meetings and get something out of them without having to read the big book in its entirety. However, reading it can be both helpful and interesting and can help the psychiatrist to better understand addiction and the AA model of recovery. Most of this type of more concrete AA work is best done by the patient's sponsor.

Facilitation The therapist uses patients' reports of their experience between sessions to actively facilitate their involvement in AA. The 12-step therapist. . .encourages attendance at AA meetings, monitors patient involvement in AA, and actively promotes a progression toward greater involvement in AA, for example in going to meetings that require more personal involvement, such as "step" meetings and "discussion" meetings. The psychiatric practitioner can productively use his or her patient's behavior and understanding of meeting discussions as therapeutic material for both disorders. One can spend a great deal of time on the issue of active involvement in AA. It is important for patients to understand that participation is necessary for recovery. On the other hand, for first-time attendees or patients with social anxiety, it may be understandable that they are reluctant to speak or meet with other members. When it is clear that this is the case for a particular patient, it should be addressed in a supportive way. For that patient, the idea that if he or she keeps going back, he or she will feel more comfortable in time should be emphasized. Sitting in the back of the meeting room and not speaking is an acceptable first step toward later involvement. Some basic meeting involvement coaching might include asking such questions as, What meetings did you attend since last session? Did you arrive early, on time, or late for meetings? Where exactly were the meetings, where did you sit, did you stay for the whole meeting, and were you able to pay attention the whole time? Discussing answers to these questions uncovers resistance and nonattendance as well as psychiatric problems that might be interfering with attendance, such as paranoia or social phobia. Dealing with the causes of nonattendance and resistance then becomes part of therapeutic work, involving medications, motivational interviewing, cognitive-behavioral techniques, or other specific cognitive approaches. Initiating discussion about AA involvement using such approaches is briefly illustrated here. Motivational interviewing: "So you thought about going to a meeting last night, but didn't quite get there. . .What do you think you might have gained if you had gone? What would have been the downside of going?" Cognitive-behavioral therapies and AA facilitation: "So you thought about going to a meeting last night, but didn't quite get there. . .Let's examine what you said to yourself to convince yourself not to go, then work out a strategy to get you there." Twelve-step disease model facilitation: "So you thought about going to a meeting last night, but didn't quite get there. . .What was responsible for not getting there—was it you or was it your disease? That kind of experience is the illness at work; it's the disease that tells you that you don't have a disease. Who could you have called?" More detailed attendance questions: "Did you offer to help with setup or cleanup at the meeting? Did you talk to anyone before or after the meeting? What were some key issues you heard discussed at the meeting? How did these issues apply to you? Did you say something in the meeting? What was it like to talk, or want to talk, but be unable or afraid to talk? Let's rehearse

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right here what you could say." An example of a specific co-occurring disorders intervention (panic disorder and social phobia): "So you thought about going to a meeting last night, but were afraid you would panic if you were called on, so you didn't go. Let's work out a strategy." Prescribe medications for social phobia (e.g., selective serotonin reuptake inhibitor, gabapentin. Note that an alcoholic patient should not receive benzodiazepines; see Alcoholics Anonymous 1984). Rehearse something very simple to say in meetings (in the patient's words) with visualization, such as "Hi, I'm Rick and I'm glad to be here." Have the patient carry a written card or have this phrase written on his or her hand. Rehearse this again and again in session and have the patient do this at home. Let the patient know that there is no requirement for individuals to say anything during meetings; even if called on, he or she can just pass. For highly anxious performance-challenged patients, a 10- to 20-mg dose of propranolol before meetings may help, until the patient is more comfortable. Clarifies the role of therapist versus sponsor and refuses to become a sponsor while helping the patient to find one. Naturally, a number of other types of issues can arise with respect to initiating AA treatment. Table 26–2 presents some common problems and offers solutions that may guide a clinician in his or her facilitation of AA participation. Table 26–3 provides specific questions and topics whose discussion can further help to facilitate involvement in treatment. Some clinicians may choose to meet a patient's sponsor so that both the sponsor and clinician both know they are on the same side and are providing consistent information to the individual seeking treatment. This is only done with the patient's approval and during a session with the patient present. Other clinicians prefer to not meet the patient's sponsor but still encourage a constructive relationship between patient and sponsor. A patient may not feel comfortable with the initial choice of sponsor and may discuss this in therapy. If this takes place, the therapist can explore the patient's concern. This may help the patient relate more comfortably to his or her sponsor. AA members may decide to get a new sponsor if they feel that would be best for them. Some patients are resistant to the idea of getting a sponsor, and this can be a problem. For those with more serious psychiatric disorders, it is best, but not absolutely necessary, that their sponsors also have co-occurring disorders. This way, problems around psychiatric diagnosis, symptoms, and treatments, especially medications, are avoided, and psychiatric treatments are reinforced rather than resisted by the sponsor. Patients are more likely to meet such sponsors by going to DRA, dual diagnosis AA meetings, or other variants of 12-step meetings that focus on persons with co-occurring disorders. Many AA schedules in larger communities even list dual diagnosis as a qualifier for certain meetings.

Desired Therapist Characteristics Twelve-step therapists, being professionals whose goal is to facilitate and encourage active participation in AA, need not be personally in recovery; however, they must be knowledgeable of and comfortable with the foundation of 12-step recovery as described in AA-approved literature. Therapist self-disclosure of recovery status is to some extent a clinical issue, but generally speaking the authors encourage honesty in the therapeutic relationship. If they are not in recovery, it is strongly recommended for therapists to attend at least 10 open AA meetings and an equal number of Al-Anon or Families Anonymous meetings, and to be thoroughly familiar with AA reading materials. In addition, to be maximally effective as a facilitator, the therapist is advised to develop a network of AA contacts—men and women—who are active in AA and who could be called on to assist in

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getting a shy or ambivalent patient to their first meetings, giving advice about particular meetings, providing directions, and so forth. Persons who have been sober and active in AA for at least a year are candidates for doing this type of 12-step work as part of their own recovery. Therapists can develop working relationships with these people by going to AA meetings on some regular basis, or by talking with recovering persons they know. First-hand knowledge of such contact people is desirable. Active, Supportive, and Involved: 12-step therapists are expected to be interactionally active and nonjudgmentally confrontational during therapy sessions, as opposed to merely reflective. This does not mean that the therapist lectures the patient, does more talking than the patient, or chastises the patient for slips. Rather, the therapist utilizing this approach should be prepared to identify denial and confront the patient consistently in a frank but respectful manner regarding the patient's attitudes or behaviors, to actively encourage the patient to get involved in the fellowship of AA, and to help the patient understand key AA concepts as they are reflected in the patient's actual experience. Patients can be expected to interpret the AA concepts presented here in light of their own experience. This is consistent with the AA approach, which allows for a great deal of individuality of interpretation within broad guidelines. For example, the 12 steps specifically allow for individuality in conceptualizing a higher power ("God as we understand him"). Similarly, what represents unmanageability (Step 1) for one patient may not be meaningful to another. What is most important is not whether patients interpret these concepts in the same way; rather, what counts is the end result: active involvement in the fellowship of Alcoholics Anonymous. Confrontation: In the context of this program, confrontation is something that therapists can think of as helpful and honest mirroring. The most appropriate form of confrontation is to share frankly but respectfully what you see the patient doing. Most often this involves confronting the patient about some form of denial. Confrontation that is patronizing or harsh or implies that the patient has a character problem as opposed to a powerful and cunning illness is likely to be counterproductive. We have discussed therapist preparation earlier in this chapter, in the section titled "Starting Out." Realistically, we doubt that many practicing clinicians will go to 10 meetings and it is our experience that many residents have become at least moderately 12-step adept by attending a couple of meetings, reading the TSF manual, and working intensively with a few patients who go to 12-step meetings, making sure to spend a good deal of each session talking about what went on at meetings. This review of meetings brings up psychiatric symptoms, relationship matters, and cognitive challenges, providing ample material for a therapist to attend to during a session. This concentration on what goes on at meetings also conveys the idea that meetings are important.

KEY POINTS Co-occurring and substance-induced disorders are common in psychiatric patients, and mental health practitioners can enhance outcomes from both disorders by applying 12-step facilitation (TSF). TSF is not Alcoholics Anonymous (AA) nor is it endorsed by AA. It is an evidence-based therapy performed by the clinician to help a patient begin to attend and benefit from 12-step meetings, including AA. Co-occurring disorders (COD) TSF is a practical enhancement of TSF that includes typical psychiatric issues and treatment but has not been separately tested. Twelve-step approaches and meetings are ubiquitous, inexpensive, and evidence based and provide long-term, recovery-based help with patients with substance use disorders.

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Twelve-step approaches to acceptance and denial for the chronic and often relapsing illness of addiction are appropriate for and benefit most psychiatric disorders. The official policy of AA is supportive to seeing psychiatrists and taking psychiatric medications for mental disorders. However, a good deal of variability exists with many 12-step communities having COD 12-step meetings and others being neutral or even hostile toward the idea. Developing COD TSF skills is an effective way for the mental health practitioner to stay productively involved with his or her COD patient, provides a good model of integrated care, and provides a great deal of low-cost but high-frequency psychosocial support to the patient.

REFERENCES Alcoholics Anonymous: Alcoholics Anonymous. New York, Alocholics Anonymous World Services Inc., 1976 Alcoholics Anonymous: Twelve Steps and Twelve Traditions. New York, Alocholics Anonymous World Services Inc., 1984 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Bolton J, Cox B, Clara I, et al: Use of alcohol and drugs to self-medicate anxiety disorders in a nationally representative sample. J Nerv Ment Dis 194:818–825, 2006 [PubMed] Carroll KM: Behavioral therapies for co-occurring substance use and mood disorders. Biol Psychiatry 56:778–784, 2004 [PubMed] Center for Substance Abuse Treatment: Substance Abuse Treatment for Persons With Co-occurring Disorders. A Treatment Improvement Protocol TIP 42 (DHHS Publ No SMA-05-3992). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2005 Comtois KA, Russo JE, Roy-Byrne P, et al: Clinicians' assessments of bipolar disorder and substance abuse as predictors of suicidal behavior in acutely hospitalized psychiatric inpatients. Biol Psychiatry 56:757–763, 2004 [PubMed] Dual Recovery Anonymous: The twelve steps of Dual Recovery Anonymous. 1993–2004. Available at: http://www.draonline.org/dra_steps.html. Accessed January 20, 2008. Galanter M: Spirituality and recovery in twelve-step programs: an empirical model. J Subst Abuse Treat 33:265–272, 2007 [PubMed] Humphreys K, Moos RH: Encouraging posttreatment self-help group involvement to reduce demand for continuing care services: two-year clinical and utilization outcomes. Alcohol Clin Exp Res 31:64–68, 2007 [PubMed] Kaskutas LA, Bond J, Humphreys K: Social networks as mediators of the effect of Alcoholics Anonymous. Addiction 97:891–900, 2002 [PubMed] Kessler RC, Chiu WT, Demler O, et al: Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 62:617–627, 2005 [PubMed] Linehan MM: Cognitive Behavioral Treatment of Borderline Personality Disorder. New York, Guilford, 1993 Mankowski ES, Humphreys K, Moos RH: Individual and contextual predictors of involvement in twelve-step self-help groups after substance abuse treatment. Am J Community Psychol 29:537–563, 2001 [PubMed] Marlatt GA, Gordon JR (eds): Relapse Prevention: Maintenance Strategies in the Treatment of Addictive

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Behaviors. New York, Guilford, 1985 Mattson ME, Del Boca FK, Carroll KM, et al: Compliance with treatment and follow-up protocols in Project MATCH: predictors and relationship to outcome. Alcohol Clin Exp Res 22:1328–1339, 1998 [PubMed] McLellan AT, Kushner H, Metzger D, et al: The Fifth Edition of the Addiction Severity Index. J Subst Abuse Treat 9:199–213, 1992 [PubMed] Minkoff K: An integrated treatment model for dual diagnosis of psychosis and addiction. Hosp Community Psychiatry 40:1031–1036, 1989 [PubMed] Morgenstern J: Pathogenesis and Treatment of Alcoholism. PsycCRITIQUES. Washington, DC, American Psychological Association, 2004 Norcross JC: Personal integration: an N of 1 study. Journal of Psychotherapy Integration 16:59–72, 2006 Nowinski J, Baker S, Carroll K: Twelve Step Facilitation Therapy Manual. Rockville, MD, National Institute on Alcohol Abuse and Alcoholism, 1995 Puchalski CM, Dorff RE, Hendi IY: Spirituality, religion, and healing in palliative care. Clin Geriatr Med 20:689–714, vi–vii, 2004 Sholomskas DE, Carroll KM: One small step for manuals: computer-assisted training in twelve-step facilitation. J Stud Alcohol 67:939–945, 2006 [PubMed] Tonigan JS, Bogenschutz MP, Miller WR: Is alcoholism typology a predictor of both Alcoholics Anonymous affiliation and disaffiliation after treatment? J Subst Abuse Treat 30:323–330, 2006 [PubMed] Weiss RD: Treating patients with bipolar disorder and substance dependence: lessons learned. J Subst Abuse Treat 27:307–312, 2004 [PubMed] Weiss RD, Ostacher MJ, Otto MW, et al: Does recovery from substance use disorder matter in patients with bipolar disorder? J Clin Psychiatry 66:730–735, 2005 [PubMed]

SUGGESTED READING Bogenschutz MP: Specialized 12-step programs and 12-step facilitation for the dually diagnosed. Community Ment Health J 41:7–20, 2005 Double Trouble in Recovery: Double Trouble in Recovery. Available at: http://www.doubletroubleinrecovery.org/index.htm. Accessed September 5, 2007. Nowinski J: The Twelve Step Facilitation Outpatient Program Facilitator Guide. Center City, MN, Hazelden, 2006 Nowinski J, Baker S: The Twelve Step Facilitation Handbook: A Systematic Approach to Early Recovery From Alcoholism and Addiction. Center City, MN, Hazelden, 2003 Nowinski J, Baker S, Carroll K: Twelve Step Facilitation Therapy Manual. Rockville, MD, National Institute on Alcohol Abuse and Alcoholism, 1995 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 27. Contingency Management

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Stephen T. Higgins, Kenneth Silverman: Chapter 27. Contingency Management, in The Am erican Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©20 11 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.353776. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Contingency Management Stephen T. Higgins, Ph.D. Kenneth Silverman, Ph.D.

CONTINGENCY MANAGEMENT: INTRODUCTION Contingency management (CM) treatments for substance use disorders (SUDs) have been in the published literature since the 1960s but have achieved a higher profile within the past two decades (see Higgins et al. 2008). CM treatments can vary in many respects, but the central feature common to all of them is the systematic application of reinforcing or punishing consequences in order to achieve therapeutic goals. With regard to treatment of SUDs, CM most commonly involves the systematic application of positive reinforcement to increase abstinence from drug use, an approach referred to as abstinence reinforcement therapy, but also to facilitate other therapeutic changes, including retention in treatment, attendance at therapy sessions, and compliance with medication regimens. Typically, CM is used as part of a more comprehensive treatment intervention. Below we outline the scientific rationale underlying this treatment approach, discuss the basic elements of CM, and discuss its treatment efficacy and effectiveness. Preparation of this manuscript was supported by research grants DA09378, DA14028, and DA08076 (Higgins); and DA13107, DA19386, and DA19497 (Silverman) from the National Institute on Drug Abuse

SCIENTIFIC RATIONALE CM is a generic behavioral intervention based on the principles of operant conditioning, namely reinforcement and punishment. The idea of using behavioral interventions to treat SUDs is quite rational considering the extensive empirical evidence demonstrating that operant conditioning plays an important role in the genesis and maintenance of repeated drug use and dependence (e.g., Higgins et al. 2004a). There is an extensive basic science literature going back to the 1940s showing that abused drugs will function as unconditioned positive reinforcers for laboratory animals in the same way that food, water, and sex do. Laboratory animals readily learn arbitrary operant responses, such as pressing a lever or pulling a chain, when the only consequence for doing so is the receipt of an injection of a prototypical drug of abuse such as amphetamines, barbiturates, cocaine, or morphine. Laboratory animals not only will voluntarily ingest abused drugs but, when given unconstrained access to cocaine and related drugs, they will consume them to the exclusion of basic sustenance and to the point of overdose and death. There is a growing understanding of the neurobiology of these drug-produced reinforcing effects, which appear to depend critically on effects in the mesolimbic dopamine system. This basic research has also revealed that, while drug-produced reinforcement is powerful, it is also malleable and sensitive to environmental context (Higgins et al. 2004a). For example, alterations in the schedule of drug availability, increases in how much the subject has to work in order to obtain the drug, and increases in the availability of alternatives to drug use can all produce orderly reductions in drug consumption. That is true with laboratory animals and with drug-dependent human research subjects as well. In fact, a highly regarded series of studies conducted in the 1970s demonstrated this point with individuals with severe alcoholism (e.g., Bigelow et al. 1975). In these studies, alcoholic subjects resided on a hospital unit where they were permitted to purchase and consume alcohol under medically supervised conditions. Abstinence from voluntary drinking increased when 1) access to an alternative reinforcer (i.e., an enriched ward environment) was made available contingent on doing so, 2) monetary reinforcement was provided contingent on abstinence from alcohol consumption, 3) the cost of drinking in the form of the amount of work required to purchase the alcohol was increased, and 4) brief periods of social isolation were imposed contingent on drinking. Each of these outcomes followed from predictions based on alcohol use being a form of operant responding, which by definition is sensitive to environmental consequences. More recent studies conducted with cocaine and opioid abusers, marijuana abusers, and cigarette smokers have similarly conformed to predictions based on operant conditioning and demonstrated sensitivity of these different forms of drug use to systematically arranged environmental consequences (Higgins et al. 2004a). An obvious question is, if drug use is so sensitive to environmental consequences, why is it that individuals continue abusing drugs despite the many horrific adverse consequences that they experience? There are many answers to that question, but here are three important ones to consider. First, many individuals do respond to adverse consequences; that is, the majority of those who experiment with drug use, including the use of highly addictive drugs like cocaine, do not go on to become dependent, and many of those who do become dependent resolve their problem without professional treatment. Also, those drug-dependent individuals who seek treatment often do so following some untoward health or social consequences related to their drug abuse. A safe assumption is that naturalistic reinforcement and punishment contingencies are operative in these scenarios. Second, the reinforcing effects of drugs are relatively immediate and reliable, while associated adverse consequences are typically more delayed and intermittent. Temporal delays and inconsistent delivery weaken the effect of behavioral consequences. These features would favor a greater influence by the reinforcing effects of abused drugs than by their adverse effects. Third, recent research has revealed potentially important individual differences with regard to sensitivity to temporal delays that may be involved in vulnerability to drug dependence (see Bickel and Marsch 2001). A normal aspect of our biological makeup is a preference for more immediate over delayed reinforcement, all else being equal. Such a bias would have had obvious survival advantage in our

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evolutionary history. However, as with most everything biological, there is variability in this characteristic, and accumulating evidence indicates that individuals with SUDs discount the value of delayed consequences to a significantly greater extent than do nonabuser matched controls (Bickel and Marsch 2001). That is, individuals with SUDs, more so than those without, are more biased toward immediate reinforcement than delayed reinforcement, even when the more immediate option is of lesser value. Note that such a bias can be expected to work against recovery from SUDs, as the benefits of quitting drug use in terms of improved health, marriage, or vocation are going to be delayed in time relative to the immediate reinforcing effects that will follow in short order from a return to drug abuse. Indeed, in one of the first studies to look into this matter, greater discounting of delayed monetary reinforcement assessed upon treatment entry predicted postpartum relapse to smoking among women who quit smoking during pregnancy (Yoon et al. 2007). This relationship held even though the antepartum baseline assessment of delayed discounting was conducted almost 1 year prior to the 6-month postpartum assessment, when most relapse to smoking was noted. Overall, when considered together, the extensive literature supporting an important role of operant conditioning in drug use, the sensitivity of drug use to systematically delivered environmental consequences, and a possible bias of drug-dependent individuals toward immediate rather than delayed reinforcement all suggest that CM should be quite useful in the treatment of SUDs. In order to drive recovery, CM interventions use the same reinforcement process that drives repeated drug use. As is discussed in the following section, CM programs are designed to produce frequent, relatively immediate positive reinforcement for abstaining from drug use, rather than relying exclusively on more delayed naturalistic reinforcing consequences of recovery. This can be thought of as tailoring treatment to the known characteristics of the patient population. As is outlined below, the extant evidence on the efficacy of CM interventions for improving treatment outcomes across a wide range of different types of SUDs, populations, and settings suggests that the reinforcement process has as important a role to play in recovery from drug abuse as it does in its genesis and maintenance (Lussier et al. 2006).

BASIC ELEMENTS OF CM Before we turn to the literature on the efficacy of CM interventions for SUDs, some discussion of the basic elements of these interventions is warranted. A brief discussion is sufficient since these basic elements have been outlined elsewhere (e.g., Higgins et al. 2008). Briefly, CM interventions promote behavioral change through the use of one of the following generic types of contingencies administered alone or in combination. Positive reinforcement The delivery of a reinforcing consequence (e.g., a monetary voucher) contingent on meeting a therapeutic goal (e.g., abstinence from recent drug use). Negative reinforcement The removal or a reduction in the intensity of an aversive event (e.g., job suspension) contingent on meeting a therapeutic goal (e.g., successful completion of treatment). Positive punishment The delivery of an aversive event (e.g., social reprimand) contingent on evidence of the occurrence of a therapeutically undesirable response (e.g., failure to attend therapy sessions). Negative punishment The removal of a positive condition (e.g., forfeiture of clinic privileges) contingent on the occurrence of an undesirable response (e.g., resumption of drug use). Reinforcement and punishment interventions are effective with SUDs, but the latter are disliked by patients and staff and can inadvertently increase treatment dropout. The evidence suggests that CM interventions that are composed largely of high rates of positive reinforcement along with judicious use of occasional negative punishment can be very effective at retaining patients in treatment, reducing drug use, and improving other therapeutic outcomes (Lussier et al. 2006). To be effective, CM interventions need to be carefully designed and implemented—with CM, the details matter. Below are 10 points to consider when designing an effective CM intervention. 1. Use a written contract. A written contract is recommended. 2. Operationally define the therapeutic target. For example, when using a CM intervention to reinforce cocaine abstinence, the target would be abstinence from recent cocaine use as defined by a cocaine-negative urine toxicology result. 3. Stipulate the schedule on which progress will be monitored. The schedule for monitoring progress should be well specified. Staying with the example of a CM intervention for cocaine abstinence, the schedule might be a three-times-a-week (Monday, Wednesday, Friday) assessment of recent cocaine use. 4. Schedule frequent opportunities for patients to experience the programmed consequences. CM interventions are designed to promote new behavior while decreasing the frequency of well-learned behavior. As in any learning experience, repetition is important. The thrice-weekly schedule mentioned above has been effective in reinforcing abstinence from cocaine and opioid abuse. When designing the frequency of monitoring, one should consider practical issues, such as the half-life of the drug in question. 5. Objectively verify that the target response occurred. The methods for verifying that the target response occurred must be specified and should be objective; reliance on patient self-reports would not be adequate for these purposes. Furthermore, because many individuals with SUDs have lost the confidence of family, friends, and employers in their veracity by the time they enter treatment, objective monitoring of abstinence has the added benefit of providing an effective means to reduce suspicion about their progress in treatment and to rebuild respect among their significant others. For CM interventions to be effective they must be precise, and that is only possible when there is precision in determining whether the target response occurred. In applications with SUDs, objective and precise verification typically entails some form of testing for biological markers of recent drug use—for example, urine toxicology testing with specimen collection observed by a same-sex staff member would be conducted at the thrice-weekly assessments. 6. When feasible, target single rather than multiple responses. CM interventions that focus on a single target (e.g., cocaine abstinence) produce larger treatment effects on average than those that have multiple targets (e.g., abstinence from multiple substances; Lussier et al. 2006). This appears to be simply a matter of trying to have a reasonable balance

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between the behavioral change that is being targeted and the magnitude of the consequence being delivered. 7. Specify what consequences will follow when the target response occurs and when it does not occur. The consequences that will follow success and failure to emit the target behavior need to be made clear. For example, cocaine-negative urine toxicology results would earn a voucher with a specified monetary value that can be used to purchase retail items in the community. Cocaine-positive urine toxicology results would result in no voucher and a recommendation to meet with one's counselor as soon as possible. The exact schedule of voucher earnings over the course of the intervention would be specified. 8. Specify the duration of the contract. For example, the voucher program would be operative from weeks 1 through 12 of treatment. 9. Minimize delays in delivering consequences following verification. Delays weaken behavioral consequences. Delivering the consequence on the same day that occurrence of the target response is verified produces larger treatment effects than delivering the consequence on the next day or later (Lussier et al. 2006). Treatment outcome studies have not shown whether differences in response occur as a function of still further delays. Human laboratory studies suggest that the size of the treatment effect would progressively decrease as the length of the delay increased, until a delay was reached beyond which efficacy would disappear (see Higgins et al. 2004a). 10. Use a consequence of sufficient magnitude or intensity to function as an effective reinforcer or punisher. On average, larger-value incentives produce larger treatment effects (Lussier et al. 2006). With respect to the last point in the list above, it is important to note that the magnitude of reinforcement or punishment necessary to change behavior will depend on the nature of the behavioral change involved and the patient population, among other things. We know empirically that larger-value reinforcement on average results in larger treatment effects, with effect size varying in a graded manner across daily incentive values of less than $5, $5–$10.99, $11–$16, and greater than $16 (Lussier et al. 2006). Direction in choosing appropriate incentive magnitudes for the various populations and types of therapeutic targets with which one may be working is best obtained by consulting previously published studies involving those populations and therapeutic targets (or at least close approximations of them). The CM literature is sufficiently large at this time that there should not be situations where one cannot find a relevant study or two that provides at least some initial guidance in selecting appropriate parameters. Thereafter, some initial pilot testing of the new intervention with the targeted clinical population is essential to working out unforeseen problems and fine-tuning the parameters. The effects on treatment of SUDs of varying the intensity of punishment have not been assessed in any systematic manner in the CM literature, because of the sparse use of all but minimal punishment interventions. Based on the basic operant literature, effect size can be expected to vary as a function of the intensity of the punishment, and if the research calls for a higher-intensity punishment, it is best to implement it early in the intervention rather than gradually escalating intensity, which fosters habituation.

THE EVOLUTION OF A TREATMENT APPROACH: TREATMENT OUTCOME STUDIES ON CONTINGENCY MANAGEMENT AND SUDS Early CM Applications As is typical of treatment development, early reports on the use of CM to treat SUDs first appeared in the form of uncontrolled case studies in which, for example, smokers earned back portions of a monetary deposit contingent on remaining abstinent from smoking, amphetamine abusers earned retail items donated by community businesses contingent on drug abstinence, or individuals with chronic alcoholic dependence earned coupon booklets contingent on submitting alcohol-negative breath specimens. A particularly impressive seminal controlled study in this area was reported by Miller (1975). In this study, 20 homeless men with severe alcohol dependence were randomly assigned to a control condition or CM intervention. Those in the control condition received the usual social services in the form of food, clothing, and housing, while those in the CM condition received those same services as long as they sustained abstinence, verified through breath alcohol testing and observation of signs of gross intoxication. Evidence of drinking resulted in a 5-day suspension from such services. Arrests for public drunkenness decreased and days of employment increased among those in the contingent condition compared with the control condition. These impressive findings were not followed up in the published literature in any systematic manner, but CM began to be pursued as a treatment for other types of SUDs. Several controlled studies reported that abstinence levels increased when cigarette smokers had to submit monetary deposits that they earned back in portions contingent on remaining abstinent (e.g., Bowers et al. 1987). Other investigators reported controlled studies demonstrating that contingent cash payments increased abstinence from cigarette smoking (e.g., Stitzer and Bigelow 1982). Large-scale workplace and community incentive-based interventions for smoking cessation also appeared in the 1980s; however, results from those interventions were not encouraging, most likely because of a failure by investigators to adhere to the points listed in the numbered list earlier in this chapter, especially the points regarding reinforcement magnitude and frequency in the monitoring of abstinence. For a more detailed examination of CM and smoking, see a review by Sigmon et al. (2008). A particularly influential and programmatic series of controlled experimental studies was conducted with patients enrolled in methadone treatment for opiate dependence (see Stitzer et al. 1984). These studies firmly established the efficacy of using contingent positive reinforcement, such as access to clinic privileges (e.g., methadone take-home privileges), cash payments, and adjustments in methadone dose, for increasing abstinence from illicit drug use. For example, 10 patients receiving methadone maintenance treatment and with consistently positive urine toxicology results for benzodiazepine use participated in a study using a within-subject reversal design (Stitzer et al. 1982). During a 12-week intervention period, patients earned 2 days of medication take-home privileges, a cash payment ($15.00), or a 20-mg methadone dose adjustment contingent on submitting benzodiazepine-negative urine toxicology results. Reinforcers were not available during the baseline periods that preceded and followed the intervention period. During the intervention period, 43% of specimens were benzodiazepine-negative compared with

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only 3.6% and 7.9% in the initial and final baseline periods. These controlled studies from the 1980s provided a strong empirical foundation and clear proof-of-concept evidence for the development of CM as a formal treatment for SUDs. Other uncontrolled studies conducted with health care workers during this same period suggested that CM may be efficacious in treating cocaine dependence (e.g., Crowley 1985–1986), which was an important observation, considering that cocaine dependence was emerging as a major public health concern in the United States at the time that the studies were conducted. The cocaine epidemic caught drug abuse experts unprepared and created a strong need for effective treatments, and many of the treatments examined, both behavioral and pharmacological, were ineffective. An exception was a CM intervention that has come to be known as voucher-based reinforcement therapy (VBRT).

Voucher-Based Reinforcement Therapy Cocaine and opiate abuse With VBRT, patients earn vouchers that are exchangeable for retail items, which is contingent on biochemically verified abstinence from recent drug use or meeting some other therapeutic target. The initial trials with VBRT integrated it with an intensive behavioral therapy known as the community reinforcement approach (CRA) and thus did not allow for inferences regarding what contributions VBRT was making to the positive outcomes obtained with the CRA-plus-vouchers intervention (Higgins et al. 1991). Nevertheless, the positive outcomes obtained with the CRA-plus-VBRT intervention were in such contrast with the many negative outcomes that were being reported in efforts to treat cocaine dependence that it garnered a large amount of attention. Inferences about the contributions of VBRT to research outcomes were made possible through a series of experiments in which 40 cocaine-dependent outpatients were randomly assigned to 24 weeks of CRA treatment, with half of the patients receiving VBRT during weeks 1–12 (Higgins et al. 1994). Seventy-five percent of patients assigned to the VBRT condition were retained in treatment for the recommended 24 weeks, compared with only 40% in the condition without VBRT. Those who received VBRT achieved an average of 11.5 + 2.0 weeks of continuous cocaine abstinence, compared with only 6.0 + 1.5 weeks of abstinence by those not receiving VBRT. This trial demonstrated that VBRT increased treatment retention and cocaine abstinence among cocainedependent outpatients, a group for whom there were no reliably efficacious treatments. Subsequent randomized clinical trials conducted in this same clinic demonstrated the reliability of the treatment effects and showed that the positive effects of VBRT on cocaine abstinence remained discernible throughout the 2 years following treatment entry (e.g., Higgins et al. 2007). Because the basic voucher schedule arrangement used in those original studies by Higgins et al. (1994) with cocaine-dependent outpatients became the prototype on which most subsequent VBRT interventions were based, we describe it in detail here. Urine specimens were collected during treatment weeks 1–12 and tested for benzoylecgonine, a cocaine metabolite. Specimens that tested negative for cocaine earned points that were recorded on vouchers and given to subjects. Each point was worth the equivalent of $0.25. The first specimen to test negative for cocaine per subject earned 10 points, or $2.50. The value of each subsequent consecutive cocaine-negative specimen increased by 5 points. The equivalent of a $10 bonus was provided for each three consecutive cocaine-negative specimens. The intent of the escalating magnitude of reinforcement and bonuses was to reinforce continuous cocaine abstinence. Cocaine-positive specimens or failure to submit a scheduled specimen reset the value of vouchers back to the initial $2.50 value. This feature was designed to punish relapse back to cocaine use following a period of sustained abstinence, with the intensity of the punishment tied directly to the length of sustained abstinence that would be broken. In order to provide patients with a reason to continue abstaining from use following a reset, submission of five consecutive cocaine-negative specimens following a cocaine-positive specimen returned the value of points to where they were prior to the reset. Points could not be lost once earned. Use of vouchers had to be approved by staff who recommended patients to use them to support the healthy lifestyle changes that were being encouraged as part of the CRA therapy they received. Of course, all purchases had to be legal and not involve alcohol, cigarettes, or firearms. Testing positive for drug use other than cocaine did not affect the voucher program or have any other programmed consequence. Key to the successful development of VBRT was demonstrating that it was efficacious when used by other investigators and, even more importantly, demonstrating that it had efficacy with an inner-city population of cocaine abusers. The VBRT studies by Higgins and colleagues were conducted in Burlington, Vermont, a small metropolitan area in a largely rural state with an almost exclusively white population (Higgins et al. 1991, 1994). That patient population included a large proportion of intranasal cocaine users (such users generally have a better prognosis). The seminal study extending VBRT to the large, inner-city setting was a randomized, controlled trial conducted with 37 intravenous cocaine abusers enrolled in methadone maintenance treatment for opiate dependence (Silverman et al. 1996). The schedule arrangement in the experimental condition was largely the same as in the studies by Higgins et al. (1991, 1994), with patients assigned to 12 weeks of VBRT in which earning vouchers was contingent on cocaine abstinence. Those assigned to a noncontingent control condition earned vouchers in an amount and pattern that was yoked to the experimental condition but delivered independent of cocaine use. Those assigned to the abstinence-contingent voucher condition achieved significantly greater cocaine abstinence compared with those assigned to the control condition—for example, 47% of patients assigned to abstinence-contingent vouchers achieved between 7 and 12 weeks of continuous abstinence, compared with 0% in the noncontingent voucher control condition. Only one patient (6%) assigned to the noncontingent control condition achieved greater than 2 weeks of continuous cocaine abstinence. The results of this study provide compelling evidence supporting the generality of earlier findings about VBRT to inner-city populations and methadone patients. Other VBRT trials investigated the efficacy of VBRT in promoting abstinence from illicit opioid abuse (Silverman et al. 1996), demonstrated that the use of opioids sometimes decreased along with cocaine use when CM explicitly targeted only cocaine abstinence (Silverman et al. 1998), and supported the efficacy of increasing the magnitude of VBRT in order to promote a treatment response in recalcitrant cocaine abusers (e.g., Silverman et al. 1999).

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Interest in and research on VBRT as a treatment for SUDs grew considerably after the first publication on that form of CM, extending use of the intervention to a wide range of different substances, populations, and settings. A meta-analysis by Lussier et al. (2006) on VBRT identified more than 60 reports of controlled studies published in peer-reviewed journals examining VBRT as a treatment for SUDs, with robust evidence supporting its efficacy. Figure 27–1 shows average effect sizes for VBRT across different drugs targeted by the intervention as well as potential moderator variables. No significant differences were noted between the different types of drug abuse targeted, although a clear trend toward smaller effect sizes when targeting multiple substances is discernible. The only drug for which the 95% confidence intervals overlapped with zero (suggesting no significant treatment effect) was alcohol, on which there was only a single study and thus larger variance. Analyses of potential moderator variables indicated that greater monetary value of potential daily earnings and immediate (same-day) versus delayed delivery of the voucher were associated with larger treatment effects. FIGURE 27–1. Estimated effect size (r) and 95% confidence intervals.

Weighted average effect sizes and 95% confidence intervals for subsets of studies as a function of the moderator variables: target, control condition, duration, daily earnings, voucher-based reinforcement therapy (VBRT) delivery immediacy, setting, and study quality. All studies target abstinence (N = 30). Weighted average effect sizes are represented by closed diamonds and 95% confidence intervals by solid lines. Where confidence intervals do not overlap, differences between subsets of studies are significantly different at the 0.05 level. Source Reprinted from Lussier JP, Heil SH, Mongeon JA, et al: "A Meta-Analysis of Voucher-Based Reinforcement Therapy for Substance Use Disorders." Addiction 101:192–203, 2006. Used with permission.

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Building upon the success of VBRT in reducing cocaine abuse among cocaine-dependent methadone patients, other studies were conducted demonstrating efficacy in reducing illicit opiate abuse in this population. In one such study, 120 methadone patients who continued to abuse heroin were randomly assigned to receive a methadone dose increase, abstinence-contingent vouchers (maximum earnings of $554 in 8 weeks), a combination of the methadone dose increase with abstinence-contingent vouchers, or continued treatment with a standard intervention technique. Contingent vouchers increased opiate abstinence significantly above the standard intervention, whereas the methadone dose increase did not. The combination treatment was equal to the vouchers-only condition, suggesting that it was the vouchers that produced the increases in abstinence (Preston et al. 2000).

Other drugs of abuse As illustrated in Figure 27–1, VBRT has been extended to a broad range of different SUDs. For illustration purposes, we discuss here the extension to marijuana use disorders. Some thought CM would not be feasible in treating marijuana abuse because of the long half-life of tetrahydrocannabinol, which might be expected to result in too long a delay in being able to deliver contingent reinforcement for abstinence. Such concerns notwithstanding, VBRT has been successfully extended to outpatient treatment of marijuana dependence. For example, a study examining the addition of VBRT to a treatment of motivational enhancement and coping skills therapy increased end-of-treatment abstinence more than threefold compared with the motivational enhancement therapy alone or motivational therapy plus coping skills (Budney et al. 2000).

Fishbowl Procedure Petry et al. (2000) developed a variation of VBRT designed to lower cost without losing efficacy. In this procedure, rather than having each occurrence of the target response reinforced, patients earned the opportunity to draw from a fishbowl that contained vouchers of varying value, including many that were of zero value but offered verbal praise, some that were of relatively low monetary value (e.g., $1), still fewer of moderate value ($20), and a very few worth high monetary value ($100). Instead of exchanging these vouchers for the opportunity to make retail purchases in the community, patients chose among prize items already available at the clinic. Importantly, this modified arrangement has been demonstrated to be efficacious for increasing cocaine and opioid abstinence in drug-free and methadone community clinics; however, there is no evidence that this more complex schedule arrangement results in better outcomes than the more conventional voucher program that uses vouchers of lower value. In the only direct comparison of the fishbowl and conventional voucher programs offered at comparable values, both methods improved outcomes above a control condition and there was no significant difference between the fishbowl and conventional voucher programs (Petry et al. 2005a). Thus the important contributions of this development are that it is less costly than the original VBRT intervention and it is efficacious, giving it a better likelihood than more expensive arrangements of being adopted by community clinics where cost concerns are an important priority. The likelihood of its increased use seems certain given the results obtained in two multisite trials conducted in community clinics as part of the National Institute on Drug Abuse Clinical Trials Network, in which the procedure was shown to improve outcomes of stimulant abusers enrolled in drug-free and methadone clinics (Peirce et al. 2006; Petry et al. 2005b). There is no evidence that lowering costs with this fishbowl arrangement gets around the relationship between treatment effect size and reinforcement magnitude in VBRT interventions. Indeed, as expected, effect sizes obtained with the fishbowl intervention appear to be smaller than those achieved with more expensive VBRT interventions in comparable populations (Lussier et al. 2006).

Treating Special Populations Identifying effective treatments for special populations of individuals with SUDs is an important challenge, and another important development of VBRT is its extension to the treatment of such populations (for a review, see Higgins et al. 2008). The application of VBRT in treating pregnant smokers provides an excellent example of this extension of VBRT. Maternal cigarette smoking is a leading preventable cause of poor pregnancy outcome and pediatric morbidity. Effective interventions for promoting smoking cessation among pregnant women are available, but only about 15% of women who receive them actually quit smoking. Controlled trials indicated that VBRT could increase quit rates to more than 30%. In one of these trials, VBRT was studied with 58 women who were still smoking upon entering prenatal care and were assigned to either contingent or noncontingent voucher conditions (Higgins et al. 2004b). In the contingent condition, vouchers were earned for biochemically verified smoking abstinence; in the noncontingent condition, vouchers were earned independent of smoking status. Contingent vouchers significantly increased abstinence at the end of pregnancy (37% vs. 9%) and at 12-week postpartum (33% vs. 0%) assessments. The effect of contingent vouchers remained significant at the 24-week postpartum assessment (27% vs. 0%), which was 12 weeks after discontinuation of the voucher program. The magnitude of these treatment effects exceeds levels typically observed with pregnant and postpartum smokers, and the maintenance of effects through 24 weeks postpartum exceeds previously reported durations. Another example of this important direction is a study by Krishnan-Sarin et al. (2008) using VBRT to promote smoking cessation among adolescents. Twenty-eight adolescent smokers participated in a 1-month, school-based smoking cessation program in which they were randomly assigned to receive either cognitive-behavioral therapy (CBT) alone or CM combined with weekly CBT. In the CM plus CBT group, biochemical verification of abstinence was obtained twice daily during the first 2 weeks, followed by daily appointments during the third week and appointments once every other day during the fourth week. Participants earned monetary reinforcement contingent on abstinence. At the end of weeks 1 and 4 , abstinence verified using quantitative urine cotinine levels was higher in participants in the CM plus CBT group (week 1: 76.7%; week 4: 53.0%) compared to CBT alone (week 1: 7.2%; week 4: 0%).

IMPROVING CM INTERVENTIONS: INITIAL TREATMENT RESPONSE AND LONGER-TERM OUTCOMES

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While the treatment effects obtained with CM are impressive, often 50% of patients treated or more do not have positive outcomes. The 10-point list earlier in this chapter (in the section titled "Basic Elements of CM") represents what is known about how to increase treatment response. Using a higher magnitude of reinforcement, minimizing delay in reinforcement delivery, targeting one response rather than multiple responses, and monitoring abstinence more frequently are all associated with larger treatment effects (Lussier et al. 2006). The parameter for which there is the greatest amount of evidence, including experimental evidence and results from meta-analyses, is reinforcement magnitude (e.g., Higgins et al. 2007; Silverman et al. 1999). Regarding longer-term outcomes, several studies have shown that VBRT effects on abstinence sometimes last for as long as 21 months following discontinuation of the intervention (e.g., Higgins et al. 2007). However, many patients exposed to VBRT or other CM interventions resume drug use following discontinuation of the intervention. Identifying ways to sustain treatment effects over time is a priority with CM just as it is with virtually all treatments for SUDs. A number of trials have investigated combining VBRT with relapse prevention therapy, but there is no evidence that this combination extends treatment effects beyond those obtained with VBRT alone (Rawson et al. 2002). Another avenue that is being pursued is to use VBRT to increase the proportion of patients who achieve a sustained period of abstinence during treatment. This approach grew out of observations in studies where VBRT effects were sustained during posttreatment follow-up as compared with control treatments. In those studies the probability of posttreatment abstinence during follow-up increased as a function of the duration of continuous abstinence achieved during treatment to a comparable extent in the VBRT and control treatments (e.g., Higgins et al. 2007). Knowing that greater reinforcement magnitude produces larger effects during the treatment period, Higgins et al. (2007) conducted a randomized clinical trial to see if posttreatment outcomes could be increased as well by increasing reinforcement magnitude. In this study, 100 cocaine-dependent adults were randomly assigned to receive treatment based on CRA plus VBRT set at a relatively high monetary value (maximal value = $1,995/12 weeks) or CRA with VBRT set at a relatively low monetary value (maximal value = $499/12 weeks). The high-value vouchers were used to test the concept and not with the idea that they would have direct practical application. Earning vouchers was contingent on cocaine-negative urinalysis results during the initial 12 weeks of the 24-week outpatient treatment. It was found that increasing voucher value significantly increased the duration of continuous cocaine abstinence achieved during treatment and, as hypothesized, point-prevalence cocaine abstinence assessed every 3 months throughout an 18-month posttreatment follow-up period was greater in the high-value than in the low-value voucher condition (Figure 27–2). As in prior studies, the duration of abstinence achieved during treatment predicted posttreatment abstinence, although that relationship weakened over time. Overall, increasing the value of abstinence-contingent incentives during the initial 12 weeks of treatment represented an effective method for increasing during-treatment and longer-term cocaine abstinence, although the positive association of during-treatment abstinence with longer-term outcome dissipated over time. This is a research avenue that will continue to be evaluated. FIGURE 27–2. Periodic abstinence assessments.

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Percentages of participants abstinent at each of the periodic assessments conducted with subjects retained in treatment as well as dropouts. Data points represent point-prevalence abstinence at the respective assessments. Abstinence was defined as a self-report of no cocaine use in the past 30 days and cocaine-negative urinalysis results. In categorical modeling, abstinence levels were significantly higher in the high-value than low-value voucher conditions based on assessments during treatment (1.5 and 3.0 months, P = 0.02) and follow-up (6- through 24-month assessments, P = 0.04). Source Reprinted from Higgins ST, Heil SH, Dantona R, et al: "Effects of Varying the Monetary Value of Voucher-Based Incentives on Abstinence Achieved During and Following Treatment Among Cocaine-Dependent Outpatients." Addiction 102:271–281, 2007. Used with permission. Silverman et al. (2004) conducted a seminal study examining the use of VBRT as a maintenance intervention. This study examined whether long-term abstinence reinforcement could maintain cocaine abstinence throughout a 1-year period. Patients who injected drugs and used cocaine during methadone treatment (N = 78) were randomly assigned to one of two abstinence-reinforcement groups or to a usual-care control group. Participants in the two abstinence-reinforcement groups could earn take-home methadone doses for providing opiate- and cocaine-free urine samples; participants in one of those groups also could earn $5,800 in vouchers for providing cocaine-free urine samples over 52 weeks. Both abstinence-reinforcement interventions increased cocaine abstinence, but the addition of the voucher intervention resulted in the largest and most sustained abstinence (Figure 27–3). Indeed, patients in the condition with take-homes and VBRT who achieved a period of continuous cocaine abstinence often sustained it through the duration of the voucher program and beyond. Patients in the other treatment conditions rarely achieved comparable levels of sustained abstinence. The study provided proof of concept that VBRT could be a highly effective maintenance intervention for cocaine abstinence in methadone patients. FIGURE 27–3. Cocaine urinalysis results across consecutive urine samples for individual participants in each of the three experimental conditions.

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Top, middle, and bottom panels represent data for the take-home plus voucher, take-home only, and usual-care control conditions. The vertical dashed lines divide each panel into three periods, the baseline (left), the intervention (center), and the postintervention (right) periods. Within each panel, horizontal lines represent the cocaine urinalysis results for individual participants across the consecutive scheduled urine collections of the study. The heavy portion of each line represents cocainenegative urinalysis results, the thin portions of each line represent cocaine-positive urinalysis results, and the blank portions represent missing urine samples. Within each panel, participants are arranged from those showing the least abstinence (fewest cocaine-negative urines) on the bottom of the panel to participants with the most abstinence on the top. The numerals on the ordinates represent participant identification numbers. Source Reprinted from Silverman K, Robles E, Mudric T, et al: "A Randomized Trial of Long-Term Reinforcement of Cocaine Abstinence in Methadone-Maintained Patients Who Inject Drugs." Journal of Consulting and Clinical Psychology 72:839–854, 2004. Used with permission.

DISSEMINATION: COMMUNITY DRUG ABUSE TREATMENT PROGRAMS Cost is an important obstacle when considering dissemination of CM into community substance abuse treatment clinics and there have been encouraging developments in this area. The positive outcomes obtained in the multisite trials using the fishbowl procedure are quite promising and are likely to facilitate successful dissemination (Peirce et al. 2006; Petry et al. 2005b). The New York City Health and Hospitals Corporation, the largest provider of public treatment for substance abuse in New York City, launched low-cost CM programs in five of its community substance abuse treatment clinics that were supported through public funds (Kellogg et al. 2005). In an initiative that received broad media coverage (e.g., Ornstein 2005), the San Francisco Department of Public Health established a VBRT program for gay and bisexual methamphetamine abusers. Another strategy is to integrate existing community services into CM arrangements. Two programs offer exciting examples of how this can be done effectively. One is a program for patients with SUDs and serious mental illness where the CM program is built around patients' Social Security disability benefits (Ries et al. 2004). The clinic serves as the designated payee and patients gain progressively greater control over the use of those benefits contingent on verified abstinence from drug use. Another exciting program is being conducted as part of the U.S. Department of Veterans Affairs Compensated Work Therapy program, which provides veterans with chronic employment problems access to paid training and supported paid employment. Perhaps not surprisingly, SUDs are an important problem in these programs. Drebing et al. (2005) have demonstrated how VBRT can be used to increase abstinence and job-seeking and job placement activities in that setting. Workplaces offer important opportunities to arrange abstinence reinforcement opportunities because of the resources that they control in the form of wages and benefits. Silverman et al. (2002) developed a model referred to as the therapeutic workplace that is designed to treat chronically unemployed adults. This program has been evaluated with pregnant and recently postpartum women who were continuing to abuse cocaine and heroin despite being enrolled in methadone treatment. Forty women were randomly assigned either to the therapeutic workplace or to usual care. For those assigned to the therapeutic workplace, daily entry into the work setting was contingent on verified abstinence from cocaine and opiate use and once in the program they earned vouchers contingent on job performance. The intervention was in place for several years, with significantly more women in the workplace abstinent from cocaine and opiates than in usual care (30% vs. 5%) during year 3 (Silverman et al. 2002). The emergence of the U.S. drug court system holds tremendous promise for the successful dissemination of CM into mainstream rehabilitation for SUDs (see Marlowe and Wong 2008). Drug courts are themselves an explicit CM program wherein reinforcers and punishers, termed incentives and sanctions within the drug court literature, are used to systematically leverage nonviolent criminals with SUDs to obtain the treatment that they need. It is difficult to imagine a better setting in which to successfully disseminate CM practices.

CONCLUSION CM treatments have developed in many exciting directions during the past two decades and represent an important part of evidence-based treatments for SUDs. The varied CM applications outlined in this chapter demonstrate the relevance of basic principles of behavioral science to the treatment of SUDs, the striking effectiveness and versatility of CM interventions, and the feasibility of disseminating these interventions in society, both through community treatment clinics and through other settings, such as workplaces, the Veterans Affairs hospital system, and drug courts. Despite the promise of CM interventions suggested in this extensive body of research, the research reviewed in this chapter also shows that more work is needed in order to find ways to increase the effectiveness of the interventions so that they will succeed with even more patients, to develop methods that will ensure longer-term maintenance of beneficial effects over time, and to continue to develop and refine practical applications that will be used widely in society. Thus, this chapter outlines the impressive effectiveness and promise of CM interventions as well as the areas where additional research and more development are needed. As is amply shown in the research reviewed in this chapter, CM interventions are not a bag of arbitrary tricks but an orderly set of procedures that are based on fundamental principles of behavioral science. As such, the further improvement and development of these procedures can be guided by the basic scientific principles on which the interventions are based. The broad success the field has achieved to date in applying these basic principles to treat SUDs across populations, drugs, and settings should give great confidence that we can continue to develop and improve CM interventions to address the costly and devastating consequences of SUDs.

KEY POINTS

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Contingency management (CM) is based on an extensive basic science literature that demonstrates an important role for operant conditioning in the genesis and maintenance of drug use. CM is an efficacious intervention for a wide range of different types of substance abuse disorders and populations. CM has some basic features outlined in the section "Basic Elements of CM" that are important to effective implementation.

REFERENCES Bickel WK, Marsch LA: Toward a behavioral economic understanding of drug dependence: delay discounting processes. Addiction 96:73–86, 2001 [PubMed] Bigelow G, Griffiths R, Liebson I: Experimental models for the modification of human drug self-administration: methodological developments in the study of ethanol self-administration by alcoholics. Fed Proc 34:1785–1792, 1975 [PubMed] Bowers TG, Winett RA, Frederiksen LW: Nicotine fading, behavioral contracting, and extended treatment: effects on smoking cessation. Addict Behav 12:181–184, 1987 [PubMed] Budney A, Higgins ST, Radonovich KJ, et al: Adding voucher-based incentives to coping skills and motivational enhancement improves outcomes during treatment for marijuana dependence. J Consult Clin Psychol 68:1051–1061, 2000 [PubMed] Crowley TJ: Doctors' drug abuse reduced during contingency-contracting treatment. Alcohol Drug Res 6:299–307, 1985–1986 [PubMed] Drebing CE, Van Ormer EA, Krebs C, et al: The impact of enhanced incentives on vocational rehabilitation outcomes for dually diagnosed veterans. J Appl Behav Anal 38:359–372, 2005 [PubMed] Higgins ST, Delaney DD, Budney AJ, et al: A behavioral approach to achieving initial cocaine abstinence. Am J Psychiatry 148:1218–1224, 1991 [PubMed] Higgins ST, Budney AJ, Bickel WK, et al: Incentives improve outcome in outpatient behavioral treatment of cocaine dependence. Arch Gen Psychiatry 51:568–576, 1994 [PubMed] Higgins ST, Heil SH, Lussier JP: Clinical implications of reinforcement as a determinant of substance use disorders. Annu Rev Psychol 55:431–461, 2004a Higgins ST, Heil SH, Solomon LJ, et al: A pilot study on voucher-based incentives to promote abstinence from cigarette smoking during pregnancy and postpartum. Nicotine Tob Res 6:1015–1020, 2004b Higgins ST, Heil SH, Dantona R, et al: Effects of varying the monetary value of voucher-based incentives on abstinence achieved during and following treatment among cocaine-dependent outpatients. Addiction 102:271–281, 2007 [PubMed] Higgins ST, Heil SH, Rogers RE, et al: Cocaine, in Contingency Management in the Treatment of Substance Use Disorders. Edited by Higgins, ST, Silverman K, Heil SH. New York, Guilford, 2008, pp 19–41 Kellogg SH, Burns M, Coleman P, et al: Something of value: the introduction of contingency management interventions into the New York City Health and Hospital Addiction Treatment Service. J Subst Abuse Treat 28:57–65, 2005 [PubMed] Krishnan-Sarin S, Duhig A, Cavallo D: Adolescents, in Contingency Management in the Treatment of Substance Use Disorders. Edited by Higgins ST, Silverman K, Heil SH. New York, Guilford, 2008, pp 222–240 Lussier JP, Heil SH, Mongeon JA, et al: A meta-analysis of voucher-based reinforcement therapy for substance use disorders. Addiction 101:192–203, 2006 [PubMed] Marlowe DB, Wong CJ: Contingency management in the adult criminal drug courts, in Contingency Management in the Treatment of Substance Use Disorders. Edited by Higgins ST, Silverman K, Heil SH. New York, Guilford, 2008, pp 298–333 Miller PM: A behavioral intervention program for chronic public drunkenness offenders. Arch Gen Psychiatry 32:915–918, 1975 [PubMed] Ornstein C: Quitting meth pays off. L.A. Times, November 14, 2005 Peirce JM, Petry NM, Stitzer ML, et al: Effects of lower-cost incentives on stimulant abstinence in methadone maintenance treatment: a National Drug Abuse Treatment Clinical Trials Network Study. Arch Gen Psychiatry 63:201–208, 2006 [PubMed] Petry NM, Martin B, Cooney JL, et al: Give them prizes, and they will come: contingency management for treatment of alcohol dependence. J Consult Clin Psychol 68:250–257, 2000 [PubMed] Petry NM, Alessi SM, Marx J, et al: Vouchers versus prizes: contingency management treatment of substance abusers in community settings. J Consult Clin Psychol 73:1005–1014, 2005a Petry NM, Peirce JM, Stitzer ML, et al: Effect of prize-based incentives on outcomes in stimulant abusers in outpatient psychosocial treatment programs: a National Drug Abuse Treatment Clinical Trials Network Study. Arch Gen Psychiatry 62:1148–1156, 2005b Preston KL, Umbricht A, Epstein DH: Methadone dose increase and abstinence reinforcement for treatment of continued heroin use during methadone maintenance. Arch Gen Psychiatry 57: 395–404, 2000 [PubMed] Rawson RA, Huber A, McCann M, et al: A comparison of contingency management and cognitive-behavioral approaches during methadone maintenance treatment for cocaine dependence. Arch Gen Psychiatry, 59:817–824, 2002 [PubMed]

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Ries RK, Dyck DG, Short R, et al: Outcomes of managing disability benefits among patients with substance dependence and severe mental illness. Psychiatr Serv 55:445–447, 2004 [Full Text] [PubMed] Sigmon SC, Lamb R, Dallery J: Tobacco, in Contingency Management in the Treatment of Substance Use Disorders. Edited by Higgins ST, Silverman K, Heil SH. New York, Guilford, 2008, pp 99–119 Silverman K, Higgins ST, Brooner RK, et al: Sustained cocaine abstinence in methadone maintenance patients through voucher-based reinforcement therapy. Arch Gen Psychiatry 53:409–415, 1996 [PubMed] Silverman K, Wong CJ, Umbricht-Schneiter A, et al: Broad beneficial effects of cocaine abstinence reinforcement among methadone patients. J Consult Clin Psychol 66:811–824, 1998 [PubMed] Silverman K, Chutuape MA, Bigelow GE, et al: Voucher-based reinforcement of cocaine abstinence in treatment-resistant methadone patients: effects of reinforcement magnitude. Psychopharmacology (Berl) 146:128–138, 1999 [PubMed] Silverman K, Svikis D, Wong CJ, et al: A reinforcement-based therapeutic workplace for the treatment of drug abuse: three-year abstinence outcomes. Exp Clin Psychopharmacol 10:228–240, 2002 [PubMed] Silverman K, Robles E, Mudric T, et al: A randomized trial of long-term reinforcement of cocaine abstinence in methadonemaintained patients who inject drugs. J Consult Clin Psychol 72:839–854, 2004 [PubMed] Stitzer ML, Bigelow GE: Contingent reinforcement for reduced carbon monoxide levels in cigarette smokers. Addict Behav 7:403–412, 1982 [PubMed] Stitzer ML, Bigelow GE, Liebson IA, et al: Contingent reinforcement for benzodiazepine-free urines: evaluation of a drug abuse treatment intervention. J Appl Behav Anal 15:493–503, 1982 [PubMed] Stitzer ML, Bigelow GE, Liebson IA, et al: Contingency management of supplemental drug use during methadone maintenance treatment. NIDA Res Monogr 46:84–103, 1984 [PubMed] Yoon JH, Higgins ST, Heil SH, et al: Delay discounting predicts postpartum relapse to cigarette smoking among pregnant women. Exp Clin Psychopharmacol 15:176–186, 2007 [PubMed]

SUGGESTED READING Higgins ST, Silverman K, Heil SH (eds): Contingency Management in the Treatment of Substance Use Disorders. New York, Guilford, 2008 Copyright © 2011 Amer can Psychiatric Associat on. All Rights Reserved.

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Chapter 28. Network Therapy

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Marc Galanter: Chapter 28. Network Therapy, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Pub lishing, Inc. DOI: 10.1176/appi.books.9781585623440.348490. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Network Therapy Marc Galanter, M.D.

NETWORK THERAPY: INTRODUCTION Network therapy (Galanter 1999) can be defined as a multimodal approach to rehabilitation in which specific family members and friends are enlisted to provide ongoing support and promote attitude change. The goal of this approach is the prompt achievement of abstinence, with relapse prevention and the development of a drug-free adaptation. Network members are part of the therapist's working team and are not recipients of treatment. A distinction can be drawn between two different approaches for engaging family and friends in moving an addict toward recovery (Stanton 2004). One way is to meet with them and a willing patient to initiate treatment. Network therapy typically employs this approach and is tailored for most addicted people who can be engaged in treatment, even if reluctant, if the option is presented in a positive manner and if the members of the network are supported in being constructive and helpful. A second approach relates to a resistant patient. In this case, the clinician may prepare the friends and family in the absence of the patient. Most mental health professionals are ill prepared to help alcoholic or drug-abusing patients achieve recovery, even though addicted patients and their families regularly turn to them for help. Furthermore, few alcoholic or drug-addicted individuals are willing to go to 12-step programs, such as Alcoholics Anonymous (AA), until they have endured their illness for a long time, and most drop out before becoming involved. A pointed question inevitably arises: How can health care providers engage and treat these troubled, addicted individuals more effectively? In recent years, length of stay in inpatient rehabilitation facilities for substance-abusing patients has become increasingly limited. Programs at these facilities have been useful in that they terminate patients' access to drugs and create a safe environment for detoxification and education. Nonetheless, family and social ties are often disrupted while patients are hospitalized. The programs also do not allow patients to deal with drinking cues in the home environment. The practitioner should therefore attempt to support a patient's rehabilitation by means of the social ties available in his or her own community. An individual's network enhances the effectiveness of ambulatory therapy and includes his or her spouse, friends, and/or family of origin. Components of the network are parts of the natural support system that usually operates without professional involvement, and if these components can be brought to act in concert, the network can serve as a therapeutic device. The network can complement individual or group therapy and AA.

ADDRESSING RELAPSE AND LOSS OF CONTROL To develop a social therapy involving network support, one must first define the target problem clearly and then consider the effect of the network on the problem. From a clinician's perspective, the problems of relapse and loss of control, embodied in the third and fourth criteria for substance dependence in DSM-IV-TR (American Psychiatric Association 2000), are central to the difficulty in treating addiction. Because addicted patients are typically under pressure to relapse, they are unlikely to attend treatment sessions regularly, and they tend to drop out of treatment precipitously. Loss of control has been used to describe an addicted individual's inability to reliably limit consumption once an initial dose is taken.

A Conditioning Model These clinical phenomena are generally described anecdotally but can also be explained mechanistically, using the model of conditioned withdrawal, which relates the psychopharmacology of dependence-producing drugs to the behaviors they produce. Wikler (1971), an early investigator of addiction pharmacology, developed this model to explain the spontaneous appearance of drug craving and relapse. He pointed out that drugs of dependence typically produce compensatory responses in the central nervous system at the same time that their direct pharmacological effects are felt, and these compensatory effects partly counter the drugs' direct actions. Thus, when an opioid antagonist is administered to addicted subjects who are receiving morphine maintenance treatment, latent withdrawal phenomena are unmasked. Similar compensatory effects are observed in alcoholic subjects maintained on alcohol, who, while still clinically intoxicated, manifest evoked response patterns characteristic of withdrawal. Other investigators found that addicted subjects could be conditioned to experience opioid withdrawal responses to neutral stimuli, such as sound and odor. This conditioning, produced in a laboratory setting, lent support to Wikler's hypothesis. Furthermore, for the alcoholic subject, the alcohol dose itself can serve as a conditioned stimulus for enhancing craving, as can the appropriate drinking context. Clinical interviews show that withdrawal feelings, and therefore craving, can be elicited by cues previously associated with the

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addicted subject's use of the drug. Hence, exposure to the smell of liquor in a bar can precipitate the "need" to drink, and seeing the "works" for injecting heroin, or going by a "shooting gallery," can lead a heroin-addicted individual to relapse. The conditioned stimulus of a drug or an environmental cue, or even the affective state regularly associated with the drug, can lead directly to the behavioral response before the addicted individual consciously experiences withdrawal feelings. The individual may automatically seek out drugs upon experiencing anxiety, depression, or narcissistic injury, all of which may have become conditioned stimuli. Often, modulations of mood are the conditioned stimuli for drug seeking, and the substance-abusing individual can become vulnerable to relapse through reflexive response to a specific affective state. Khantzian (1985) described such phenomena clinically as self-medication. Such mood-related cues, however, are not necessarily mentioned spontaneously by the patient in conventional therapy because the triggering feeling may not be associated with a memorable event and the drug use may avert memorable distress. More dramatic is the phenomenon of affect regression, observed among addicted patients who were studied in a psychoanalytic context. Khantzian pointed out that when addicted subjects sustain narcissistic injury, they are prone to a precipitous collapse of ego defenses, followed by intense and unmanageable affective flooding. In the face of such vulnerability, these subjects handle stress poorly and may turn to drugs for relief. This vulnerability can be considered in light of the model of conditioned withdrawal, whereby drug seeking can become an immediate reflexive response to stress, undermining the stability and effectiveness of a patient's coping mechanisms. Drug seeking can occur quite suddenly in patients who have long associated drug use with their attempts to cope with stress, as illustrated in the following case: In the course of therapy, an alcoholic lawyer found that his drinking had often been precipitated by situations that threatened his self-esteem. After 6 months of sobriety, he had a relapse that was later examined in a session as follows: Immediately before his relapse, he had received an erroneous report that his share of the partnership's profits would be cut back, which he took to be evidence of failure. He reported feeling humiliated and then very anxious. Without weighing the consequences, he went out and purchased a bottle of liquor, returned to his office, and began drinking. He said that he had not thought to control this behavior at the time. This model helps to explain why relapse is such a frequent and unanticipated aspect of addiction treatment. Exposure to conditioned cues, ones that were repeatedly associated with drug use, can precipitate reflexive drug craving during the course of therapy, and such cue exposure can also initiate a sequence of conditioned behaviors that lead addicted individuals to relapse unwittingly into drug use. Loss of control can be the product of conditioned withdrawal. The sensations associated with ingestion of an addictive drug, such as the odor of alcohol or the euphoria produced by opioids, are temporally associated with the pharmacological elicitation of a compensatory response to that drug and can later produce drug-seeking behavior. For this reason, the first drink can serve as a conditioned cue for further drinking. These phenomena lead to relapse in patients who have very limited capacities to control consumption once a single dose of drug has been taken.

Dealing With the Issue of Relapse What minimally noxious aversive stimuli are specific for the conditioned stimuli associated with drug craving and can thus provide a maximally useful learning experience? To answer this question, one may look at Wikler's (1971) initial conception of the implications of his conditioning theory: The user would become entangled in an interlocking web of self-perpetuating reinforcers, which perhaps explain the persistence of drug abuse, despite disastrous consequences for the user, and his imperviousness to psychotherapy which does not take such conditioning factors into account, because neither the subject nor the therapist is aware of their existence. (p. 611) Since Wikler's time, specific techniques have been developed to overcome this problem. The model of conditioned drug seeking has been applied in training patients to recognize drug-related cues and avert relapse. Annis (1986), for example, used a self-report schedule to assist patients in identifying the cues, situations, and moods most likely to lead to alcohol craving. Marlatt evolved the approach he described as relapse prevention (Marlatt and Gordon 1985), in which patients are taught strategies for avoiding the consequences of the alcohol-related cues they have identified, and a similar approach has been used to extinguish cocaine craving through cue exposure in a clinical laboratory (Childress et al. 1988). These approaches can be introduced as part of a single-modality behavioral regimen, but they also can be used in expressive or family-oriented psychotherapy. By means of cognitive labeling, drinking cues can be associated with readily identified guideposts to aid the patient in consciously averting the consequences of prior conditioning. Similarly, guided recall can be used to explore the sequence of antecedents of given episodes of craving or drinking "slips" that were not previously clear to a patient. These approaches can be applied concomitantly with an examination of general adaptive problems in exploratory therapy. A problem can occur, however, when such an approach is applied. If a patient is committed to becoming abstinent from an addictive drug but is in jeopardy of making occasional slips, cognitive labeling can facilitate consolidation of an abstinent adaptation. However, such an approach is less valuable in the context of inadequate motivation for abstinence, fragile social

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supports, or compulsive substance abuse unmanageable by the patient in his or her usual social settings. Hospitalization or replacement therapy (e.g., methadone therapy) may be necessary in these situations because ambulatory stabilization through psychotherapeutic support is often not feasible. Under any circumstances, cognitive labeling is an adjunct to psychotherapy and not a replacement for group supports such as AA, family counseling, or community programs.

USE OF NETWORK THERAPY Having examined the need for behavioral techniques in the ongoing treatment of addiction, I now consider the model of network therapy for addiction. This model enhances the effectiveness of office-based individual therapy by drawing on the recent advances described in the preceding section. Network therapy has been validated in general terms. In an evaluation of family treatment for alcohol problems, it was concluded that "research data support superior outcomes for family-involved treatment, enough so that the modal approach should involve family members and carefully planned interventions" (Institute of Medicine 1990, p. 84). Indeed, the idea of the therapist intervening with the patient's family and friends to start treatment was introduced by Johnson (1986) as one of the early ambulatory techniques in the addiction field. More broadly, greater social support for patients contributes to positive outcome in addiction. In a clinical trial involving 60 patients, network therapy was associated with a positive outcome (Galanter 1993). Patients attended one session per week of network therapy for the first month; subsequent sessions were less frequent, typically every other month after 1 year of ambulatory care. Individual therapy was carried out concomitantly once or twice a week. On average, networks had 2.3 members, and the most frequent participants were mates, peers, parents, and siblings.

The Couple as a Network: Medication Under Observation A cohabiting couple serves as an example of how natural affiliative ties can be used to develop a network to support the patient in rehabilitation. Couples therapy for addiction has been described in both ambulatory and inpatient settings, and a favorable marital adjustment is associated with a diminished likelihood of dropping out and with a positive overall outcome (McCrady et al. 1986). In controlled trials, disulfiram has produced relatively little benefit overall when prescribed for patients to take on their own (Fuller et al. 1986). This agent is effective only if ingested as instructed, typically daily. Alcoholic patients who forget to take required doses will likely resume drinking in time. Such forgetting often reflects initiation of a sequence of conditioned drug-seeking behaviors. Although patient characteristics have not been shown to predict compliance with a disulfiram treatment regimen, changes in the format of patient management have been beneficial. For example, involvement of a spouse in observing the patient's consumption of disulfiram considerably improves outcome because such involvement introduces a system of monitoring (Azrin et al. 1982). Patients alerted to take disulfiram each morning by this external reminder are less likely to experience conditioned drug seeking when exposed to addictive cues and are more likely to comply with the dosing regimen on subsequent days. The technique also helps clearly define the roles in therapy of both the alcoholic patient and his or her spouse. The spouse does not need to monitor drinking behaviors he or she cannot control, nor does the spouse actively remind the alcoholic patient to take each disulfiram dose. The spouse merely notifies the therapist if he or she does not observe the pill being ingested on a given day. Decisions concerning management of compliance are then allocated to the therapist, thereby preventing entanglement of the couple in a dispute over the patient's attitude and the possibility of drinking in secret. This system of observation, like other applications of network therapy, depends on a collaboration between therapist, patient, and network. It can be applied to the use of disulfiram, but it can also be applied in initiating buprenorphine treatment and in assuring that the patient complies with taking naltrexone (see the section "Engagement in Buprenorphine Treatment"). The network member should be reliably available to observe the patient taking the pill. In order to assure that the observer continues to maintain this role in a systematic manner, he or she should be expected to fill in a form each morning, as illustrated in Figure 28–1, and bring it to a network session at regular intervals for the therapist's review. FIGURE 28–1. Format for network member's recorded observation of pill ingestion by the patient.

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Other behavioral devices demonstrated to improve outcome can be incorporated into this couples therapy format. For example, setting the first appointment as soon as possible after an initial telephone contact can improve outcome by undercutting the possibility of early loss of motivation. Spouses can also be engaged in history taking at the outset of treatment in order to minimize the possibility of the introduction of denial into the patient's presentation of his or her illness. The initiation of treatment with such a regimen is illustrated in the following case: A 39-year-old alcoholic man was referred for treatment. The psychiatrist initially engaged both the patient and his wife in an exchange on the telephone, so that all three could plan for the patient to remain abstinent on the day of the first session. They agreed that the wife would meet the patient at his office at the end of the workday on the way to the appointment. This would ensure that cues presented by the patient's friends going out for a drink after work would not lead him to drink. In the session, an initial history was obtained from both the patient and his wife, an approach that allowed the wife to expand on ill consequences of the patient's drinking, thereby avoiding minimization of the problem by the patient. A review of the patient's medical status revealed no evidence of relevant organ damage, and the option of initiating treatment with disulfiram at that time was discussed. The patient, with encouragement from his wife, agreed to take his first dose that day and to continue under her observation. Subsequent sessions with the couple were dedicated to dealing with implementation of this plan, and concurrent individual therapy was initiated. Couples therapy for alcohol and drug abuse has been widely studied. For example, the alcohol behavioral couples therapy (ABCT) model has been successfully shown to yield a positive drinking outcome. For marital couples it has been found to yield decreased violence as well as improvement in the drinking problem where violence during intoxication was an issue (O'Farrell et al. 1999).

The Network's Membership Networks generally consist of a number of members. Once the patient has come for an appointment, establishment of a network is undertaken with active collaboration between the patient and the therapist. The two, aided by those parties who join the network initially, must search for the right balance of members. The therapist, however, must carefully promote the choice of appropriate network members; the network will be crucial in determining the balance of the therapy. This process is not without problems, and the therapist must think strategically of the interactions that may occur among network members. The following case illustrates the nature of the therapist's task: A 25-year-old graduate student had been abusing drugs since high school, in part drawing on funds from his affluent family, who lived in a remote city. At two points in the process of establishing his support network, the reactions of his live-in girlfriend were particularly important. They both agreed to bring in his 19-year-old sister, a freshman at a nearby college. He then mentioned a "friend" of his, a woman whom he had apparently found attractive, even though there was no history of an overt romantic involvement. The expression on his girlfriend's face suggested that she was uncomfortable with this option. The therapist temporarily put aside the idea of the friend and moved on to evaluating

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the patient's uncle. Initially, the patient was reluctant to include him in the network because he perceived the uncle as a potentially disapproving representative of the parental generation. The therapist and the girlfriend nonetheless encouraged him to accept the uncle as a network member to round out the range of relationships within the group. The uncle proved to be caring and supportive, particularly after he was helped to understand the nature of the addictive process.

The Network's Task The therapist's relationship to the network is one of a task-oriented team leader rather than of a family therapist oriented toward restructuring relationships. The network is established to implement a straightforward task: aiding the therapist to sustain the patient's abstinence. The network must be directed with the same clarity of purpose that a task force is directed in any effective organization. Competing and alternative goals must be suppressed or at least prevented from interfering with the primary task. Unlike family members involved in traditional family therapy, network members are not led to expect symptom relief or self-realization for themselves. This approach prevents development of competing goals for the network's meetings. It also protects members from having their own motives scrutinized and thereby supports their continuing involvement without the threat of an assault on their psychological defenses. Because network members have kindly volunteered to participate, their motives must not be impugned. Their constructive behavior should be commended and they should be acknowledged for the contribution they are making to the therapy. Network members have a counterproductive tendency to minimize the value of their contribution. The network must therefore be structured as an effective working group with good morale. This approach is illustrated below: A 45-year-old single woman served as an executive in a large family-held business, except when her alcohol problem led her into protracted binges. Her father, brother, and sister were prepared to banish her from the business but decided first to seek consultation. The father was a domineering figure who intruded in all aspects of the business, evoking angry outbursts from his children. The children typically reacted with petulance, provoking him in return. The situation came to a head 2 months into treatment, when the patient's siblings angrily petitioned the therapist to exclude the father from the network. This presented a problem because the father's control over the business made his involvement important in securing the patient's compliance. Relapse by the patient was still a real possibility. The father implied that he might compromise his son's role in the family business. The father's potentially coercive role, however, was an issue that the group could not deal with easily. The therapist supported the father's membership in the group, pointing out the constructive role he had played in getting the therapy started. It was clear to the therapist that the father could not deal with a situation in which he was not accorded sufficient respect and that there was no place in this network for addressing the father's character pathology directly. The children became less provocative as the group responded to the therapist's pleas for civil behavior.

Contrasts With an Intervention The Johnson Institute intervention approach, first developed by Vernon E. Johnson in the 1960s (Johnson 1986), is what people generally mean when they use the term intervention Unlike network therapy, this approach convenes a number of people from the substance abuser's family and close friends who might otherwise constitute members of a network. In a series of preparatory meetings, letters and statements are prepared for the substance abuser describing the compromise to them and to himself or herself because of his or her addiction. A confrontation is then planned in which the threat is explicitly made of withdrawal of support and personal contact if the patient does not agree to enter treatment—typically in a residential setting. In some cases of network therapy, distressed family or friends may call and meet for consultation about a reluctant addicted person over whom they are concerned. The network therapist may then meet with those potential network members before an encounter with the addicted person. If the addicted individual is reluctant to enter treatment, the collaterals can be instructed to approach him or her as a group and press him or her to meet with them and with the therapist, but an aggressive confrontation is not used. The encounter is not meant to be highly confrontational like that employed in a Johnson intervention approach. This network initiation can be applied to engaging patients in both outpatient and inpatient treatment. A similar approach has been formalized in the ARISE (A Relational Intervention Sequence for Engagement) format developed by Garrett et al. (1998). A strategy, however, may have to be worked out with potential network members as to how a patient who is initially reluctant will be pressed to come to treatment, as follows: A 40-year-old man who had managed his family-owned company had devolved into heavy cocaine use. He was now spending much of his time in his apartment ordering the cocaine, which he was using on a daily basis, by phone. When members of his family came to seek consultation, it emerged that he was sustaining himself with credit card charges from a family-managed account. The therapist said that they should each press him to come in, but inform him as well that his economic resources could be cut back if he did not come with them to a therapy session. Although the therapist promoted a supportive exchange between the patient and family when they all arrived at a joint session, the patient was under pressure to comply with treatment to assure continuing access to family funds. An exchange ensued in which the patient acknowledged his problem and agreed to come to another network meeting, while seeing the therapist

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individually. After an individual session followed by another network and individual session, an agreement was reached: he would participate in ongoing therapy, both individually and with the network. Because of implied pressure from network members, the therapist had been able to serve as a mediator in the network sessions and avoid an unduly defensive response to him on the part of this potential patient.

Some Specific Techniques Yalom (1974) described anxiety-reducing tactics that he used in therapy groups with alcoholic patients to avert disruptions and promote cohesiveness. These tactics included setting an agenda for the session and using instruction. In the network format, a cognitive framework can be achieved in each session by starting out with the patient recounting events related to cue exposure or substance use since the last meeting. Network members are then expected to comment on this report; this ensures that all members are engaged in a mutual task with correct, shared information. Their reactions to the patient's report are also addressed. Here is one example of how this was done: An alcoholic man began one of his early network sessions by reporting a minor lapse into drinking. His report was disrupted by an angry outburst from his older sister. She said that she had "had it up to here" with his frequent unfulfilled promises of sobriety. The psychiatrist addressed this source of conflict by explaining in a didactic manner how behavioral cues affect vulnerability to relapse. This didactic approach was adopted to deal with the assumption that relapse is easily controlled and to relieve consequent resentment. The psychiatrist then led members in concretely planning with the patient how he might avoid further drinking cues in the period preceding their next conjoint session. Patients undergoing detoxification from depressant medication taken for long periods often experience considerable anxiety, even when dose reduction is gradual. The expectation of distress, coupled with conditioned withdrawal phenomena, may cause patients to balk at completing a detoxification regimen. In individual therapy alone, the psychiatrist has little leverage on this point. When individual therapy is augmented by network therapy, however, the added support can be invaluable in securing compliance under these circumstances, as indicated below: A patient elected to undergo detoxification from chronic use of diazepam, which she had been taking at a dosage of approximately 60 mg/day. In network meetings with the patient, her husband, and a friend, the psychiatrist discussed the need for added support toward the end of the patient's detoxification. As her daily dosage was brought to 2 mg three times a day, she became anxious, said that she had never intended to stop completely, and insisted on continuing the low dosage on a permanent basis. Network members supportively but explicitly pointed out that this had not been the plan. She then relented, and the dosage was reduced to 0 mg/day over 6 weeks. Contingency contracting as used in behavioral treatment stipulates that an unpalatable contingency will be applied should a patient engage in a prohibited symptomatic behavior. Crowley (1984) successfully applied this technique to rehabilitating cocaine-addicted patients by preparing a written contract with each patient that indicated a highly aversive consequence that would be initiated upon any use of the drug. For example, for an addicted physician, a signed letter admitting addiction was prepared for mailing to the state licensing board. This approach can also be adapted to the network setting. Patients are strongly inclined to deny drinking problems during relapse. The network may be the only resource the psychiatrist has for communicating with a relapsing patient and for assisting in reestablishing abstinence, as occurred in the following situation: A patient began drinking again after 6 months of abstinence. One of the network members consulted with the psychiatrist and then stayed with the patient in his home for a day to ensure that he would not drink. The network member then brought the patient to the psychiatrist's office, along with the other members of the network, to reestablish a plan for abstinence.

Use of Alcoholics Anonymous Use of AA is desirable. For the alcoholic individual, certainly, participation in AA is strongly encouraged. Groups such as Narcotics Anonymous, Pills Anonymous, and Cocaine Anonymous are modeled after AA and play a similarly useful role among drug-abusing individuals. One approach is to tell the patient that he or she is expected to attend at least two AA meetings each week for at least 1 month to familiarize himself or herself with the program. If after 1 month the patient is quite reluctant to continue, and other aspects of the treatment are going well, his or her nonparticipation may have to be accepted. Some patients are easily convinced to attend AA meetings. Others may be less compliant. The therapist should mobilize the support network as appropriate in order to continue pressing the patient to give participation in AA a reasonable try. It may take considerable time, but ultimately the patient may experience something of a conversion, wherein he or she adopts the group ethos and expresses a deep commitment to abstinence—a measure of commitment rarely observed in patients who only undergo psychotherapy. When this conversion occurs, the therapist may assume a more passive role in monitoring the patient's abstinence and should keep an eye on the patient's ongoing involvement in AA. Network therapy can be regularly employed in conjunction with the patient's attendance at 12-step meetings. There is a distinction to be noted, however, between the role promoted for the spouse in network therapy and the role encouraged in

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Al-Anon, the 12-step program for family members of an alcoholic individual, usually spouses. Al-Anon encourages a relatively removed stance on the part of the spouse while avoiding enabling the patient's drinking. Emphasis in Al-Anon is then placed on the Al-Anon member's assuring his or her own personal needs. The main purpose of Al-Anon is to reduce the personal problems of the alcoholic individual's spouse, and referral to Al-Anon has been shown to produce relief in the spouse. However, it has not been shown to materially increase treatment entry or change in drinking in the alcoholic person (Sisson and Azrin 1986).

Contrasts With Family Therapy Like family and group therapy, network therapy brings several people together to address a psychological problem. Approaches vary among practitioners of group and family therapies: the therapist may focus on the individual patient or try to shape the family or group overall. In network therapy, however, the focus is always on the individual patient and his or her addictive problem. In network therapy, unlike in family therapy, the practitioner avoids focusing on the patient's family history in the network sessions themselves, because involvement in family conflicts can hinder the network in performing its primary task of helping the therapist maintain the patient's abstinence. Such a focus would establish an additional agenda and set of goals, potentially obliging the therapist to assume responsibility for resolving conflicts that are not necessarily tied to the addiction itself. Family and interpersonal dynamics can be addressed individually with the patient on his or her own, as illustrated below: A patient brought his estranged wife and his brother in as network members as he embarked on treatment for prescription drug abuse. The tension between the patient and his spouse was considerable because both were competitive and controlling. She interrupted too often, offering her opinions, and he was dismissive of her and sat with his back to her. His brother tried his best to remain neutral. By listening with interest and respect to both husband and wife, letting each play a positive role in framing the treatment, the therapist could tap their initiative and their desire to shine in the session. This approach allowed the therapist to draw on the wife's knowledge of the patient's drug use and focused all three participants on the task of considering more members for this emerging network. The traits that might have served as grist for a family therapist were not discussed. A technique of family therapy that bears considerable similarity to the network format is the strategic family approach (Haley 1977). The focus of this approach, like the focus of network therapy, is on the current problem rather than on the dynamics of the family system. Treatment is begun with a careful examination of the nature of the symptoms, their time course, and the events that take place as they emerge. As in other behaviorally oriented therapies, the focus is a relatively narrow one, and an understanding of behavioral sequences associated with the problematic situation is of primary importance. This identification of circumstances surrounding the problem's emergence can be likened to ferreting out conditioned cues that lead to the addicted subject's sequence of drug use. The assumption in both strategic family therapy and the behavioral approach is that these circumstances will suggest options for bringing about resolution of the problem. Indeed, as he developed this strategic model, Haley (1977) observed that certain behaviors within a family can unintentionally promote the symptoms they are designed to suppress, similar to the conception of the alcoholic subject's spouse unwittingly serving as an enabler. The engagement of the patient in community-based activities has been combined with family-based treatment in the community reinforcement and family training (CRAFT) format (Miller et al. 1999). The CRAFT approach is similar to network therapy in that members of the network are encouraged to plan with the patient how he or she can become engaged in constructive activities in the community and can then help develop resources for the alcoholic individual in the promotion of his or her sobriety. The community reinforcement approach has also been successfully combined with disulfiram observation (Azrin 1976).

RULES OF NETWORK THERAPY: A SUMMARY Network therapy is meant to be straightforward and uncomplicated by theoretical bias. In this section, the main points to be observed in treatment are reviewed.

Determine Who Needs Network Therapy Network therapy is appropriate for individuals who cannot reliably control their intake of alcohol or drugs once they have taken their first dose; those who have tried to stop and have relapsed; and those who have not been willing or able to stop. Individuals whose problems are too severe for the network approach in ambulatory care include those who cannot stop their drug use even for a day or who cannot comply with outpatient detoxification. Individuals who can be treated with conventional therapy and without a network include those who have demonstrated the ability to moderate their consumption without problems.

Start a Network as Soon as Possible It is important to see the alcohol- or drug-abusing patient promptly, because the window of opportunity for openness to treatment is generally brief. If the patient is married, the spouse should be engaged in the therapy early on, preferably at the time of the first telephone call. The clinician should point out that addiction is a family problem. In the case of most drugs, the therapist

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can enlist the spouse in ensuring that the patient arrives at the therapist's office with a day's sobriety. In the initial interview, the exchange should be framed so that a good case is built for the grave consequences of the patient's addiction, and this should be done before the patient can introduce a system of denial. That way the therapist does not put the spouse or other network members in the awkward position of having to contradict a close relation. Then the clinician must make it clear that the patient needs to be abstinent, starting immediately. When seeing an alcoholic patient for the first time, the clinician should prescribe disulfiram as soon as possible. The patient should continue taking disulfiram under observation of a network member. At the first session, the clinician should make arrangements for a network to be assembled, generally involving a number of the patient's family members or close friends. From the first meeting, the clinician should consider whatever is necessary to ensure sobriety until the next meeting, and these tactics should be planned with the network. Initially, the plan might consist of the network's immediate company and a scheme for daily AA attendance. People who are close to the patient, who have a long-standing relationship with him or her, and who are trusted should be included in the network. Members with substance abuse problems should be avoided because they may let the clinician down when he or she needs their unbiased support. The group should be balanced. A network composed solely of the parental generation, of younger people, or of people of the opposite sex should be avoided. The tone should be directive. The therapist must give explicit instructions to support and ensure abstinence.

Highlight Three Priorities During Therapy 1. Maintain abstinence At the outset of each session, the patient and the network members should report any events related to the patient's exposure to alcohol and drugs. The patient and network members should be instructed about the nature of relapse and should plan with the therapist how to sustain abstinence. Cues to conditioned drug seeking should be examined. 2. Support the network's integrity The patient is expected to make sure network members keep their meeting appointments and stay involved. The therapist sets meeting times explicitly and summons the network when there is an emergency, such as a relapse; he or she does whatever is necessary to secure membership stability if the patient is having trouble doing so. 3. Secure future behavior The therapist should combine all modalities necessary to ensure the patient's stability, such as a stable, drug-free residence; avoidance of substance-abusing friends; attendance at 12-step group meetings; compliance in taking medications such as disulfiram or blocking agents; observed urinalysis; and ancillary psychiatric care. Also, the patient should meet with the therapist as frequently as necessary to ensure abstinence—perhaps once a week for 1 month, every other week for the next few months, and every month or two by the end of 1 year. Individual sessions run concomitantly. The therapist should make sure that the mood of meetings is trusting and that meetings are free of recrimination. He or she should explain issues of conflict in terms of the problems presented by addiction rather than get into personality conflicts. Once abstinence is stabilized, the network can help the patient plan for a new drug-free adaptation.

End Network Therapy Appropriately Network sessions can be terminated after the patient has been stably abstinent for at least 6 months to 1 year. Before network therapy is stopped, the therapist should discuss with the patient and network the patient's readiness to handle sobriety. An understanding is established with the network members that they will contact the therapist at any point in the future if the patient becomes vulnerable to relapse. The network members can also be summoned by the therapist. These points should be made clear to the patient before termination in the presence of the network, but they also apply throughout treatment.

RESEARCH ON NETWORK THERAPY In the American Psychiatric Association's (1995) practice guidelines for the treatment of substance use disorders, network therapy is included as an approach for facilitating adherence to a treatment plan. Four studies have demonstrated the effectiveness of network therapy in treatment and training. Each study addressed the technique's validation from a different perspective: a trial in office management; studies of its effectiveness in the training of psychiatry residents and of counselors who work with cocaine-addicted persons; and an evaluation of acceptance of the network approach in an Internet technology transfer course.

An Office-Based Clinical Trial A chart review was conducted involving a series of 60 substance-dependent patients, with follow-up appointments scheduled through the period of treatment and up to 1 year thereafter (Galanter 1993). For 27 patients, the primary drug of dependence was alcohol; for 23, it was cocaine; for 3, it was marijuana; and for 1, it was nicotine. Opiates were the primary drugs of dependence for 6 patients. For all but 8 of the patients, networks were fully established. Of the 60 patients, 46 experienced full improvement (i.e., abstinence for at least 6 months) or major improvement (i.e., a marked decrease in drug use to

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nonproblematic levels). The study demonstrated the viability of establishing networks and applying them in the practitioner's treatment setting. It also served as a basis for the ensuing developmental research supported by the National Institute on Drug Abuse.

Treatment by Psychiatry Residents We (Galanter et al. 1997a) developed and implemented a network therapy training sequence in the New York University psychiatry residency program and then evaluated the clinical outcomes of a group of cocaine-dependent patients treated by the residents. The psychiatry residency was chosen because of the growing importance of clinical training in the management of addiction in outpatient care in residency programs, in line with the standards set for specialty certification. A training manual was prepared on the network technique, defining the specifics of the treatment in a manner allowing for uniformity in practice. The manual was developed for use as a training tool and then as a guide for the residents during the treatment phase. Network therapy tape segments drawn from a library of 130 videotaped sessions were used to illustrate typical therapy situations. A network therapy rating scale was developed to assess the technique's application, with items emphasizing key aspects of treatment (Keller et al. 1997). The scale was evaluated for reliability in distinguishing two contrasting addiction therapies (network therapy and systemic family therapy), both of which were presented to faculty and residents on videotape. The internal consistency of responses for each of the techniques was high for both the faculty and the resident samples, and both groups consistently distinguished the two modalities. The scale was then used by clinical supervisors as an aid in training and to monitor therapist adherence to the study treatment manual. We trained third-year psychiatry residents to apply the network therapy approach and we emphasized distinctions in technique between treatment of addiction and treatment of other major mental illnesses or personality disorder. The residents then worked with a sample of 47 cocaine-addicted patients. Once treatment was initiated, 77% of subjects established a network (i.e., brought in at least one member for a network therapy session). In fact, an average of 1.47 collaterals attended any given network therapy session, across all subjects and sessions. This is notable, given that compliance after initial screening was not necessarily assured. Of the patients who completed a 24-week regimen, almost all (15 of 17 patients) tested negative for cocaine in their last three urine toxicology screenings. However, only a minority of those who attended the first week but did not complete the sequence (4 of 18 subjects) met this outcome criterion (Galanter et al. 2002). The residents, inexperienced in drug treatment, achieved results similar to those reported for experienced professionals (Carroll et al. 1994; Higgins et al. 1993; Shoptaw et al. 1994). These comparisons supported the feasibility of successful training of psychiatry residents new to the administration of addiction treatment, as well as the efficacy of the treatment in their hands (Galanter et al. 1997a).

Treatment by Addiction Counselors Another study was conducted in a community-based addiction treatment clinic, and the network therapy training sequence was essentially the same as the one applied to the psychiatry residents (see the previous section, "Treatment by Psychiatry Residents") (Keller and Galanter 1999). A cohort of 10 cocaine-dependent patients received treatment in the community program with a format that included network therapy, along with the clinic's usual package of modalities. An additional 20 cocaine-dependent patients received treatment as usual and served as control subjects. Network therapy was found to enhance the outcome of the experimental patients. Of the 107 urinalyses conducted in the network therapy group, 88% yielded negative results, but only 66% of the 82 urine samples from the control subjects were negative for cocaine, a significantly lower proportion. The mean retention in treatment was 13.9 weeks for the network therapy patients, reflecting a trend toward greater retention than the 10.7 weeks for control subjects. The results of this study supported the feasibility of transferring the network technique into community-based settings, with the potential for enhancing outcomes. Addiction counselors working in a typical outpatient rehabilitation setting were able to learn the technique and then incorporate it into their largely 12-step-group–oriented treatment regimens without undue difficulty and with improved outcome.

Engagement in Buprenorphine Treatment During the initial stages of buprenorphine treatment, opioid addicts, particularly those dependent on heroin, often continue to use heroin intermittently, and may also abuse other substances. In order to minimize this, it is advantageous to initiate buprenorphine treatment with the support of network therapy. We (Galanter et al. 2004) studied the effectiveness of this approach to initiating buprenorphine by comparing two groups of patients who were prescribed the drug. Most had had previous experience with addiction treatment. One criterion for inclusion in both groups was the willingness to bring in at least one collateral during the initial evaluation. Most lived with family or friends and were employed. All patients received a standard course of buprenorphine/naloxone tablets (16 mg/40 mg) daily and underwent random urine toxicologies. The subjects were randomized to one of two treatment groups, network therapy or medication management. Patients in each group were provided the same amount of time overall in therapy sessions. The study consisted of an 18-week trial during which patients were inducted onto buprenorphine and then tapered to zero dose. By the end of the study, the abstinence rate of patients who participated in network therapy was twice that of the patients in the comparison group who received standard medication management (50% vs. 23%), indicating the effectiveness of the network support.

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For patients who enter treatment with secondary substance abuse, such as cocaine dependence, it is important that a pattern of addictive behavior to the secondary drug also be addressed because continuation of any abuse of a substance is more likely to be associated with an unsuccessful long-term outcome. Because of this, the network approach can be particularly useful in addressing this latter issue, given the support provided for abstinence from all drugs.

Multisite Comparison With Motivational Enhancement Network therapy is premised on establishing an ongoing, trusting relationship among patient, network members, and therapist. As the network sessions draw to a close, it is explained that the patient and network members maintain an open-ended willingness to reinitiate contact with the therapist at any time subsequent to treatment that a concern might arise relative to a possible relapse. Because of this aspect of the treatment, it is useful to consider how it compares to a brief intervention that does not offer such an ongoing mutual commitment. Insight into this was provided by a multisite study undertaken in the United Kingdom comparing motivational enhancement to an adaptation of network therapy. The feasibility of treatment in the network modality was demonstrated with the use of a brief training course, video observation, and subsequent supervision (Copello et al. 2006). Alcoholic patients (N = 742) were then divided among 52 nonphysician therapists and randomized to either of the two treatments. The network approach consisted of eight 50-minute sessions over 12 weeks, whereas the motivational enhancement approach comprised three 50-minute sessions over the 12 weeks. An evaluation at 12 months showed equivalent outcomes in terms of days abstinent and number of drinks per drinking day (UKATT Research Team 2005b). Although the network approach involved greater staff time, a calculation of the relative cost-saving, as measured by additional factors such as health care costs, social services, and the expense of the criminal justice system when indicated, showed no difference in overall cost of the two approaches (UKATT Research Team 2005a). When applied as described in this chapter, the open-ended nature of the network commitment may well provide an incremental benefit in maintaining long-term positive availability of support that may not be available with the use of a brief motivational intervention.

Use of the Internet We (Galanter et al. 1997b) studied ways in which psychiatrists and other professionals could be offered training by a distance learning method using the Internet. An advertisement was placed in Psychiatric News, the newspaper of the American Psychiatric Association, offering an Internet course combining network therapy with the use of naltrexone for the treatment of alcoholism. The material presented on the Internet was divided into three didactic "sessions," followed by a set of questions, with a hypertext link to download relevant references and a certificate of completion. The course took about 2 hours for the student to complete. Our assessment was based on 679 sequential counts, representing 240 unique respondents who went beyond the introductory Web page. Of these respondents, 154 were psychiatrists, who responded positively to the course. A majority of them responded "a good deal" or "very much" (a score of 3 or 4 on a 4-point scale) to the following statements about the course: "It helped me understand the management of alcoholism treatment" (56%); "It helped me learn to use family or friends in network treatment for alcoholism" (75%); and "It improved my ability to use naltrexone in treating alcoholism" (64%).

Conclusion The four studies described in this section support the use of network therapy as a treatment for addictive disorders. The studies are especially encouraging given the relative ease with which different types of clinicians were engaged and trained in the network approach. Because the approach combines a number of well-established clinical techniques that can be adapted to delivery in typical clinical settings, it is apparently suitable for use by general clinicians and addiction specialists.

KEY POINTS One network member should be solicited in collaboration with the patient at the outset of treatment. Network members, preferably three to five, should have a close ongoing relationship with the patient and should not be substance abusers. The addictive process and the basis for diagnosis should be explained to the patient and network members. The sessions should be framed to sustain abstinence, with a full explanation for the rationale. Discussion should be nonjudgmental, with a tone of team support for the patient. Ingestion of medications such as disulfiram or naltrexone should be monitored by a network member. If urine toxicologies are employed, results should be shared with the network members.

REFERENCES American Psychiatric Association: Practice guideline for the treatment of patients with substance use disorders: alcohol, cocaine, opioids. Am J Psychiatry 152:5–59, 1995 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000

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Annis HM: A relapse prevention model for treatment of alcoholics, in Treating Addictive Behaviors: Processes of Change. Edited by Miller WR, Heather NH. New York, Plenum, 1986, pp 407–434 Azrin NH: Improvements in the community-reinforcement approach to alcoholism. Behav Res Ther 14:339–348, 1976 [PubMed] Azrin NH, Sisson RW, Meyers R: Alcoholism treatment by disulfiram and community reinforcement therapy. J Behav Ther Exp Psychiatry 13:105–112, 1982 [PubMed] Carroll KM, Rounsaville BJ, Gordon LT, et al: Psychotherapy and pharmacotherapy for ambulatory cocaine abusers. Arch Gen Psychiatry 51:177–187, 1994 [PubMed] Childress AR, McLellan AT, Ehrman R, et al: Classically conditioned responses in opioid and cocaine dependence: a role in relapse? NIDA Res Monogr 4:25–43, 1988 Copello A, Williamson E, Orford J, et al: Implementing and evaluating social behaviour and network therapy in drug treatment practice in the UK: a feasibility study. Addict Behav 31:802–810, 2006 [PubMed] Crowley TJ: Contingency contracting treatment of drug-abusing physicians, nurses, and dentists. NIDA Res Monogr 46:68–83, 1984 [PubMed] Fuller RK, Branchey L, Brightwell DR, et al: Disulfiram treatment of alcoholism. A Veterans Administration cooperative study. JAMA 256:1449–1455, 1986 [PubMed] Galanter M: Network therapy for substance abuse: a clinical trial. Psychotherapy 30:251–258, 1993 Galanter M: Network Therapy for Addiction: A New Approach, Expanded Edition. New York, Guilford, 1999 Galanter M, Keller DS, Dermatis H: Network therapy for addiction: assessment of the clinical outcome of training. Am J Drug Alcohol Abuse 23:355–367, 1997a Galanter M, Keller DS, Dermatis H: Using the Internet for clinical training: a course on network therapy for substance abuse. Psychiatr Serv 48:999–1000, 1008, 1997b Galanter M, Dermatis H, Keller D, et al: Network therapy for cocaine abuse: use of family and peer supports. Am J Addict 11:161–166, 2002 [PubMed] Galanter M, Dermatis H, Glickman L, et al: Network therapy: decreased secondary opioid use during buprenorphine maintenance. J Subst Abuse Treat 26:313–318, 2004 [PubMed] Garrett J, Landau J, Shea R, et al: The ARISE intervention. Using family and network links to engage addicted persons in treatment. J Subst Abuse Treat 15:333–343, 1998 [PubMed] Haley J: Problem-Solving Therapy. San Francisco, CA, Jossey-Bass, 1977 Higgins ST, Budney AJ, Bickel WK, et al: Achieving cocaine abstinence with a behavioral approach. Am J Psychiatry 150:763–769, 1993 [Full Text] [PubMed] Institute of Medicine: Broadening the Base of Treatment for Alcohol Problems: Report of a Study by a Committee of the Institute of Medicine, Division of Mental Health and Behavioral Medicine. Washington, DC, National Academy Press, 1990 Johnson VE: Intervention: How to Help Someone Who Doesn't Want Help. Minneapolis, MN, Johnson Institute Books, 1986 Keller DS, Galanter M: Technology transfer of network therapy to community-based addictions counselors. J Subst Abuse Treat 16:183–189, 1999 [PubMed] Keller DS, Galanter M, Weinberg S: Validation of a scale for network therapy: a technique for systematic use of peer and family support in addiction treatment. Am J Drug Alcohol Abuse 23:115–127, 1997 [PubMed] Khantzian EJ: The self-medication hypothesis of addictive disorders: focus on heroin and cocaine dependence. Am J Psychiatry 142:1259–1264, 1985 [PubMed] Marlatt GA, Gordon J (eds): Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors. New York, Guilford, 1985 McCrady BS, Noel NE, Abrams DB, et al: Comparative effectiveness of three types of spouse involvement in outpatient behavioral alcoholism treatment. J Stud Alcohol 47:459–467, 1986 [PubMed] Miller PM, Meyers RJ, Tonigan JS: Engaging the unmotivated in treatment for alcohol problems: a comparison of three strategies for intervention through family members. J Consult Clin Psych 67:688–697, 1999 [PubMed] O'Farrell TJ, Van Houton V, Murphy CM: Domestic violence after alcoholism treatment: a two-year longitudinal study. J Stud Alcohol 60:317–321, 1999 [PubMed] Shoptaw S, Rawson RA, McCann MJ, et al: The Matrix model of outpatient stimulant abuse treatment: evidence of efficacy. J Addict Dis 13:129–141, 1994 [PubMed]

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Sisson RW, Azrin NH: Family member involvement to initiate and promote treatment of problem drinkers. J Behav Ther Exp Psychiatry 17:15–21, 1986 [PubMed] Stanton MD: Getting reluctant substance abusers to engage in treatment/self-help: a review of outcomes and clinical options. J Marital Fam Ther 30:165–182, 2004 [PubMed] UKATT Research Team: Cost effectiveness of treatment for alcohol problems: findings of the randomised UK alcohol treatment trial (UKATT). BMJ 331:545–549, 2005a UKATT Research Team: Effectiveness of treatment for alcohol problems: findings of the randomised UK alcohol treatment trial (UKATT). BMJ 331:541–544, 2005b Wikler A: Some implications of conditioning theory for problems of drug abuse. Behav Sci 16:92–97, 1971 [PubMed] Yalom ID: Group therapy and alcoholism. Ann N Y Acad Sci 233:85–103, 1974 [PubMed]

SUGGESTED READING Copello A, Williamson E, Orford J, et al: Implementing and evaluating social behaviour and network therapy in drug treatment practice in the UK: a feasibility study. Addict Behav 31:802–810, 2006 Galanter M: Network Therapy for Addiction: A New Approach, Expanded Edition. New York, Guilford, 1999 Galanter M, Dermatis H, Glickman L, et al: Network therapy: decreased secondary opioid use during buprenorphine maintenance. J Subst Abuse Treat 26:313–318, 2004 UKATT Research Team: Cost effectiveness of treatment for alcohol problems: findings of the randomised UK alcohol treatment trial (UKATT). BMJ 331:544, 2005 Copyright © 2011 Amer can Psychiatr c Associat on. All Rights Reserved.

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Chapter 29. Group Therapy

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David W. Brook: Chapter 29. Group Therapy, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.348732. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Group Therapy David W. Brook, M.D.

GROUP THERAPY: INTRODUCTION Group therapy has become the most widely used psychosocial treatment for substance abuse and addiction, and for most patients it remains the treatment of choice. Group therapy has been found to be clinically effective and cost-effective for both the prevention and treatment of substance abuse. The use of group therapy can address some of the relevant psychosocial issues leading to substance abuse, many of the symptoms and difficulties resulting from substance abuse and dependence, and the treatment of co-occurring psychiatric disorders. The etiology of substance abuse is most likely multifactorial, including genetic, developmental, familial, physiological, intrapsychic, interpersonal, sociocultural, and environmental factors and interpersonal attachment issues. Therefore, the treatment of substance abuse and dependence must also be multidisciplinary, using a biopsychosocial framework and including the use of medications; outpatient, inpatient, and residential treatment; and psychosocial interventions. Substance abuse may be regarded as a familial disorder, so that the parent–child mutual attachment relationship, peer interactions, personality and behavioral issues, and cultural factors such as ethnic identification (J. S. Brook et al. 2006), are important areas to explore in group therapy. Such a broad multidisciplinary approach has allowed group therapists to address diverse areas in the treatment of patients (Vannicelli 1992, 1995). Group therapy can be especially effective in the prevention and treatment of behavioral risk factors. Psychosocial and cultural risk factors (and corresponding protective factors) may be targets for change through the use of group therapy. Psychosocial and cultural risk and protective factors have been identified in a number of developmental areas, including the personality, the parent–child relationship, the spouse/significant other attachment relationship, interactions with peers, and ethnic, cultural, and environmental factors (D. W. Brook et al. 2003; J. S. Brook et al. 1990,1998b). One model of the interaction of risk and protective factors in the etiology and maintenance of substance abuse is family interactional theory. This theoretical formulation is discussed in further detail in Chapter 3 of this volume, "Epidemiology of Addiction." Group interactions play an important part in the development of substance abuse disorders (D. W. Brook 1996; J. S. Brook et al. 2006), such that group therapy can play a significant role in the prevention and treatment of these disorders. The successful use of group approaches depends first on the development of the therapeutic alliance between the group therapist and each group member, as well as on the development of group cohesion, the attachment that forms between group members over the course of treatment. Group cohesion is of great importance because patients with substance use disorders have a disturbed ability to establish and maintain an attachment to other people (Flores 2001). Other functional disturbances seen in patients with substance abuse and dependence include emotional dysregulation, decreased self-esteem, and an inability to care for oneself adequately (Albanese and Khantzian 2002; Khantzian 2001). The defenses of substance abusers tend to be rather primitive, with particular use of denial, projection, and rationalization. These disturbances can result in a loss of contact with other people, emotional lability, and self-destructive behavior, all of which can be addressed through group therapy. The mutual understanding developed by group members can have a positive effect on parent–child interactions, relationships with significant others and peers, the course of further emotional

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development, and the maintenance of health. The group has the ability to provide support, and confirmation that others share problems is supportive to the patient and has a therapeutic effect in itself. Social support and provision of appropriate limits and rules in the group help the members establish relationships with other people and offer them relief from shame and social isolation. Over time, the group process and interactions in the group can help group members establish more mature defenses and can provide symptomatic relief. In general, better treatment outcome is related to longer duration of group treatment. Groups can help substance-abusing patients control the urge to use substances, particularly through their ability to help group members establish satisfying relationships with other members (Flores 2004).

SPECIFIC ISSUES Because of the characteristics of patients with substance abuse problems (detailed in the previous section), specific features of group treatments are necessary in order to address the particular needs of these patients, including the appropriate selection of patients for each group, pre-group preparation, the establishment and maintenance of group structure and safety, the use of supportive confrontation in the group process, and the particular role of the group therapist. The selection of appropriate patients for each group is important for the effectiveness and longevity of the group. For example, patients who appear likely to give or sell substances of abuse to other group members require a special group structure. Acutely suicidal patients, homicidal patients, acutely psychotic patients, and patients with serious organicity, which precludes their participation in the group discussion, are not suitable for most groups, though they may be suitable for specific groups under carefully delimited circumstances. Pre-group preparation sessions with each individual member help increase members' motivation and reduce premature dropouts. These preparatory sessions help new group members learn the ground rules of the group, which most often include confidentiality, the need for regular and prompt attendance, understanding that the eventual goal is abstinence, and understanding the gains possible through membership in the group (Hoffman 1999). The expectations of each potential group member may be clarified in these sessions, and the therapeutic alliance between each group member and the group therapist has its beginning in the statement and acceptance of the group contract and in the relationship formed in such preparatory sessions. Group structure is enhanced by the development of shared group norms, the shared goal of eventual abstinence from substances of abuse, and the shared understanding about the goals of treatment. Such structure in the group is important because of the relative lack of internal and external structures in the lives and experiences of the group members. Safety in the group is focused on setting appropriate limits, helping members attend to caring for themselves appropriately with feedback from the other group members, and becoming aware of the early signs of relapse. Because individuals who abuse substances tend to experience extremely painful emotions, which often result in self-destructive behavior, it is important for the group to provide a safe environment for the shared acknowledgment of these feelings. This can be accomplished by the use of supportive confrontation, which can provide an empathic "holding" environment where members can address each other's painful feelings and self-destructive behaviors with mutual understanding and support (Ganzarain 1992). Self-destructive behaviors or loss of control of emotions can be addressed without blame or shame. It is important for the group therapist to play an active role, enhancing the sense of safety and structure felt by the group members and promoting the ability of the group members and the group therapist to set appropriate limits, help the group members deal with anxiety and acting-out behavior, and maintain the group contract. This stance of the group therapist helps the group form stable cohesion and progress with the work of the group process. Experienced group leaders develop specific methods to keep the group process active in the face of frustrations and conflicts in therapy (Vannicelli 2001). Early signs of patient relapse are identified by the group leader and by group members paying attention to "people,

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places, and things" that might serve as triggers or cues to resume substance abuse. The therapist and group members utilize the "here and now" interactions in the group to help provide support and guidance for group members who must deal with the adverse consequences of substance abuse and dependence. In addition to psychosocial and interpersonal consequences, the group leader and group members can use the group process to help group members cope with traumatic and medical consequences of substance abuse. Managed care issues may arise during the course of group treatment of substance abusers and addicts. Third-party payers may require specific patient characteristics or goals to be met, or they may be reluctant to provide payment for the treatment of patients unless the group therapist carefully explains the utility and cost-effectiveness of group treatment for each patient. Another managed care issue is the requirement for the group therapist to ensure confidentiality for the group members. (For a more detailed discussion of these and other managed care issues, please see MacKenzie 1995; Spitz 1995, 2002.)

TYPES OF GROUPS A number of types of group treatments are available for patients with substance abuse and dependence issues and for patients with co-occurring psychiatric disorders, including self-help groups, groups using the concepts and techniques of interpersonal group psychotherapy (IGP), cognitive-behavioral therapy groups, psychodynamically oriented groups using the concepts of modified dynamic group therapy (MDGT), phase models of group treatment, relapse prevention groups, groups in therapeutic communities, and a variety of homogeneous groups used to treat specific populations and patients abusing or addicted to specific drugs of abuse. Group therapy is used in treatment programs in a wide variety of settings, including outpatient, inpatient, and partial hospitalization.

Self-Help Groups General group features Self-help groups may make up the greatest number of groups used for treatment today. Such groups are usually composed of members who share something in common, such as experiences as substance abusers and addicts (Lieberman and Humphreys 2002). Self-help groups utilize the relationships between members as the therapeutic force for change; therapeutic forces include cognitive and behavioral elements aimed at changing thinking and behavior, as well as group support and mutual understanding and caring. Such groups establish and maintain their own norms, with an emphasis on the creation of close relationships, talking about feelings, and not engaging in self-destructive behaviors, particularly around the use of alcohol in the case of Alcoholics Anonymous (AA). The large self-help group may have no formal structure, and each group may offer interactions with other people in person or over the phone. Attendance at groups is free of charge, and groups support themselves. A wide variety of self-help groups exist to serve people with any number of behavioral and substance use disorders. Self-help groups for substance abusers and addicts may serve as the only source of treatment for such patients or may be utilized along with psychosocial and medical treatments offered by health care professionals. Most substance abuse and addiction professionals emphasize the need for patients to join self-help groups in addition to utilizing other treatment methods.

Twelve-step groups The 12-step group is one particular type of self-help treatment and is discussed in depth in Chapter 26 of this volume, "Twelve-Step Facilitation: An Adaptation for Psychiatric Practitioners and Patients." This section provides a brief summary, focusing primarily on aspects of the group dynamics noted in such groups. Self-help groups have a long history, resulting in the formation of the 12-step movement and AA. The founding of AA dates to 1935, when two men, William Griffith Wilson (known as Bill Wilson) and Dr. Robert Holbrook Smith (known as Bob Smith or Dr. Bob), formed an alliance in an effort to help each

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other manage their alcoholism. Their fellowship was historically related to earlier examples of Christian self-help fellowship groups. Indeed, for a number of years alcoholic individuals met for mutual support under the aegis of the Oxford Group, which emphasized the importance of confession and redeeming oneself for one's sins among a group of peers. In an effort to separate themselves from the Oxford Group's religious nature and rigid structure, alcoholics formed their own group. The "big book" of AA, Alcoholics Anonymous, was published in 1939 (Alcoholics Anonymous 1939) and outlines the focus of the 12-step process of AA, including the acceptance of one's self as an alcoholic, the acceptance of a "higher power," the examination of one's self to identify needed changes, the recognition of defects in character, making restitution for harm done to other people, and working with others (Orford 1985, p. 309). The functions of AA were codified in another publication in 1953, Twelve Steps and Twelve Traditions (Alcoholics Anonymous 1953). AA has additional available publications and online information (Alcoholics Anonymous 1976, 2007). AA groups currently exist in many countries and serve millions of members, by some estimates. Using AA as an example, self-help groups usually consist of a large group treatment as well as additional smaller groups. Members of self-help groups agree that they share a common condition and a common goal, usually the achievement of long-term abstinence. Both large and small groups are conducted by the members, without the presence or assistance of professional group leaders or mental health professionals. There is no charge for attendance at the meetings, and relationships made in the group are encouraged and commonly continue outside of the group setting. In AA, particular importance is placed on the relationship with a sponsor, a more experienced group member to whom an individual entering AA can turn for help and with whom a special relationship may develop. Twelve-step self-help groups provide mutual support and encourage adherence to group norms. The new group member is expected to accept the ongoing group's values and beliefs about the use of alcohol. Examination of the 12 steps of AA reveals that alcohol is mentioned only once, in the first step, and that the other steps consist of gradual movement toward self-assessment, reestablishment of successful relationships with others, and eventual personality change. AA members become aware of the inability to control drinking. In AA's perspective, alcoholism is a disease. The disease process can be stopped, but the disease itself is incurable. Therefore, recovery is an ongoing process that takes place over the course of each person's life. The last step (step 12) focuses on the altruistic goal of AA members helping other people enter into the recovery process. Group members participate over the course of a person's lifetime, and members may attend continuously or on an as-needed basis. Group acceptance, spirituality, and the wish to help others are seen as having therapeutic value and the ability to generate personality and behavioral change. AA remains neutral to political or social issues and has no formal relationship with organized medicine. However, AA members have been involved in furthering the treatment of alcoholism, and AA approaches and methods have become essential parts of a number of treatment programs. The widespread success of AA in the seven decades since its foundation has led to its use as a model for other, similar 12-step programs that focus on a variety of other kinds of addictive behaviors. Twelve-step groups have been formed for the treatment of a variety of kinds of drug use, as well as compulsive behavior, such as gambling and compulsive sexual behavior. AA itself has a spiritual, religious basis, but a number of other self-help groups have been formed without this emphasis. Although research efforts involving AA members and AA groups are difficult to conduct, there have been some successful studies of the process and outcome; their findings have indicated that regular attendance at AA meetings may result in a reduction in drinking and an increase in a member's ability to function successfully (Emrick et al. 1993).

Interpersonal Group Psychotherapy IGP focuses on the view that interpersonal relationships and attachments affect and regulate all aspects of living. The development of IGP has been greatly influenced by the work of Irvin D. Yalom (Yalom 1995; Yalom and Leszcz 2005) and others, such as Philip J. Flores and Molyn Leszcz (Flores 2004; Leszcz

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1992). According to the IGP perspective, substance abuse and addiction may be seen as attachment disorders caused by genetic and early developmental failures, which lead to inadequate and self-destructive attempts at self-repair. Attachment theory lends itself to a comprehensive understanding of the vicissitudes of the substance use disorders (Flores 2001, 2002): the substanceabusing or addicted individual attempts to use drugs and alcohol as a substitute for satisfying and fulfilling interpersonal relationships (Flores 1993). Such individuals have severely impaired object relations and therefore are unable to form mutually satisfying and mutually regulating relationships with other people. According to Matano and Yalom (1991), substance abusers can be defiant, grandiose, and cunning. Such difficulties in both the internal and external regulation of connections with other people also have an adverse effect on the internal homeostatic and neurophysiological mechanisms used by these patients to regulate and care for themselves. The occurrence of physical dependence leads to further loss of function and further difficulty in affect regulation, self-care, interpersonal relationships, the ability to verbalize feelings, and the capacity to empathize with other people and to experience pleasure. These basic formulations of IGP can lead to effective group treatment methods. The focus of IGP is on the here-and-now interactions in the group, with the active approach of the group leader encouraging the establishment of group cohesion, therapeutic norms, and member interactions. The group leader's ability to establish a therapeutic alliance with each group member and to form empathic interactions with members enhances the development of interpersonal relationships in the group and encourages the development and maintenance of group cohesion; therefore, the group leader focuses less on the group as a whole perspective. IGP assists members in achieving and maintaining abstinence, and group members are encouraged to join 12-step programs (Flores 1997). Group therapy can be used in a collaborative relationship with 12-step programs (Freimuth 2000). IGP differentiates early-stage treatment from later-stage treatment. In early-stage treatment, the emphasis in the group is on the continued development of the therapeutic alliance and on helping patients develop the capacity to express feelings appropriately. Early-stage treatment also emphasizes the ongoing importance of continued efforts at relapse prevention. Later-stage treatment focuses more on assisting each group member in the development and maintenance of self-care and also emphasizes the mutuality of treatment interactions. With the development of group cohesion and the active interventions of the group leader, group members develop the ability to resolve intrapersonal and interpersonal conflicts without using drugs to regulate affect. Group members become increasingly able to cope with internal deficits, and feel enhanced self-esteem and decreased shame. During the course of group interactions, group members become increasingly able to empathize with one another. The development of more satisfying relationships in the group helps group members to achieve the capacity to have satisfactory relationships outside of the group without the use of substances of abuse. An important aspect of later-stage treatment is the growth in members' abilities to repair disturbances in the therapeutic alliance, and the growth of group cohesion over time enables group members to change earlier self-destructive ways of interacting with people and to establish mutuality and emotionally healthy relationships with other people outside of the group setting.

Cognitive Therapy Groups Cognitive-behavioral theories of substance abuse and dependence have played an important role in the formulation and development of cognitive therapy groups (Marlatt 1985; Rose 2002). These theories have focused on relapse prevention and harm reduction, and cognitive-behavioral concepts play a substantial role in the techniques of other kinds of groups and group processes as well. Group therapy using cognitive-behavioral principles focuses on changing cognitive processes, such as thoughts, opinions, and assumptions, around substance abuse and dependence (Liese et al. 2002; Rose 2002). These cognitive processes interact with environmental, physiological, developmental, and affective processes, resulting in the development of addictive behavior (Beck and Liese 2005).

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Knowledge of the model of cognitive processes is necessary for group leaders to use the group to treat the addictive behaviors of members. At each highly structured group session, the group leader reviews the model of cognitive processes in order to help group members understand the relationship of these processes to their life difficulties and addictive behaviors. The group leader or facilitator plays an active role in setting goals for group members and in modeling behavior. As described by Liese et al. (2002), a wide range of mental activities are examined during the course of cognitive therapy groups. These mental activities include activating stimuli consisting of triggers or cues. Internal cues may be felt as disturbing emotions, such as anxiety and depression, that motivate individuals to use substances of abuse as a coping mechanism. The anticipated positive feelings resulting from the use of substances of abuse in turn may motivate individuals toward addictive behaviors. External cues, consisting of exposure to people, places, and things associated with substance abuse, serve as triggers in the environment that motivate addictive behaviors. Cognitive processes also include urges and cravings, which may be experienced physically. An urge may be thought of as a "relatively sudden impulse to engage in an act," while a craving represents "the subjective desire to experience the effects or consequences of a given act" (Marlatt 1985, p. 48). Group members learn to deal with urges and cravings rather than to gratify them. Other kinds of cognitive processes, such as beliefs about addictive behaviors, also play a role in the development of substance abuse. For example, anticipatory beliefs focus on the benefits resulting from the use of substances of abuse, and relief-oriented beliefs focus on the reduction of negative feelings. Facilitating beliefs and instrumental beliefs are cognitive processes that substance abusers utilize to help themselves participate in addictive behaviors. In cognitive therapy groups, group members are helped by the group leader's active interventions to understand, control, and change members' thought processes and behaviors around substance abuse and dependence. Such groups use psychoeducational techniques as well as the group process, and group members are taught specific coping skills, such as affect regulation, crisis management, and maintenance of nonconflictual relationships with other people. Group members are given homework assignments to develop specific coping skills and to achieve specific goals (Center for Substance Abuse Treatment 2005, pp. 16–17). Group leaders may adopt a harm-reduction approach as a preliminary but necessary phase toward the achievement of long-term abstinence. The identification of goals is an important step for group members. Goals may help members to focus on achievements that are possible and to utilize internal and external resources in the further development of effective coping without the use of substances of abuse.

Modified Dynamic Group Therapy MDGT relies on explanations proposed by the self-medication hypothesis to understand substance abuse as a self-regulation disorder (Albanese and Khantzian 2002). The self-medication hypothesis is based on clinical findings that deficits in the personality structure of substance abusers result in impairments of the self-regulation mechanism; these impairments in self-regulation may be seen in difficulty with regulation of affect, impairment in self-care, an impediment in regulating self-esteem, and difficulties in maintaining interpersonal relationships (Golden et al. 1993). Difficulties in regulating affect include poor tolerance of changes in affect, loss of emotional control, and difficulty in neutralizing internalized affect, with particular reference to feelings of anger, shame, and isolation. Substance abuse patients may experience extremes of affect—feeling too intensely or having a less-than-appropriate amount of affect (Khantzian 1997). In some patients, feelings are so vague that patients are unable to distinguish what they are feeling (alexithymia); in other patients, feelings of overwhelming anger and loss of emotional control dominate—such patients use substances of abuse to control painful affective states. Patients with difficulty taking care of themselves are unable to adequately consider future consequences of their actions. Such difficulties may affect their decisions about using substances of abuse as well as decisions relating to other aspects of their lives. With regard to difficulties in the maintenance of

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self-esteem, substance-abusing patients have difficulty in mobilizing inner resources to soothe themselves. Therefore, they may turn to substances of abuse to make themselves feel more at ease and better about themselves. Perhaps because of early developmental defects in parent–child relationships, substance abusers may experience difficulty in relating to other people and maintaining relationships with mutuality and appropriate interactions. Substance abusers may become either manipulative of other people or detached and uncaring about others. Because of deficits in self-regulation, such individuals turn to the use of substances of abuse as external sources of self-regulation and self-comfort. Substance abusers may utilize specific substances of abuse to regulate specific painful effects or to make themselves feel good, or feel better. For example, opiate abusers may use opiates to control feelings of overwhelming anger, while patients with ongoing depressive symptoms may turn to the abuse of stimulants, such as cocaine. Individuals with attentiondeficit/hyperactivity disorder may also abuse stimulants as self-treatment, whereas patients with feelings of overwhelming anxiety and fear of closeness to others may treat themselves with alcohol or sedative-hypnotic drugs—such drugs may allow these patients to overcome feelings of shyness and inhibition and to reach out to other people to establish relationships based on their common use of alcohol. Although drugs are used in an effort to achieve temporary relief from pain and difficulty in relating to others, their use leads to further difficulties with self-regulation. MDGT utilizes these concepts of the self-medication hypothesis to help group members examine substance abuse through a focus on an interpersonal approach toward the treatment of characterological problems, which stem from ego deficits in self-regulation. The group provides a corrective emotional experience for members (Khantzian 2001). While the group leader works to facilitate a safe environment within the group, group members examine shared difficulties with self-regulation, isolation, and shame. The group leader serves as a model for group members to achieve self-control, sets the goal of the group as abstinence, and helps group members achieve and maintain abstinence through an examination of interactions in the group, with special attention to self-destructive behaviors, painful affects, and loss of emotional control. Through sharing feelings and identifying shared difficulties, group members learn about their own difficulties with affect regulation, low self-esteem, difficulties in relationships with peers, and shared difficulties in self-care. MDGT helps group members identify such deficits and self-destructive behaviors, using the interactions in the group to help group members learn new or more satisfactory ways of dealing with affects and relating to each other. Group members help each other look at the use of drugs as a way to help control painful feelings, and they help each other understand how particular affects may lead to the use of particular drugs. Through mutual support, sharing, and caring about one another and with the help of the group leader, the group members become able to utilize healthy measures of self-regulation and to achieve and maintain abstinence from substances of abuse.

Phase Models of Treatment A number of models of treatment have been developed that utilize the movement of group members from one phase of treatment to the next. Each phase involves the completion of phase-specific tasks, and patients only move to the next phase upon completion of the previous phase. Such a phase model of treatment using group therapy has been described in detail by Banys (2002). This model uses four specific phases: crisis, abstinence, sobriety, and recovery. The tasks of treatment include the repair of damaged interpersonal relationships and the achievement and maintenance of abstinence. In those cases in which self-destructive behavior has led to a disruption of relationships, therapeutic efforts may focus on dealing with loss, shame, sorrow, and guilt. Each phase of treatment requires specific therapeutic techniques to help group members successfully master the tasks of each specific phase. Early phases focus on meeting the requirements of the treatment program and managing behavior. Later phases emphasize learning to verbalize feelings and identify affects. In phase models of treatment, relapse may be seen as a failure in treatment structure and may lead to a return to earlier-phase groups, with more focus on behavioral control and the maintenance of

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abstinence. Using this model, group members in the crisis phase focus on problem solving and achieving behavioral control and abstinence. In this phase, a clear understanding of each group member's specific difficulty is essential, as is taking concrete steps to assist the patient in dealing with a particular life crisis. The support of the other group members helps each patient deal with his or her psychosocial crisis; concurrent individual sessions and group sessions are often most helpful. The needed intervention must be appropriate to the particular crisis with which the patient presents. In the abstinence phase, group members focus on relapse prevention techniques using cognitive-behavioral methods. In the sobriety phase, which is regarded as an advanced phase, group members focus on difficulties with affect, especially depression, grief, and sorrow. The recovery phase, a still more advanced phase, focuses on establishing and maintaining relationships in the group and on the here and now of the group's interactions. With this method of behavior-focused group treatment, the behavior of each group member must be carefully observed. Particularly in the earlier phases of treatment, what patients say is not as important as how they behave. Group members may become very involved with intellectual explanations of their behavior, while continuing to abuse drugs. Therefore, an insight-oriented approach may be counterproductive (Greif [1996] has addressed a number of other common errors in group treatment). Group cohesion can be helpful as group members assist one another in bringing about and maintaining behavioral change.

Relapse Prevention Groups Formal relapse prevention groups focus on the specific stages that substance abusers go through as they move toward recovery and the maintenance of abstinence. Rawson and Obert (2002) discussed an approach to relapse prevention groups that is based on a model developed by Marlatt (1985), in which the treatment of substance abuse and addiction involves a change in habits. This differs from the AA view of addiction as a disease. This approach considers relapse a result of a sequence of cognitive and behavioral steps and maintains that it has identifiable precursors. Using this approach, the specific risks to relapse can be identified and addressed using a variety of coping methods—specifically, cognitive and behavioral methods are used to develop strategies to avoid such risks and to achieve constructive behaviors. The use of a psychoeducational approach to teach group members about issues involved with substance abuse and dependence helps patients achieve changes in behavior and relationships and helps people cope with risks for relapse. Relapse prevention groups can include motivational components in order to enable members to become aware of the reasons for changing substance use behaviors (Miller et al. 2002). Groups may also address issues related to abstinence in order to assist members in the action stage of change to alter behavior and stop substance use (Prochaska and DiClemente 1986). Relapse prevention groups are time limited and focus on the maintenance of abstinence through the use of cognitive-behavioral techniques, including education, peer support, and an active therapeutic approach. Under certain conditions, a harm-reduction approach is also useful (Marlatt and Tapert 1993; Marlatt and Carlini-Marlatt 2005). The active group leader helps group members formulate topics for discussion and plays a directive role in helping members learn to deal with problems. Interventions may address any behavioral issues evident in the group or brought up by the group members. Group members commit themselves to abstinence for the duration of the group treatment and are encouraged to attend self-help groups as well. Many patients are not able to make the commitment to abstinence that is necessary for participation in a relapse prevention group. Such patients may be treated in a series of preparatory groups, each of which has a specific technique and goals related to the particular needs of the patients. The transtheoretical stages of change model (Prochaska and DiClemente 1986; Velasquez et al. 2001) is useful in identifying stages of change that patients experience on the road to changing substance abuse behaviors. The stages of change identified by Prochaska and DiClemente include 1) the precontemplation stage, in which the patient does not realize that substance abuse behavior is

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problematic; 2) the contemplation stage, in which the patient experiences indecision or difficulty in dealing with substance abuse behavior that is now seen as problematic; 3) the preparation stage, in which the patient decides change is needed and action is necessary and prepares to take action; 4) the action stage, in which the patient has decided on a pathway to change and takes action to change substance abuse behavior; and 5) the maintenance stage, in which the patient attempts to maintain abstinence and avoid relapse. In this structure of stages of change, relapse is seen as regressing backward from one stage of change to a previous stage. Using this model, one can identify particular interventions most appropriate for patients in each stage. Preparatory group interventions are appropriate for patients in the stages of precontemplation, contemplation, or preparation; beginning techniques of abstinence are appropriate for patients in the action stage; and relapse prevention techniques are most useful for patients in the maintenance stage. Suggestions for such preparatory or beginning group treatments have been proposed by Washton (2002). For example, a self-evaluation group (SEG) is a group intervention most suitable for patients who are in one of the three stages of change prior to the action stage. These include patients who show signs of substance use in their behavior and physical condition, yet deny it or do not see it as problematic. Such patients may have fairly good psychosocial functioning or may fit the diagnostic criteria for substance abuse or dependence. Patients with cognitive difficulties, suicidal behavior, or a major Axis I psychiatric disorder are not suitable for such a group (Washton 2002). The goal of this group is to help people assess the problematic nature of substance abuse behavior and to evaluate each group member's motivation for further change. Members in this group have not yet made the decision that they want to enter formal treatment, and the group leader does not urge them to. Instead, the group leader actively encourages group members to engage in self-evaluation and mutual understanding, with the goal of helping each other identify substance abuse and resulting behaviors. The group is time limited, and members are asked to refrain from substance use during the period of group treatment even if they eventually decide not to maintain abstinence. The SEG is a structured intervention, which encourages active participation of group members as they attempt to assess the problematic nature of substance abuse and decide whether or not to take action regarding substance abuse. Another preparatory group is the initial abstinence group (IAG), which is most appropriate for patients in the action stage who have decided to change behavior and stop substance abuse, at least for a trial period (Washton 2002). The goal of participation in the IAG is the eventual determination to maintain abstinence. Following successful participation in an IAG, patients may move into formal relapse prevention groups. The IAG is also a time-limited group, which meets frequently over 8–12 weeks. Group members agree to abstain from substances of abuse for the duration of the group, to have urine testing regularly and as needed, to attend group sessions regularly and on time, and to avoid inappropriate sexual or emotional involvement with other group members. Group members focus on the achievement of specific goals, which include 1) understanding the motivation for abstinence; 2) maintaining a realistic perspective of substance abuse and dependence; 3) acquiring skills such as avoiding people, places, and things that might put the member at risk and appropriately managing anger without engaging in inappropriate self-destructive behavior; 4) participating regularly in the group and in the interactions of the group; and 5) beginning attendance at 12-step meetings. Patients remain in the IAG for variable lengths of time and the progress of each group member is discussed on a regular basis. Supervised urine testing is used to validate stated abstinence (Washton 2004). By validating behavior, urine testing may deter further use and deter lying about behavior and may serve to verify progression in treatment. During the course of achieving initial abstinence, each group member attends the group meetings regularly, which provide structure, support, and continuing psychoeducation. Learning specific coping skills helps group members maintain initial abstinence and also enhances the motivation of group members to maintain long-term abstinence. The IAG gives group members mutual support, a chance to share experiences, and an opportunity to learn new coping skills to avoid risk-taking behavior. If a

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group member has a slip, this must be discussed at once, and the group leader must help the group avoid using members who experience repeated slips as scapegoats. The group must reach a mutual decision about temporary exclusion of a member with repeated slips. Membership in the group is open, with the group size ranging from 8 to 12 members. Eventual participation in a formal relapse prevention group follows the achievement of stable abstinence. As noted, relapse prevention group sessions include psychoeducation, group support, the further development of coping skills, and participation in recovery-based treatment. Participation in a longer relapse prevention group may involve addressing changes in each group member's self-destructive patterns of thinking and behavior and may promote more satisfying and appropriate interpersonal relationships as well as the maintenance of abstinence.

Group Therapy in Therapeutic Communities A therapeutic community is a group of individuals living together for therapeutic purposes. According to the work of De Leon (2002), a variety of group-based intervention types are used in therapeutic communities. The basic treatment element of the therapeutic community is the community of peers itself (i.e., the large group) acting as the motivating force to bring about change in substance use. Group process is basic to therapeutic community treatment programs. Group process occurs in regularly held community meetings, in smaller therapeutic groups, and in educational groups. Group process also takes place as residents of the therapeutic community interact with one another informally and in peer groups. A number of small groups in the therapeutic community explore issues of interest to individual community residents, including treatment and educational issues. As noted above, group processes and interactions set the stage for progress and treatment. Therapeutic communities may be used in a variety of settings, including residential and day treatment programs, although the typical therapeutic community is located in a residential setting composed of members of the therapeutic community. Although therapeutic communities help members in many practical ways, the basic method of treatment is self-help, as the community of peers helps to bring about change in its members through group processes. All activities in therapeutic communities are focused on treatment efforts. Members of the therapeutic community working together in a cohesive manner enhance the alliance between each member and the group as a whole. Use of group processes in the peer group improves trust among the members and brings about a safe environment within which change may occur. Daily functioning at work roles in the therapeutic community brings about an increase in self-esteem and responsibility. Shared experiences are discussed publicly, and an examination of interactions among members is essential for the maintenance of recovery. Although trained professionals at times may participate in the community, they are also regarded as community members, and all community members serve as role models. There are a variety of kinds of groups utilized in the therapeutic community, including clinical groups focused on individual issues; "probes" that help members explore feelings and history in depth; "marathons," which are large groups intended to bring about a focused resolution of conflicts; and encounter groups, which are fundamental to the group process in the therapeutic community and which utilize confrontation and sharing to facilitate change. Psychoeducational groups with an emphasis on enhancing cognitive and behavioral skills include seminars, which attempt to bring about cognitive change, and tutorials, which are theme related and emphasize personal growth, job skills, and clinical skills necessary for the more effective use of encounter groups in the therapeutic community. Therapeutic communities also offer groups with specific themes that are often conducted by trained staff. These may include family-based groups to foster familial support of the therapeutic community treatment program. Although space limitations prevent a further, more detailed explanation of the use of group therapy in the therapeutic community, the use of such groups has been extensively described in the literature (e.g., De Leon 2002; Jainchill 1994).

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Among the treatments of special patient populations, that of adolescent substance abusers presents unique problems for group therapists (D. W. Brook 1996). Adolescents undergo a series of fundamental and often tumultuous changes over the course of a relatively short time span; the developmental milestones experienced during this period include psychosexual development and pubertal growth, with their accompanying psychological and physical changes; the development of increasingly important and close relationships with peers of both genders; separation from the family of origin; the establishment of independence; and the achievement of educational and vocational goals. The peer group becomes increasingly important over the course of adolescence, as does the relationship with a number of other groups, which are often related to school. Furthermore, there is a change of emotional focus and psychosocial attachments as the adolescent moves away from parents and develops increasingly important relationships with other people. Substance dependence, with some exceptions (e.g., tobacco), is less common than substance abuse over the course of adolescence, perhaps because of the short time span involved and the initial period of experimentation with substances, which precedes heavier use and the development of dependence. However, substance abuse by adolescents is especially harmful because both the psychosocial and cultural aspects of substance abuse and the psychopharmacological effects of such substances interfere with the usual developmental tasks of adolescence. Growth and development may be delayed during adolescence or may proceed in pathological directions, leading to the development of concurrent or later psychiatric disorders (D. W. Brook 1996). Therefore, group therapists who treat adolescent substance abusers must be familiar with child and adolescent development, family issues, group and individual therapy, psychopathology and the substance use disorders, and issues of prevention and treatment. Substance abuse commonly begins in early adolescence or a few years before that; it is relatively unusual to encounter adult substance abusers who have not used substances of abuse over the course of adolescence. Certain substances of abuse are more commonly used during adolescence, including tobacco, alcohol, marijuana, and inhalants, although stimulant abuse is also a significant problem during this period. Adolescent substance abuse often occurs in a setting of disturbed familial functioning, such that some therapists prefer the use of family therapy, either alone or in conjunction with group therapy (Liddle and Rowe 2002). However, group therapy for adolescent substance abusers is by itself "safe and effective" (Burleson et al. 2006). The psychosocial risk and protective factors for adolescent substance use have been extensively studied (D. W. Brook et al. 2003; J. S. Brook et al. 2006). The development of problem behaviors and co-occurring psychiatric disorders in conjunction with substance abuse during adolescence is the rule (D. W. Brook 1996; J. S. Brook et al. 1998a). The most common comorbid psychiatric disorders noted in adolescent substance abusers are affective disorders, conduct disorders, and anxiety disorders (Kaminer and Bukstein 2005). There is a strong relationship between substance abuse and gender, as well as between substance abuse and adolescent suicide, substance abuse and physical and sexual abuse of adolescents of both genders, and substance abuse and risky sexual behavior (D. W. Brook et al. 2006). The goals of group therapy for adolescent substance abuse include the development of mutually satisfying and appropriate relationships with others; the development of responsibility; the establishment of affective control (especially anger); cessation of self-destructive behavior, including risky sexual behavior; and the achievement and maintenance of abstinence from substances of abuse (Spitz and Spitz 1996). Involvement of family members often plays a crucial role in the effectiveness of therapy; family therapy and multiple family group therapy may be helpful in this regard (Kymissis et al. 1995). Group therapy has been the most commonly used treatment method for adolescents with substance use disorders (Kaminer and Bukstein 2005). Several types of group treatments are appropriate for use with this population, all of which require clearly stated therapeutic contracts (Vannicelli 1995) and clearly stated goals; adolescent substance abusers should know what to expect from treatment—for example, an important goal is to substitute the ties of constructive relationships for those of substance abuse and

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dependence (Flores 2004). These groups may include a substance abuse education group, a relapse prevention group, separate male and female groups, a problem-solving coping skills group, a family issues group, and a group focused on health. Groups may have members of both sexes or of a single sex. Although some therapists prefer to treat adolescent substance abusers in a homogeneous group of substance abusers, other therapists add one or two substance abusers to a mixed-diagnosis adolescent group. In general, for adolescents, behavioral techniques based more on interventions focused on the here and now in the group are often more useful than more interpretive techniques (Galanter et al. 2005). However, an interactional approach (Vannicelli 1992) that encourages self-disclosure and mutual acceptance may also be useful; the confrontation of denial and limit setting may be more effective through the interventions of other group members rather than the group therapist. The group therapist should actively focus on helping adolescent group members stop substance-abusing behavior. Although this goal is of primary importance, dealing with interpersonal conflicts and the expressions of emotions in the group is also of great importance. Adolescent group members need help focusing both on the group and group issues as well as on issues concerning each individual group member. In all such groups, peer support and supportive peer confrontation play essential therapeutic roles. Psychoeducational groups, which are used to provide information, may also result in behavioral changes through patient interactions and discussions of the expression of affect and problem-solving skills. Most meaningful changes in behavior occur in the here-and-now interactions of the group process, with a focus on such interactions despite interpersonal conflict, denial, and emotional outbursts. Active limit setting and the use of structured guidelines are important in the provision of a safe and supportive group environment. The group therapist should be able to help group members deal with impulsivity and acting out, both of which are characteristics of adolescents in general and of adolescent substance abusers specifically, in order to minimize any possible iatrogenic effects of the group (Kaminer 2005). Peer support and peer pressure are useful in bringing about changes in behavior in group members. Groups for the treatment of adolescent substance abusers may be time limited or long-term; the goals of treatment, the treatment setting, and practical issues all play a role in making this decision. The group treatment of adolescents with comorbid substance abuse and psychiatric disorders may utilize a special relational approach (Pressman et al. 2001). Network therapy, an innovative treatment (Galanter et al. 2005) that combines aspects of both group therapy and family therapy, has been tested empirically and proven effective. Network therapy is described in more detail in Chapter 28 of this volume, "Network Therapy."

Other Types of Group Therapies Although space limitations preclude discussion of other group types for substance-abusing patients, it is important to note that homogeneous groups for female substance abusers (Najavits et al. 1996), elderly substance abusers (a problem of increasing prevalence), and substance-abusing gay men and lesbians (McDowell 2002) all present specific treatment issues and require specific treatment techniques. Medically ill patients who abuse substances and patients with co-occurring substance abuse and psychiatric disorders also benefit from group therapy. Also of value are homogeneous groups for patients abusing or dependent on specific substances of abuse (Daley and Mercer 2002; Reilly and Shropshire 2000). Ethnically homogeneous groups can present unique problems and opportunities (D. W. Brook et al. 1998). Group therapy approaches are also useful for inpatients and in partial hospitalization settings. Many groups for substance abusers have a time-limited format (Piper and Joyce 2002).

RESEARCH IN GROUP THERAPY FOR SUBSTANCE ABUSE Although a number of authors have addressed research issues concerning group therapy for substanceabusing or addicted patients, much remains to be learned about the use of groups with these patients

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(Leshner 1997). A number of reviews of the literature indicate a dearth of well-designed and carefully conducted studies; many studies have methodological limitations and a lack of clarity regarding treatment methods and outcomes. As noted by Greene (2002), a number of studies have focused on a cognitive-behavioral approach while omitting a consideration of the group process. In a comprehensive review, titled "Group Therapy for Substance Use Disorders: What Do We Know?" Weiss et al. (2004) examined 24 prospective treatment outcome studies assessing the effectiveness of group therapy for substance use disorders. These studies compared group therapy with other methods of treatment or compared types of group therapy (e.g., Litt et al. 2003). The authors noted three important patterns: 1) added specialized group therapy increased the effectiveness of "treatment as usual"; 2) there were no differences between group therapy and individual therapy; and 3) there were few differences when different kinds of group therapies were compared, and no specific type of group therapy was better than any other type. The authors found no evidence of a "unique benefit" of group therapy for substance abusers. In a cogent discussion with reference to outcome, the authors noted that "a failure to detect differences does not necessarily imply equivalence" (p. 347) and pointed out the likelihood that, in some cases at least, a failure to find such differences might be related to insufficient statistical power. As Weiss et al. (2004) further stated, despite the widespread enthusiasm of clinicians for the use of group therapy for treatment of the substance use disorders, there is a lack of well-designed, carefully conducted, and carefully analyzed outcome studies in the field. As they stated, conclusions about the effectiveness of particular treatments remain unclear. Research has shown the risks for the development of comorbid disorders with substance use (D. W. Brook et al. 2002). Research into the group treatment of comorbid disorders shows the value of integrated group treatment (Weiss et al. 2007). There are a number of difficulties that enter into research efforts in this field, including finding adequate and appropriate numbers of groups and group members, maintaining group membership throughout the period of study, maintaining a treatment plan that is suitable for all group members, and managing problems related to the likelihood of changes in group membership over time and their effects. Although group therapists treating substance abusers and substance-dependent patients think they understand the processes of change that result in effective treatment, little clinical research to date validates their beliefs. A number of theorists and clinicians are interested in pursuing further research in the use of group therapy and group process in the treatment of substance abusers (Liese et al. 2002; Piper 1993). It may be that, despite the many difficulties that are involved in designing, conducting, and analyzing both processes of change and outcome and effectiveness over the course of the group therapy of these patients, future research using sophisticated conceptual, methodological, and statistical approaches may result in enhancing our understanding of both group process and group outcome. Both process and outcome studies are necessary in order to further more effective group therapy treatment efforts. As Greene (2002) noted, such research can add to our understanding of "how, when, why, and for whom group treatment works" (p. 406). In spite of the difficulties in conducting research on the group therapy of substance abusers, the National Institute on Drug Abuse is interested in research on this topic (National Institute on Drug Abuse 2003; Weiss et al. 2004).

CONCLUSION The group treatment of substance abusers has been found by clinicians to be therapeutically effective and cost-effective. The type of group chosen and the techniques and goals of treatment depend on the stage of treatment of each patient; the therapist should create a treatment plan that is unique and specific for each patient. Positive therapeutic changes in groups depend primarily on the therapist's understanding and use of the attachments of group members to each other and the interactions between them. The sociocultural context must be taken into account in substance abuse treatment, as ethnic and cultural factors influence the development and expression of substance abuse and dependence. Linguistic and cultural understanding and competence are necessary for effective

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treatment (D. W. Brook 2002). Multicultural treatment programs are of increasing importance given the extent of immigration to the United States and the presence of people of varying ethnic groups living together in close proximity. The therapeutic alliance and group cohesion can have powerful therapeutic effects. Group therapy for substance abusers can provide corrective emotional experiences (Khantzian 2001) with regard to specific issues in the lives of substance abusers, including difficulties in relationships with other people, the regulation of emotions, self-esteem, and self-care.

KEY POINTS Substance abuse and dependence are biopsychosocial disorders. Group therapy is a particular kind of psychosocial intervention for the treatment of these disorders. However, group therapy may be used in conjunction with other treatment methods, including individual therapy, psychopharmacological approaches, and other methods still in development. Concurrent individual sessions held at appropriate times may enhance the effectiveness of group therapy. Patients should be encouraged to attend some type of 12-step program in addition to ongoing group therapy treatment, with some exceptions. Abstinence should be the goal of treatment, although a harm-reduction approach may be useful in the course of achieving abstinence. The therapist should maintain a relatively active role, regardless of the kind of group therapy approach he or she utilizes. Substance abuse and dependence may be viewed as chronic, relapsing disorders of the brain with psychosocial, behavioral, and cultural antecedents and consequences. Psychosocial and cultural risk factors (and corresponding protective factors) that influence the development and course of substance abuse include the parent–child mutual attachment relationship, as well as peer and significant other interactions, personality and behavioral issues, and cultural factors, including ethnic identification. Viewed from this perspective, substance abuse and dependence have important familial and grouprelated etiological components. Not only are family and group issues important in the development of substance abuse, a group approach to the treatment of such issues can have important therapeutic effects. Consequences of substance abuse also almost inevitably involve family members, and are relevant for group therapy. Because of the chronic nature of these disorders, patients may return to group therapy again and again. Although group therapy may be given in time-limited doses, its use should be viewed as part of a long-term treatment approach often necessary for the successful treatment of these patients. Many patients remain in treatment throughout their lives. Cultural and linguistic understanding and competence are essential for the effective treatment of substance abusers. Poor communication between the group therapist and the group members will lead to poor treatment outcome and early dissolution of the therapy group. Relationships in the group and group interactions during the course of the group process come to take the place of "relationships" with substances of abuse and interactions with "people, places, and things" that serve as risk factors for relapse. Early-stage treatment techniques and goals differ from later-stage treatment techniques and goals. A number of different types of group therapy use similar techniques with many points in common to treat the adverse effects of the genetic, developmental, and cognitive deficits seen in substance abusers and addicts.

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by Brook DW, Spitz HI. New York, Haworth, 2002, pp 275–291 Lieberman MA, Humphreys K: Self-help groups and substance abuse: an examination of Alcoholics Anonymous, in The Group Therapy of Substance Abuse. Edited by Brook DW, Spitz HI. New York, Haworth, 2002, pp 203–221 Liese BS, Beck AT, Seaton K: The cognitive therapy addictions group, in The Group Therapy of Substance Abuse. Edited by Brook DW, Spitz HI. New York, Haworth, 2002, pp 37–57 Litt MD, Kadden RM, Cooney NL, et al: Coping skills and treatment outcomes in cognitive behavioral and interactional group therapy for alcoholism. J Consult Clin Psychol 71:118–128, 2003 [PubMed] MacKenzie KR: Effective Use of Group Therapy in Managed Care. Washington, DC, American Psychiatric Press, 1995 Marlatt GA: Relapse prevention: theoretical rationale and overview of the model, in Relapse Prevention: Maintenance Strategies in the Treatment of Addictive Behaviors. Edited by Marlatt GA, Gordon TR. New York, Guilford, 1985, pp 3–67 Marlatt GA, Tapert SF: Harm reduction: reducing the risks of addictive behaviors, in Addictive Behaviors Across the Life Span: Prevention, Treatment, and Policy Issues. Edited by Baer JS, Marlatt GA. Thousand Oaks, CA, Sage, 1993, pp 243–273 Marlatt GA, Carlini-Marlatt B: Harm reduction: a pragmatic approach for alcohol-related problems, in Alcohol Use and Prevention: A Resource for College Students. Edited by Fearnow-Kenney M, Wyrick DL. Greensboro, NC, Tanglewood Research, 2005, pp 61–70 Matano EJ, Yalom ID: Approaches to chemical dependency: chemical dependency and interactive group therapy—a synthesis. Int J Group Psychother 41:269–294, 1991 [PubMed] McDowell DM: Group therapy for substance abuse with gay men and lesbians, in The Group Therapy of Substance Abuse. Edited by Brook DW, Spitz HI. New York, Haworth, 2002, pp 257–274 Miller WR, Rollnick S, Conforti K: Perils and possibilities of group-based motivational interviewing, in Motivational Interviewing: Preparing People for Change, 2nd Edition. New York, Guilford, 2002, pp 377–390 Najavits LM, Weiss RD, Liese BS: Group cognitive behavioral therapy for women with PTSD and substance abuse disorder. J Subst Abuse Treat 13:13–22, 1996 [PubMed] National Institute on Drug Abuse, National Institute on Alcohol Abuse and Alcoholism: Request for applications for group therapy for individuals in drug abuse or alcoholism treatment (Publ No RFA-DA 04-008). Washington, DC, Department of Health and Human Services, 2003 Orford J: Excessive Appetites: A Psychological View of Addiction. New York, Wiley, 1985 Piper WE: Group psychotherapy research, in Comprehensive Group Psychotherapy, 3rd Edition. Edited by Kaplan HI, Saddock BJ. Baltimore, MD, Williams & Wilkins, 1993, pp 673–682 Piper WE, Joyce AS: Time-limited groups, in The Group Therapy of Substance Abuse. Edited by Brook DW, Spitz HI. New York, Haworth, 2002, pp 173–187 Pressman MA, Kymissis P, Hauben R: Group psychotherapy for adolescents comorbid for substance abuse and psychiatric problems: a relational constructionist approach. Int J Group Psychother 51:83–100, 2001 [PubMed] Prochaska JO, DiClemente CD: Toward a comprehensive model of change, in Treating Addictive Behaviors: Processes of Change. Edited by Miller WR, Miller N. NY, Plenum, 1986, pp 3–27 Rawson RA, Obert JL: Relapse prevention groups in outpatient substance abuse treatment, in The Group Therapy of Substance Abuse. Edited by Brook DW, Spitz HI. New York, Haworth, 2002, pp 121–138

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Reilly PM, Shropshire MS: Anger management group treatment for cocaine dependence: preliminary outcomes. Am J Drug Alcohol Abuse 26:161–177, 2000 [PubMed] Rose SD: Cognitive behavior group therapy, in Encyclopedia of Psychotherapy, Vol 1. New York, Elsevier, 2002, pp 435–450 Spitz HI: Group Psychotherapy and Managed Mental Health Care: A Clinical Guide for Providers. New York, Brunner/Mazel, 1995 Spitz HI: The impact of managed care on the group therapy of substance abuse, in The Group Therapy of Substance Abuse. Edited by Brook DW, Spitz HI. New York, Haworth, 2002, pp 3–18 Spitz HI, Spitz SI: A five-phase model for adolescents who abuse substances, in Group Therapy With Children and Adolescents. Edited by Halperin DA, Kymissis P. Washington, DC, American Psychiatric Press, 1996, pp 265–279 Vannicelli M: Removing the Roadblocks: Group Psychotherapy With Substance Abusers and Family Members. New York, Guilford, 1992 Vannicelli M: Group psychotherapy with substance abusers and family members, in Psychotherapy and Substance Abuse: A Practitioner's Handbook. Edited by Washton AM. New York, Guilford, 1995, pp 337–356 Vannicelli M: Leader dilemmas and countertransference considerations in group psychotherapy with substance abusers. Int J Group Psychother 51:43–62, 2001 [PubMed] Velasquez MM, Maurer GG, Crouch C, et al: Group Treatment for Substance Abuse: A Stages-of-Change Therapy Manual. New York, Guilford, 2001 Washton AM: Outpatient groups at different stages of substance abuse treatment: preparation, initial abstinence, and relapse prevention, in The Group Therapy of Substance Abuse. Edited by Brook DW, Spitz HI. New York, Haworth, 2002, pp 99–119 Washton AM: Group therapy with outpatients, in Substance Abuse: A Comprehensive Textbook, 4th Edition. Edited by Lowinson JH, Ruiz P, Millman RB, et al. Philadelphia, PA, Lippincott Williams & Wilkins, 2004, pp 671–680 Weiss RD, Jaffee WB, de Minil VP, et al: Group therapy for substance use disorders: what do we know? Harv Rev Psychiatry 12:339–350, 2004 [PubMed] Weiss RD, Griffin ML, Kolodziej ME, et al: A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence. Am J Psychiatry 164:100–107, 2007 [Full Text] [PubMed] Yalom ID: The Theory and Practice of Group Psychotherapy, 4th Edition. New York, Basic Books, 1995 Yalom ID, Leszcz M: The Theory and Practice of Group Psychotherapy, 5th Edition. New York, Basic Books, 2005

SUGGESTED READING Brook DW (guest ed): Int J Group Psychother (special issue on group therapy and substance abuse) 51:3–122, 2001 Brook DW, Spitz HI (eds): The Group Therapy of Substance Abuse. New York, Haworth, 2002 Burleson JA, Kaminer Y, Dennis ML: Absence of iatrogenic or contagion effects in adolescent group therapy: findings from the Cannabis Youth Treatment (CYT) study. Am J Addict 15(suppl):4–15, 2006 Colom F, Vieta E, Martinez-Aran A, et al: A randomized trial on the efficacy of group psychoeducation in the prophylaxis of recurrences in bipolar patients whose disease is in remission. Arch Gen Psychiatry 60:402–407, 2003

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Daley DC, Mercer D, Spotts CE: Group therapies, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 839–850 Flores PJ: Addiction as an Attachment Disorder. Lanham, MD, Jason Aronson, 2004 Kaminer Y, Bukstein OG: Adolescent substance abuse, in Clinical Textbook of Addictive Disorders, 3rd Edition. Edited by Frances RJ, Miller SI, Mack AH. New York, Guilford, 2005, pp 559–587 Khantzian EJ, Golden SJ, McAuliffe WE: Group therapy for psychoactive substance use disorders, in Treatments of Psychiatric Disorders, 3rd Edition, Vol 1. Edited by Gabbard GO. Washington, DC, American Psychiatric Press, 2001, pp 891–900 Vannicelli M: Leader dilemmas and countertransference considerations in group psychotherapy with substance abusers. Int J Group Psychother 51:43–62, 2001 Washton AM: Group therapy with outpatients, in Substance Abuse: A Comprehensive Textbook, 4th Edition. Edited by Lowinson JH, Ruiz P, Millman RB, et al. Philadelphia, PA, Lippincott Williams & Wilkins, 2004, pp 671–680 Weiss RD, Jaffee WB, de Minil VP, et al: Group therapy for substance use disorders: what do we know? Harv Rev Psychiatry 12:339–350, 2004 Weiss RD, Griffin ML, Kolodziej ME, et al: A randomized trial of integrated group therapy versus group drug counseling for patients with bipolar disorder and substance dependence. Am J Psychiatry 164:100–107, 2007 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Timothy J. O'Farrell, William Fals-Stewart: Chapter 30. Family Therapy, in The Ameri can Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Gal anter, Herbert D Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.348954. Printed 10/7/2011 from www.psychiatryonline com Textbook of Substance Abuse Treatment >

Family Therapy Timothy J. O'Farrell, Ph.D. William Fals-Stewart, Ph.D.

FAMILY THERAPY: INTRODUCTION Any review of the development and applications of the family treatment model for addictions over the last half-century reveals a rapid progression in the acceptance of family-involv treatment for alcoholism and drug abuse. For example, the treatment literature from the 1950s and early 1960s primarily conceptualized substance abuse as an individual problem (e.g., Jellinek 1960). However, throughout the 1960s, this view was gradually supplanted by what would now be the prevailing clinical wisdom that family members can play a centr drug abuse (Stanton and Heath 1997). In the early 1970s, couples and family therapies were described by the National Institute on Alcohol Abuse and Alcoholism as "one of the mos psychotherapy of alcoholism" (Keller 1974, p. 161). By the late 1970s, family therapy for substance abuse was embraced by the majority of substance abuse treatment programs an Coleman and Davis 1978; Kaufman and Kaufman 1992), and since the late 1980s, family-based assessment and intervention have become widely viewed as part of standard care fo have argued that the only reason not to include family members in the treatment of a substance-abusing patient is refusal by the patient or members of the family to be involved (e In addition, the popular literature on families and substance abuse has grown into its own cottage industry of sorts, with a wide range of books appearing on bookstore shelves desc children of alcoholic individuals. Thus, the role of family factors in the etiology and maintenance of addictive disorders and the application of family therapy in substance abuse treatm Historically, family interventions used to treat alcoholism grew out of couples therapy approaches and focused primarily on the spousal system. In contrast, family treatments for dr therapy, focusing on the entire family. More recently, this distinction has blurred, with both alcoholism and drug abuse treatment programs often providing a wide array of family th members. This chapter describes different types of family therapy commonly used in the treatment of alcoholism and drug abuse. It also summarizes the evidence base for each type of family family-involved treatments to 1) help the family, 2) initiate change when the substance-abusing individual refuses to seek help, and 3) aid recovery once the substance abuser has s Preparation of this chapter was supported by a grant from the National Institute on Alcohol Abuse and Alcoholism (K02 AA00234) and by the Department of Veterans Affairs.

HELPING THE FAMILY WHEN THE SUBSTANCE ABUSER REFUSES TO GET HELP Spouses and other family members often experience many stressors and heightened emotional distress caused by the negative consequences of the substance abuser's drinking and the substance abuser refuses to get help. Two approaches try to help family members cope with their emotional distress and concentrate on their own motivations for change rather to change. These approaches 1) help the family member use the concepts and resources of Al-Anon and 2) teach specific coping skills to deal with alcohol- and drug-related situation

Al-Anon Facilitation and Referral Al-Anon is a 12-step program that is by far the most widely used source of support for family members troubled by a loved one's substance abuse. Al-Anon advocates that family me abuser's drinking and drug use in a loving way, accept that they are powerless to control the substance abuser, and seek support from other members of the Al-Anon program (Al-A There are two ways in which a psychiatrist or other addiction professionals might use Al-Anon to help family members. The first is referral to the Al-Anon program. This includes pro nearby Al-Anon meetings and discussing any concerns the family member may have about the program. Arranging for the family member to go to his or her first few meetings with particularly effective. Like any other referral, checking back to see if the person has followed through is important. The second is Al-Anon facilitation therapy (AFT), which is a therap encourage involvement in Al-Anon. Nowinski (1999) developed and tested a therapist manual for this approach. It consists of 10–12 sessions designed to engage the family member session explores one of the Al-Anon 12 steps (e.g., admitting one is powerless over another person's addiction) or a closely related Al-Anon concept (e.g., detaching with love). AFT member is asked to pursue between sessions, including attending Al-Anon meetings and reading Al-Anon literature.

Coping Skills Therapy Coping skills therapy (CST) teaches family members of substance abusers how to deal with alcohol- and drug-related situations involving the substance abuser. Rychtarik and McGill manual for an eight-session CST group for spouses and family members of substance abusers. Based on a family stress and coping perspective, CST helps group members apply a p problem situations commonly experienced by families of substance abusers (e.g., dealing with intoxicated behavior, partner violence, failure to maintain household responsibilities) presents a stressful situation drawn from a master list of possible situations, leads the group in problem solving, and provides situation-specific skill hints. For example, the group le substance abuser asking for money when in the past he has used these occasions to go out and drink. Responses discussed by participants might range from passive acquiescence to therapist then models the recommended response, group members role-play the situation, and the therapist and group provide feedback. Participants keep a diary of personal prob discussed and role-played in the group as well.

Evidence for Family Therapy Research reviewed in detail elsewhere (O'Farrell and Fals-Stewart 2001, 2003) shows that Al-Anon referral, AFT, and CST all produce improvements in family members' emotional d waitlist control group. Evidence that Al-Anon facilitation and referral help family members as intended and believed by its many adherents comes from controlled studies that suppor Gilbertson 1996; Miller et al. 1999). Although they produce similar improvements in emotional distress, CST leads to less drinking and less violence by the alcoholic individual than does AFT. Specifically, spouses of alco less violence from their male partners and their male partners drank less in the year after treatment than did women who received AFT (Rychtarik and McGillicuddy 2005). These ad because one-half to two-thirds of substance abusers have been violent toward a female partner in the past year (O'Farrell et al. 2003, 2004). In addition, reduced drinking by the al an important indirect effect of CST. Although CST is not widely used, these findings suggest it should receive more attention from clinicians and program administrators. Table 30–1 summarizes key points about family-based methods to help the family when the substance abuser refuses to get help.

INITIATING CHANGE WHEN THE SUBSTANCE ABUSER REFUSES TO GET HELP Many, if not most, substance abusers seek treatment in response to external pressure. With the possible exception of legal system coercion, pressure by a family member is the mo to enter treatment (Stanton 1997). Several family-based methods have been developed to motivate resistant substance abusers to enter treatment. These include the Johnson Inst sequence for engagement (ARISE), pressure to change (PTC), and community reinforcement and family training (CRAFT).

Johnson Institute Intervention The best known of these family-involved motivational techniques is the Johnson Institute intervention (Johnson 1986; Liepman 1993). The intervention, as it is most commonly calle rehearsal sessions to prepare family members and others (e.g., neighbors, friends) for a confrontation meeting. After these preparation sessions, the confrontation meeting is sched meeting, typically not knowing the agenda of the group. Once the substance user is in their midst, family members then share their concerns and feelings; these are to be presented intervention team members also express their hope that the substance user will enter treatment, and they outline the consequences if the substance user refuses and openly discuss itself and the recommended treatment. A referral to treatment is then made. Often, the members of the intervention team meet with the therapist at a later date to go through a d family members and others in the substance user's social network to follow.

A Relational Intervention Sequence for Engagement ARISE (Landau and Garrett 2006) was developed as a less coercive alternative than the traditional Johnson intervention. ARISE is a three-stage approach, with each successive stag therapist involvement, and coercion. The ARISE model advocates use of less coercive steps early in the process and gradually proceeds to the use of greater counselor and family in successful in motivating the substance abuser to engage in treatment. The first stage involves one or more telephone sessions with the family member who contacted the treatment agency, followed by an in-person meeting of the family and other netw them in support of treatment for the substance abuser. The second stage involves an informal "invitational intervention" with a therapist present. This meeting is not a surprise to th consequences for refusing treatment. Family and relevant others and the substance abuser are invited to attend this meeting, although the meeting can still be conducted without th the members collectively consider possible approaches that might be used to motivate the substance abuser to enter treatment. If, after repeated attempts, the substance user rem to the third and final stage, which involves a formal intervention similar to the Johnson approach.

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The Pressure to Change Approach James G. Barber (e.g., Barber and Crisp 1995) developed the PTC approach for partners living with heavy drinkers who deny their alcohol problem and refuse treatment. PTC make coping responses that are designed to empower the non-substance-abusing partner and provide incentive for the alcoholic partner to change. PTC involves five to six structured counseling sessions to instruct the non-substance-abusing partner how to use five gradually increasing levels of pressure on the drinker to seek he course of these five levels, the partner 1) receives feedback from the therapist about the seriousness of the drinker's problem and receives education on PTC; 2) plans activities for for times when he or she usually drinks (e.g., taking children to an amusement park, going to dinner with friends or relatives who do not drink); 3) responds to drinking by withdraw related crises by suggesting treatment; 4) establishes a contract in which the partner agrees to exchange some reinforcer for sobriety; and 5) confronts the drinker, when prior step effects of the drinking and a simple, direct request to seek change or seek help.

Community Reinforcement and Family Training The CRAFT approach (Smith and Meyers 2004) involves six to eight sessions that draw heavily on learning theory. CRAFT teaches a family member how to use positive reinforcemen drug use or drinking by the substance abuser. Positive reinforcement might include the family member engaging in pleasant activities (e.g., discussing enjoyable topics, giving gifts) using drugs. In addition, the family member would expressly state that reinforcement is being given because the substance user is not drinking or using drugs. Negative consequenc reinforcements, explaining why, and ignoring the substance abuser during periods of intoxication. Emphasis is also placed on the family member decreasing stress in general and inc This might include establishing new friendships, engaging in positively rewarding activities outside of the relationship with the substance abuser, or joining a therapy group. A unique aspect of CRAFT is its emphasis on identifying dangerous situations as behavioral changes are introduced at home. The family member is taught how to identify potentially immediate action before getting hurt. The therapist helps the family member identify the sequence of events that lead to violence and teaches him or her to identify significant cues member develops a specific plan for leaving these situations until it is safe to return. Finally, CRAFT teaches the family member effective ways to suggest treatment to the substance abuser. Often this involves picking a time and situation when the substance abuser because substance use has caused unacceptable behavior. Such situations may occur after the substance abuser has engaged in embarrassing behavior when drinking, disappointed driving.

Evidence for Family Therapy Research reviewed in detail elsewhere (O'Farrell and Fals-Stewart 2001, 2003) shows that, of these family-based methods to promote change and treatment entry by the resistant s evidence base. Across four randomized trials (two for alcoholics and two for drug abusers), the average treatment engagement rate for CRAFT was 68% (range from 59% to 85%), than comparison groups of AFT or Al-Anon referral (20%) or the Johnson intervention (30%). Thus, CRAFT is a more effective alternative to engage substance abusers in treatment approaches. The Johnson Institute intervention showed a disappointing treatment engagement rate of 30% in the first randomized, controlled study of this popular method. This was similar to th not much higher than for Al-Anon, which does not try to change the substance abuser's behavior. The reason for these disappointing findings is that 70% of families in these two stud not go through with the family confrontation meeting. When family members completed the confrontation in these two studies, most succeeded in getting their substance abuser int intervention have cited "a 90% success rate," which we now know does not apply for an intent-to-treat basis (which has a 25%–30% success rate) but only for the minority of famili ARISE has a less coercive multistep process that is conceptually appealing and may lead to better engagement rates than the Johnson intervention. However, although ARISE has sh controlled studies have not been reported. Outcomes for PTC were better in three controlled studies than a waitlist control on initiating change defined as treatment entry or reduced drinking for the rather brief period of 2 we half of that found for CRAFT. PTC has been used with spouses of heavy drinkers, not drug abusers or other family members. Nonetheless, PTC may be a promising approach. It is br therapists and a self-help manual for spouses. If it can be shown that PTC produces durable reductions in the drinker's alcohol use, it may be of particular use in countries without ex Table 30–2 summarizes key points about family-based methods to initiate change when the substance abuser refuses treatment.

AIDING RECOVERY WHEN THE SUBSTANCE ABUSER HAS SOUGHT HELP Preceding sections have examined interventions to help the family and support the substance abuser's entry into treatment. Regardless of the impetus for seeking help, once the su therapy interventions are often used as part of the treatment to aid the substance abuser's recovery and help the family. Network therapy, family systems therapy (FST), and beha influential approaches. We will now examine the hallmark therapy techniques and the evidence base for these approaches.

Network Therapy Network therapy (Galanter 1999) involves key members of the patient's social network at the outset and at regular intervals during treatment to support the patient's recovery. Net here because Chapter 28 of this volume, "Network Therapy," is devoted to a detailed consideration of this approach.

Family Systems Therapy FST has incorporated many core concepts of family systems theory as applied to substance abuse (Stanton et al. 1982; Steinglass et al. 1987). Therapy focuses on the interactional of techniques to affect interactions within the family. Greatest emphasis is put on identifying and altering family interaction patterns that are associated with problematic substance u The family systems approach views substance abuse as a major organizing principle for patterns of interactional behavior within the family system. A reciprocal relationship exists b with an individual's drug and alcohol use being best understood in the context of the entire family's functioning. According to family systems theory, substance abuse often evolves d member is having difficulty addressing an important developmental issue (e.g., leaving the home) or when the family is facing a significant crisis (e.g., marital discord). During thes distract family members from their central problem or 2) slow down or stop a transition to a different developmental stage that is being resisted by the family as a whole or by one From a family systems perspective, substance abuse represents a maladaptive attempt to deal with difficulties that develop a homeostatic life of their own and regulate family trans important role in the family and once the therapist understands the function of the substance abuse for the family, he or she can then explain how the behavior has come about and aimed at restructuring the interaction patterns associated with the substance abuse, thereby making the drinking or drug use unnecessary in the maintenance of the family system f systems therapists use a variety of therapy techniques. These techniques fall into two broad categories, joining and restructuring.

Joining with the family Joining consists of techniques designed to promote therapeutic alliance and increase the therapist's leverage within the family. The therapist alternates between joining that support joining that challenges the system. This involves making a connection with each family member engaged in treatment and instilling a sense of confidence that the therapist has a firm family members on identified problems. In the joining process, the therapist typically solicits from each family member his or her perception of the problems in the family and his or attending to each person's views, the therapist conveys that each family member's viewpoint is important and that differences in perception about the identity, nature, and severity attempts to communicate to each family member that he or she understands the family member's perceptions of the problems and has a clear idea about how to address the issues The process of joining may involve the therapist promoting areas of strength in the family, supporting a threatened member of the family, and using the family member's methods o introduce new ideas and concepts (Minuchin 1974). Of course, joining is an ongoing process that is ultimately supported and reinforced as the therapist demonstrates his or her unde course of treatment.

Restructuring family alliances and interactions Unlike joining, the second category of intervention techniques, restructuring, involves challenging the family's homeostasis. Restructuring takes place through modifications in the fa individuals and subsystems in the family (e.g., Haley 1976; Minuchin 1974). Several different techniques are used in the process of restructuring, including contracting, enactment, r boundaries. Contracting is an agreement to work on agreed-upon issues, with an emphasis on helping the substance abuser with his or her problems prior to expanding to and probi the end of the first interview and is maintained throughout treatment. As part of the contract, the family must choose to develop a family system that is conducive to abstinence by contract after it has been agreed upon as part of the initial evaluation. Enactment involves the therapist eliciting, observing, and interrupting recurring problematic behavioral sequences in family interaction patterns. To do this, the therapist requires fa problems in sessions rather than direct their communications to the therapist. The therapist carefully observes these enactments. Once the therapist has observed problematic inter these customary behavioral exchanges among family members. Reframing requires the therapist to help family members understand the interrelatedness of their behaviors and to see and understand how the substance abuse serves an importan composed of shifting family interaction patterns and establishing new, healthier behaviors. For example, this might include changing seating arrangements to strengthen the role of solvable form, and teaching methods of communication and problem solving that preclude triangulation or conflict avoidance.

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Marking boundaries is accomplished by clearly delineating individual and subsystem boundaries. For example, the parental subsystem should be protected from intrusion by children the family. To strengthen the parental subsystem, sessions with parents that exclude other family members may be held. FST is more than a set of techniques. It involves a conceptual framework that explains common puzzling clinical phenomena (e.g., a family member seeming to sabotage a patient's From this perspective, substance abuse by a family member serves an important function for the family, helping to maintain the homeostasis of the family system. Thus, if a family substance-abusing member, subsequent sobriety would likely threaten homeostasis and may be resisted on some level.

Behavioral Couples Therapy BCT (O'Farrell and Fals-Stewart 2006) works directly to increase relationship factors conducive to abstinence. A behavioral approach assumes that family members can reward absti individuals from happier, more cohesive relationships with better communication have a lower risk of relapse. BCT is designed for married or cohabiting couples seeking help for alcoholism or drug abuse. The purposes of BCT are to build support for abstinence and to improve relationship fun "recovery contract" that includes a daily ritual to reward abstinence. BCT improves the relationship with techniques for increasing positive activities and improving communication. F recovery to prevent or minimize relapse. The BCT therapist sees the substance-abusing patient together with the spouse or live-in partner typically for 12–20 weekly outpatient couples sessions over a 3–6 month period, fol usually is an adjunct to individual or group counseling for the substance abuser. Generally, couples are married or cohabiting for at least a year, without current psychosis, and one m with alcoholism and/or drug abuse. The couple starts BCT soon after the substance abuser seeks help.

The BCT recovery contract Before the substance abuser seeks help, the problems from substance abuse lead the couple into an intense, hostile struggle in which the spouse tries desperately to control the sub although at times promising to reform or staying abstinent for short periods, continues to drink or use drugs. Such repeated unkept promises to change and problems caused by the high level of distrust and conflict in the relationship. The BCT recovery contract specifies behaviors that each member of the couple can enact to reduce distrust and conflict about substance abuse and to reward abstinence and actions contract starts with the trust discussion, in which the patient states his or her intent not to drink or use drugs that day (in the tradition of "one day at a time," from Alcoholics Anonym for the patient's efforts to stay abstinent, and the patient thanks the spouse for the encouragement and support. For patients taking a recovery-related medication (e.g., disulfiram, witnessed and verbally reinforced by the spouse also takes place during the trust discussion. The couple performs the trust discussion in each BCT session to highlight its importance performance of this important ritual. Self-help meetings and drug urine screens are part of the contract for most patients. Performance of the trust discussion and other recovery activities (self-help meetings, drug scre is provided. At the start of each BCT session, the therapist reviews the recovery contract calendar to see how well each spouse has done his or her part. The calendar provides an on verbally at each session. The couple also agrees not to discuss substance-related conflicts that can trigger relapse, reserving these discussions for the counseling sessions. The follow BCT recovery contract. The second case illustrates that when both members of a couple have a current substance problem and both want abstinence, BCT often is workable. Recovery contract for Mary and Jack Mary was an addicted daily drinker and marijuana smoker who came to treatment after being suspended from her job for drinking. Her husband, Jack, was a light drinker with no 30–1, their recovery contract had 1) a daily trust discussion, 2) at least two AA meetings per week, and 3) drug urine screens at each BCT session. They were very compliant, as FIGURE 30–1. Recovery contract and calendar for Mary and Jack.

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Source. Reprinted from O'Farrell TJ, Fals-Stewart W: Behavioral Couples Therapy for Alcoholism and Drug Abuse. New York, Guilford, 2006, p. 48. Used with permission. Jack was upset about the positive urine screens for marijuana in the first few weeks. The counselor explained that marijuana could stay in the system for some time and suggeste over Mary's suspected drug use. Soon thereafter, Mary's drug screen results were negative for marijuana and stayed that way. Jack found Al Anon helpful, so they added to the c local church where Mary attended AA and Jack went to Al Anon. Recovery contract for Sue and Gene—a dual problem couple Sue came to BCT after detoxification for heavy daily drinking plus cocaine and marijuana use three to four times per week. Gene had similar problems but did not need detoxifica temporary custody when Gene was arrested for drunk driving while Sue (also intoxicated) and the kids were in the car. Both Sue and Gene wanted to "quit for good" to get their Gene had 6 months weekly BCT. Their "dual recovery contract," shown in Figure 30–2, committed them to 1) a daily trust discussion, 2) taking disulfiram (Antabuse) daily togeth week, and 4) undergoing weekly urine screens. FIGURE 30–2. Contract and calendar for Sue and Gene, a dual problem couple.

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Source. Reprinted from O'Farrell TJ, Fals-Stewart W: Behavioral Couples Therapy for Alcoholism and Drug Abuse. New York, Guilford, 2006, p. 48. Used with permission. About 5 weeks after starting BCT, Sue used cocaine on Friday night when she went to the local bar with a girlfriend. At the next BCT session her urine screen was positive for coca the bar. They had planned to just socialize, but when cocaine was offered they did not refuse and did one line each. The next night they went to the bar again and each used mult turning point. They got more committed to their recovery. They planned things to do Friday and Saturday nights, starting with an AA meeting together on Friday night. Each got a After weekly BCT, they had quarterly checkups for 2 more years. They regained custody of their children and stayed abstinent except for a few isolated days for Gene and a 5-da sessions with the BCT counselor to help them get back on track.

Other support for abstinence BCT also supports abstinence by 1) reviewing substance use or urges to use since the last session; 2) decreasing exposure to alcohol and drugs (e.g., deciding whether to have alcoh problems to reduce relapse risk and make abstinence more rewarding; and 4) decreasing partner behaviors that trigger or reward substance use. These aspects are part of many ty they are carried out with the participation of the spouse.

Improving relationship functioning Using a series of behavioral assignments, BCT increases positive feelings and activities and teaches constructive communication because these relationship factors are conducive to a positives. First, "catch your partner doing something nice" asks each person to notice and acknowledge one nice thing each day that his or her partner did. Second, "caring day" invo or her partner with a day when the person does some special things to show his or her caring. Third, "shared rewarding activities" for fun together, either by themselves or with the couple closer together. Such shared activities are associated with positive recovery outcomes (Moos et al. 1990). Teaching communication skills can help the substance abuser and spouse deal with stressors in their relationship and in their lives, and this may reduce the risk of relapse. BCT inclu listening and speaking, and use of planned communication sessions. Couples also learn more advanced skills of conflict resolution, skills in negotiating agreements for desired chang

Continuing recovery Most couples who attend BCT sessions faithfully show substantial improvement. However, when the structure of the weekly BCT sessions ends, there is a natural tendency for backs maintain the gains they made in BCT and prevent or minimize relapse. Near the end of weekly sessions, the BCT counselor helps the couple make a continuing recovery plan that sp discussion) they wish to continue and an action plan of steps to prevent or minimize relapse. Couple checkup visits every few months for an extended period can encourage continue problems may benefit from periodic couple relapse prevention sessions in the year after weekly BCT ends (O'Farrell 1993a).

Evidence for Family Therapy Research reviewed in detail elsewhere (Epstein and McCrady 1998; O'Farrell and Fals-Stewart 2001, 2003, 2006) shows that of these family-based methods to aid recovery when th the strongest evidence base. Over 15 randomized trials have compared substance abuse and relationship outcomes for alcohol- and drug-abusing patients treated with BCT or indivi equally intensive treatments of BCT plus individual counseling with individual counseling alone. The studies show a fairly consistent pattern of results. Substance-abusing patients wh

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abstinence and had fewer substance-related problems, happier relationships, and lower risk of couple separation and divorce than those who received only individual treatment (e.g al. 1992; Winters et al. 2002). Although earlier studies of BCT were done with white male alcohol- and drug-abusing patients and their female partners, more recent studies have sh African American and Hispanic patients, heterosexual female patients, and both male and female same-sex couples with a substance-abusing member. Finally, BCT produces greate treatment in compliance with recovery-related medication (e.g., disulfiram for alcoholic patients, naltrexone for opioid patients), intimate partner violence, and emotional problems O'Farrell 2003; Fals-Stewart et al. 2002; Kelley et al. 2002). There is also evidence supporting the clinical utility of FST. Evidence for the effectiveness of FST is strongest for adolescent substance abusers (e.g., Szapocznik et al. 1988) and you al. 1982). Although family systems concepts have influenced clinicians' working with adult alcoholic patients and their families (e.g., Steinglass et al. 1987), the evidence base suppo have been only a small number of studies, generally with small sample sizes, and without a consistent pattern of favorable results. Interestingly, however, one study (Shoham et al retaining in treatment couples with more seriously disturbed communication patterns. If replicated, these findings might implicate a patient–treatment matching effect. Table 30–3 summarizes key points about family-based methods to aid recovery when the substance abuser has sought help.

CONCLUSION This chapter described a variety of family interventions to help the family and initiate change when the substance abuser resists treatment and to aid recovery once treatment has b may or may not have a strong evidence base. In helping the family, Al-Anon facilitation and referral helps family members as intended and believed by its many adherents. Howeve the family but also reduces violence and drinking better than Al-Anon, is virtually unknown. For initiating change, the Johnson Institute intervention is very popular and proponents o but research has demonstrated that methods such as CRAFT are far more effective. For aiding recovery, BCT appears to be a very effective treatment for married or cohabiting sub substance abuse treatment providers in non-research settings (Fals-Stewart and Birchler 2001). Dissemination of effective family-based treatment methods is a shared responsibility between researchers and treatment providers. Investigators need to examine family treatmen the economic and system constraints faced by community programs. For example, the involvement of managed care in substance abuse treatment has resulted in the more routine treatment methods that require multiple therapy sessions over the course of several months may not be adopted, regardless of effectiveness. Conversely, it is the responsibility of p using family-based treatment methods that may be less familiar (e.g., behavioral interventions), but nonetheless more effective, than traditional approaches. This would require ch long-standing clinical wisdom may dictate as effective. Although these changes may be difficult to implement, the beneficiaries are likely to be substance-abusing patients and their

KEY POINTS Family therapy interventions have been designed for three main purposes: 1) to help the family when the substance abuser refuses help, 2) to initiate change when the substance recovery once treatment has begun. Major approaches to help the family when the substance abuser refuses help are 1) Al-Anon facilitation and referral and 2) coping skills therapy (CST). Studies show that both Al-Anon and CST reduce emotional distress and improve coping by the family member. However, CST leads to less drinking and less violence by the substa Major approaches to initiate change when the substance abuser resists treatment are 1) the Johnson Institute intervention, 2) a relational intervention sequence for engagement ( community reinforcement and family training (CRAFT). Studies show that CRAFT is most effective in initiating change, averaging a 68% treatment engagement rate across four randomized trials. Although popular, the Johnson interven because many families do not follow through with the confrontation meeting that is the hallmark of this approach. Major approaches to aid recovery once treatment has begun are 1) network therapy, 2) family systems therapy (FST), and 3) behavioral couples therapy (BCT). Studies show that BCT is effective with alcoholism and drug abuse. BCT produces more abstinence, happier relationships, better compliance with recovery-related medication, and emotional problems of the couple's children than does individual-based treatment. Studies support FST for adolescent and young adult drug abusers, but evidence supporting FST with adult alcoholism is not very extensive.

REFERENCES Al-Anon Family Groups: Al-Anon Faces Alcoholism. New York, Al-Anon Family Groups, 1985 Barber JG, Crisp BR: The "pressure to change" approach to working with the partners of heavy drinkers. Addiction 90:269–276, 1995 [PubMed] Barber JG, Gilbertson R: An experimental study of brief unilateral intervention for the partners of heavy drinkers. Res Soc Work Practice 6:325–336,1996 Coleman SB, Davis DT: Family therapy and drug abuse: a national survey. Fam Process 17:21–29, 1978 [PubMed] Epstein EE, McCrady BS: Behavioral couples treatment of alcohol and drug use disorders: current status and innovations. Clin Psychol Rev 18:689–711, 1998 [PubMed] Fals-Stewart W, Birchler GR: A national survey of the use of couples therapy in substance abuse treatment. J Subst Abuse Treat 20:277–283, 2001 [PubMed] Fals-Stewart W, O'Farrell TJ: Behavioral family counseling and naltrexone for male opioid dependent patients. J Consul Clin Psychol 71:432–442, 2003 [PubMed] Fals-Stewart W, Birchler GR, O'Farrell TJ: Behavioral couples therapy for male substance-abusing patients: effects on relationship adjustment and drug-using behavior. J Consul Clin Fals-Stewart W, Kashdan TB, O'Farrell TJ, et al: Behavioral couples therapy for male-drug abusing patients and their partners: the effect on interpartner violence. J Subst Abuse Tre Fals-Stewart W, Birchler GR, Kelley ML: Learning sobriety together: a randomized clinical trial examining behavioral couples therapy with female alcoholic patients. J Consul Clin Psy Galanter M: Network Therapy for Alcohol and Drug Abuse. New York, Guilford, 1999 Haley J: Problem-Solving Therapy. San Francisco, CA, Jossey-Bass, 1976 Jellinek EM: The Disease Concept of Alcoholism. New Haven, CT, Hillhouse Press, 1960 Johnson VE: Intervention: How to Help Someone Who Doesn't Want Help. Minneapolis, MN, Johnson Institute Books, 1986 Kaufman E, Kaufman P: Family Therapy of Drug and Alcohol Abuse, 2nd Edition. Needham Heights, MA, Allyn & Bacon, 1992 Keller M: Trends in treatment of alcoholism, in Second Special Report to the U.S. Congress on Alcohol and Health. Washington, DC, Department of Health, Education, and Welfare, Kelley ML, Fals-Stewart W: Couples versus individual-based therapy for alcoholism and drug abuse: effects on children's psychosocial functioning. J Consul Clin Psychol 70:417–427, Landau J, Garrett J: Invitational Intervention: A Step by Step Guide for Clinicians Helping Families Engage Resistant Substance Abuses in Treatment. New York, Haworth, 2006 Liepman MR: Using family influence to motivate alcoholics to enter treatment: the Johnson Institute intervention approach, in Treating Alcohol Problems: Marital and Family Interve Guilford, 1993, pp 54–77 Miller WR, Meyers RJ, Tonigan JS: Engaging the unmotivated in treatment for alcohol problems: a comparison of three strategies for intervention through family members. J Consul Minuchin S: Families and Family Therapy. Cambridge, MA, Harvard University Press, 1974 Moos RH, Finney JW, Cronkite RC: Alcoholism Treatment: Context, Process, and Outcome. New York, Oxford University Press, 1990 Nowinski JK: Family Recovery and Substance Abuse: A Twelve-Step Guide for Treatment. Thousand Oaks CA, Sage, 1999 O'Farrell TJ: Couples relapse prevention sessions after a behavioral marital therapy couples group program, in Treating Alcohol Problems: Marital and Family Interventions. Edited b 305–326 O'Farrell TJ (ed): Treating Alcohol Problems: Marital and Family Interventions. New York, Guilford, 1993b O'Farrell TJ, Fals-Stewart W: Family involved alcoholism treatment: an update, in Recent Developments in Alcoholism, Vol 15: Services Research in the Era of Managed Care. Edited 329–356 O'Farrell TJ, Fals-Stewart W: Alcohol abuse. J Marital Fam Ther 29:121–146, 2003 [PubMed] O'Farrell TJ, Fals-Stewart W: Behavioral Couples Therapy for Alcoholism and Drug Abuse. New York, Guilford, 2006 O'Farrell TJ, Cutter HSG, Choquette K, et al: Behavioral marital therapy for male alcoholics: marital and drinking adjustment during two years after treatment. Behav Ther 23:529–

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O'Farrell TJ, Fals-Stewart W, Murphy M, et al: Partner violence before and after individually based alcoholism treatment for male alcoholic patients. J Consult Clin Psychol 71:92–102 O'Farrell TJ, Murphy CM, Stephen S, et al: Partner violence before and after couples-based alcoholism treatment for male alcoholic patients: the role of treatment involvement and 2004 [PubMed] Rychtarik RG, McGillicuddy NB: Coping skills training and 12-step facilitation for women whose partner has alcoholism: effects on depression, the partner's drinking, and partner phy 73:249–261, 2005 [PubMed] Shoham V, Rohrbaugh MJ, Stickle TR, et al: Demand-withdraw couple interaction moderates retention in cognitive-behavioral versus family systems treatments for alcoholism. J Fa Smith JE, Meyers RJ: Motivating Substance Abusers to Enter Treatment: Working With Family Members. New York, Guilford, 2004 Stanton MD: The role of family and significant others in the engagement and retention of drug-dependent individuals, in Beyond the Therapeutic Alliance: Keeping the Drug-Depende LS, Blaine JD, Boren FJ. Rockville, MD, National Institute on Drug Abuse, 1997, pp 157–180 Stanton MD, Heath AW: Family and marital treatment, in Substance Abuse: A Comprehensive Textbook, 3rd Edition. Edited by Lowinson JH, Ruiz P, Millman RB, et al. Baltimore, MD Stanton MD, Todd TC, and associates: The Family Therapy of Drug Abuse and Addiction. New York, Guilford, 1982 Steinglass P, Bennett L, Wolin S, et al: The Alcoholic Family. New York, Basic Books, 1987 Szapocznik J, Perez-Vidal A, Brickman AL, et al: Engaging adolescent drug abusers and their families in treatment: a strategic structural systems approach. J Consult Clin Psychol 56 Winters J, Fals-Stewart W, O'Farrell TJ, et al: Behavioral couples therapy for female substance-abusing patients: effects on substance use and relationship adjustment. J Consul Clin

SUGGESTED READING Al-Anon Family Groups: Al-Anon Faces Alcoholism. New York, Al-Anon Family Groups, 1985 Johnson VE: Intervention: How to Help Someone Who Doesn't Want Help. Minneapolis, MN, Johnson Institute Books, 1986 Landau J, Garrett J: Invitational Intervention: A Step by Step Guide for Clinicians Helping Families Engage Resistant Substance Abuses in Treatment. New York, Haworth, 2006 Nowinski JK: Family Recovery and Substance Abuse: A Twelve-Step Guide for Treatment. Thousand Oaks, CA, Sage, 1999 O'Farrell TJ, Fals-Stewart W: Behavioral Couples Therapy for Alcoholism and Drug Abuse. New York, Guilford, 2006 Rychtarik RG, McGillicuddy NB, Duquette JA: Coping skills training program for women with alcoholic partners: therapist manual. Unpublished manuscript, University at Buffalo, The from Robert Rychtarik, Ph.D., Research Institute on Addictions, 1021 Main St, Buffalo, NY 14203 Smith JE, Meyers RJ: Motivating Substance Abusers to Enter Treatment: Working With Family Members. New York, Guilford, 2004 Steinglass P, Bennett L, Wolin, S, et al: The Alcoholic Family. New York, Basic Books, 1987 Copyright © 2011 Amer can Psychiatr c Association. All Rights Reserved.

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Chapter 31. Inpatient Treatment

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Roger D. Weiss, Jennifer Sharpe Potter, Rocco A. Iannucci: Chapter 31. Inpatient Treatment, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.359576. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Inpatient Treatment Roger D. Weiss, M.D. Jennifer Sharpe Potter, Ph.D., M.P.H. Rocco A. Iannucci, M.D.

INPATIENT TREATMENT: INTRODUCTION In recent years, few subjects in the field of addiction research have generated as much debate as the role of inpatient treatment for patients with substance use disorders (SUDs). This controversy has been fueled in part by the enormous cost of SUD treatment in the United States: in 2005, the direct cost for their treatment was estimated at $18 billion (Mark et al. 2005). In contrast, the annual cost to society of alcohol- and drug-related problems has been estimated to be more than $410 billion (Mojtabai and Zivin 2003). Therefore, establishing effective treatment methods for patients with SUDs is both a public health and a financial priority. Because the resources available to tackle this issue are finite, treatment should be not only effective but also cost-effective. While the treatment of SUDs overall has a favorable cost-benefit ratio compared with other medical care, questions have been raised about the cost-effectiveness of inpatient treatment for substance-related problems (Mojtabai and Zivin 2003). Because the cost differential between inpatient and outpatient treatment is substantial, and because there is wide variation in per diem costs even among inpatient facilities, determining the proper role of hospital treatment is critical. Unfortunately, discussions regarding inpatient treatment have often been fueled by political and financial considerations rather than by clinical research data. This has sometimes led to the promulgation of extremist positions. As a result, arguments have been presented that support either the extraordinary effectiveness of (McElrath 1988) or the virtual lack of need for (Miller and Hester 1986) inpatient treatment. This debate has been intensified by the fact that in the late 1970s and early 1980s, private sector (much of it for-profit) hospital treatment of substance-dependent individuals increased dramatically at the same time that the number of public hospital units decreased. By the mid-1980s, however, inpatient treatment of SUDs had become the focus of cost-containment efforts (Steenrod et al. 2001). As clinicians, researchers, government officials, and entrepreneurs attempted to develop less costly alternatives to hospitalization, the rationale for inpatient treatment was questioned, and this treatment has remained a subject of considerable controversy. In part as a result of efforts to manage health care costs, relative spending on inpatient treatment from 1991 to 2001 decreased from 46% to 30% of total spending on SUD treatment (Mark et al. 2005). Nonetheless, inpatient facilities remain important venues for the treatment of SUDs, with approximately 29% of those receiving any treatment in 2005 doing so in an inpatient rehabilitation setting (Substance Abuse and Mental Health Services Administration 2006). In this chapter, we present an overview of inpatient treatment, discuss current thinking about the indications for inpatient care, and review research on the effectiveness of treatment in this setting. Supported by National Institute on Drug Abuse grants DA022288, DA15831, and DA15968; National Institute on Alcohol Abuse and Alcoholism grant AA11756; and a grant from the Dr. Ralph and Marian C. Falk Medical Research Trust.

WHAT IS INPATIENT TREATMENT?

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The term inpatient treatment actually refers to a variety of forms of treatment that take place in many different settings. Inpatient treatment may involve detoxification and rehabilitation, in combination or succession. The treatment may take place either in a medical or general psychiatric setting or on a specialized substance dependence unit, in a general hospital, a psychiatric hospital, or a freestanding substance dependence treatment facility. The level and nature of staffing may vary as well, depending on the facility and the patient population. For example, an inpatient substance abuse treatment facility that treats patients with complex medical comorbidity has more medical staff than does a facility that primarily treats patients who have both SUDs and psychiatric illnesses; the latter setting, conversely, requires more psychiatric staff. The American Society of Addiction Medicine (ASAM) Patient Placement Criteria (Mee-Lee et al. 2001) distinguish between "medically managed" and "residential" intensive inpatient treatment; in some facilities, the latter is referred to as acute residential treatment. This form of treatment offers the psychosocial intensity of an inpatient program, with less need for physician and nursing services. Increasingly, however, inpatient treatment has come to involve detoxification only (Mark et al. 2002), with other aspects of treatment taking place in other settings or not at all. Many clinicians who work with substance-dependent patients recommend that these patients be treated in a specialized setting because of the availability of peer support, the presence of a knowledgeable and dedicated clinical staff, and the fact that substance-dependent patients and patients with other psychiatric disorders may feel uncomfortable around each other. Although little empirical research has been conducted to test this idea, one study found that heroin-dependent patients treated on a specialized unit had better long-term outcomes than did heroin-dependent patients who underwent detoxification on a general psychiatric unit (Strang et al. 1997).

Dual Diagnosis Patients Recognition of the frequent comorbidity of addictive disorders and another psychiatric illness (Grant et al. 2004; Kessler et al. 2005) has led to the creation of numerous dual diagnosis inpatient units that are devoted to the treatment of patients with coexisting mental illness and SUDs. One problem with the use of the term dual diagnosis patients is that it connotes more similarities among this population than actually exist (Weiss et al. 1992). Patients with coexisting mental illness and SUDs are heterogeneous. Thus, although such patients may be grouped together for the purpose of creating greater cohesion on an inpatient unit, this desired result might not occur. For example, a young, bulimic, cocaine-dependent patient will not necessarily feel commonality with an elderly, depressed, alcohol-dependent patient merely because they each have two disorders. Thus, although treating patients with dual diagnoses together may make programmatic sense in a particular institution, it is important to recognize the potential pitfalls of this approach. Dual diagnosis treatment may occur on a unit with a primarily psychiatric focus, on an SUD unit with a psychiatric consultant (who may be either peripherally involved or well integrated), or on a unit that attempts to integrate principles of psychiatric and SUD treatment. Minkoff (2001), for example, has argued that substance-dependent patients, psychiatric patients, and individuals with both types of disorders are best treated together in an integrated therapeutic model. He has posited that many of the concepts that have traditionally been associated with substance dependence treatment (e.g., acceptance of and recovery from a chronic illness, the need to overcome denial and shame, the importance of asking for help, active use of treatment, development of new coping skills) are equally useful in the treatment of patients with other primary psychiatric disorders. The rationale behind an integrated treatment approach is that the likelihood of recovery in an individual with an SUD and a co-occurring psychiatric disorder will be enhanced if the treatment addresses both problems concurrently (Busch et al. 2005). Kofoed (1993) has suggested that for patients with coexisting psychiatric illness and SUDs, the choice of setting should be based on the stage of illness, level of motivation, and current symptom picture (e.g., acute withdrawal, substance-induced psychiatric symptoms). Not surprisingly, on formal dual diagnosis units there is a tendency toward more frequent use of

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psychotropic medications, longer stays, and greater emphasis on psychiatric aftercare (post-inpatient continuing care) compared with other SUD treatment programs (Swindle et al. 1995). Other common program elements include the use of psychosocial interventions likely to be of benefit to patients with co-occurring SUDs and major mental illness (e.g., motivational enhancement therapy and relapse prevention based on cognitive-behavioral therapy) as well as relatively intensive case management (Busch et al. 2005). While recent studies support integrated treatment of co-occurring disorders in outpatient settings (for example, see Weiss et al. 2007), research on integrated approaches in inpatient settings is sparse. Brunette et al. (2004) reviewed 10 controlled studies of integrated residential programs for people with SUDs and co-occurring severe mental illness. They concluded that further research is required to establish the effectiveness of such programs, though existing evidence suggests that programs providing greater integration of treatment are generally more effective (Brunette et al. 2004). Despite the promise of this approach, addiction treatment settings vary widely in their ability to provide integrated treatment (McGovern et al. 2006).

The Minnesota Model In virtually all inpatient SUD treatment programs in the United States, abstinence from all drugs of abuse, including alcohol, is considered the cornerstone of successful treatment. The most common form of inpatient treatment in this country is the Minnesota Model (Cook 1988a), so named because of its development in that state in the 1950s. A Minnesota Model treatment program often features a standardized, relatively fixed length of stay, commonly 4 weeks (although in recent years, there has been more flexibility in this regard). After initial detoxification, patients attend educational lectures based on the disease concept of chemical dependence. In addition to learning about the harmful psychological and medical consequences of drug and alcohol use, patients are typically taught about the natural history of alcoholism; the effects of substance abuse on the family; conditioned cues and relapse prevention techniques; the importance of making lifestyle changes; and alternative coping mechanisms. Patients are often asked to recount their drug and alcohol histories in front of other patients and staff members in a forum similar to Alcoholics Anonymous (AA) meetings. The purpose of this exercise is to help patients confront and accept the adverse effects of their substance use; minimization or denial of the severity of their problems is common among patients admitted to inpatient units. Minnesota Model programs rely strongly on group therapy and peer confrontation and heavily employ recovering alcoholic individuals as primary counselors. Systems interventions, including involvement of employers and family members, are also frequently used in these programs. Many therapy groups in Minnesota Model programs are based on principles of AA and Narcotics Anonymous. Indeed, orienting patients to AA and establishing their continued AA and group therapy involvement after discharge are major goals of such programs. Psychiatrists may be involved to a variable extent in Minnesota Model treatment programs, often playing a consultative role in dealing with patients who have clear coexisting psychiatric disorders. The degree of integration between the psychiatric and counseling staff is variable, ranging from cooperation and integration to mutual distrust. Minnesota Model programs provide immersion in an environment that is dedicated to challenging addictive thoughts and beliefs through group therapy, peer evaluation, and meetings with counselors who themselves are recovering from SUDs. One of the most powerful tools in these programs is the instillation of hope, which is helpful for many individuals who have felt trapped in their addiction. To this end, these programs generally emphasize the importance of spirituality in the recovery process. Cook (1988b) referred to the "comprehensive and dogmatic ideology" of Minnesota Model programs as one of their most powerful therapeutic tools. This aspect of these programs, however, has also been a target of criticism. For example, some patients who have objected to the spiritual aspects of these programs or who have found AA distasteful (for whatever reason) have believed that treatment staff members have given up on them. Some of these patients are accused of being resistant to treatment,

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when in fact they are merely resistant to AA. Alternative self-help groups such as SMART Recovery and Secular Organizations for Sobriety have arisen partly in response to this complaint. Despite these criticisms, however, Minnesota Model programs remain popular in the United States.

RATIONALE FOR INPATIENT TREATMENT Inpatient treatment offers several advantages over less intensive programs. First, a hospital setting permits a high level of medical supervision and safety for individuals who require intensive physical and/or psychiatric monitoring. Thus, inpatient treatment in a hospital setting is indicated for patients with medically dangerous conditions or for those who represent an acute danger to themselves or others. The intensity of inpatient treatment may also be helpful for patients who, for whatever reason, do not respond to lesser measures. For example, inpatient treatment may benefit patients who are too discouraged or unmotivated to regularly undergo outpatient treatment on their own. Moreover, inpatient treatment may benefit some individuals by increasing their awareness of the internal triggers that place them at risk for returning to substance abuse. For example, the intensity and degree of discomfort that some patients feel in a 24-hour/day treatment setting may precipitate drug urges. Experiencing these urges in a protected setting, where patients are not in danger of acting on them, may help patients learn enough about their vulnerability to either avoid such situations in the future or learn to cope with them. Moreover, inpatient treatment can help to interrupt a cycle of drug use, even in the absence of medically dangerous withdrawal symptoms. The safety of an inpatient environment and a period of respite from a barrage of conditioned cues may help some patients in their attempts to make life decisions that are in their best interests. The protectiveness of an inpatient unit can also be a disadvantage. Because one of the major determinants of craving is drug availability (Meyer and Mirin 1979), patients admitted to inpatient units may not experience drug urges simply because they are living in a drug-free environment. Thus, they may not be fully prepared to handle the drug urges that they will surely have after discharge, when they return to a setting in which drugs are once again available. Therefore, some inpatient programs gradually expose patients to such triggers by granting them brief passes during their hospital stay. The other disadvantages of inpatient treatment are obvious. First, hospital treatment is expensive, typically costing more than several hundred dollars per day. Second, patients who enter a hospital are unable to work, care for their families, study, or conduct their normal daily activities. Finally, patients may be stigmatized as a result of being hospitalized. Thus, inpatient treatment should not be recommended lightly and should generally be used only when less intensive treatment methods have failed or are considered too risky.

WHEN SHOULD PATIENTS BE HOSPITALIZED? Cost-containment efforts, when combined with data challenging the effectiveness of inpatient treatment, have led clinicians to hospitalize substance-dependent patients less often and for shorter periods of time than was done in the past (Mark et al. 2005). Lists of indications for inpatient treatment have been developed by a variety of health care insurers, managed care companies, hospitals, and professional groups. In one widely used example, the ASAM Patient Placement Criteria, Mee-Lee et al. (2001) have listed six areas that should be assessed when determining whether a patient requires inpatient treatment, partial hospital care, or less intensive ambulatory treatment. These areas are 1) acute intoxication and/or withdrawal potential; 2) biomedical conditions and complications; 3) emotional, behavioral, or cognitive conditions and complications; 4) readiness to change; 5) the potential for relapse, continued use, or continued problems; and 6) the recovery environment or living environment (see also Chapter 6 in this volume, "Patient Placement Criteria," for more on this topic). In a study of the feasibility of implementing these criteria in a hospital-based SUD treatment center, a cohort of 281 applicants for alcoholism treatment was recommended to enter treatment according to ASAM criteria (Kosanke et al. 2002). While the majority of patients (72%) were matched to the recommended level of care, a substantial minority were not. Institutional issues such as availability of insurance coverage were cited as common reasons for overtreatment, while patient-related issues such as work schedule conflicts and patient reluctance were cited most commonly as reasons for relative undertreatment (Kosanke et

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al. 2002). Magura et al. (2003) evaluated the predictive validity of the ASAM criteria in a naturalistic study of alcohol-dependent patients and found that receiving routine outpatient care when intensive outpatient care was recommended was associated with worse drinking outcomes. Overtreatment, on the other hand, did not result in better outcomes in this study (Magura et al. 2003). Although one may argue with the emphasis placed on specific aspects of the ASAM criteria or any other document, it is important to recognize the importance of a multidimensional assessment in determining the optimal treatment plan for a substance-dependent patient. When this assessment has been completed, the clinician must ultimately consider two major issues in deciding whether to hospitalize a patient: 1) the danger that the patient might imminently be harmful to himself or herself or others and 2) the likelihood that the patient would achieve treatment success in a less restrictive environment. These issues can sometimes be extremely difficult to evaluate in patients abusing substances. For example, although patients who engage in active homicidal ideation and/or those who have made a recent suicide attempt might be considered clear candidates for hospitalization, substance-abusing patients may be a danger to themselves or to others in the absence of overt threats or self-destructive or violent acts. Patients who regularly drive while intoxicated, share needles with others, or commit violent crimes to finance their drug habits may also represent a substantial risk to themselves and to society. Because one of the functions of inpatient treatment is to protect the substance-dependent patient and/or the people around him or her during a period of acute danger, decisions regarding the timing of hospitalizing individuals who represent a chronic recurrent danger are complicated. An inpatient setting may also provide safety during detoxification. This is particularly true for patients who are being detoxified from alcohol and/or sedative-hypnotic drugs, because withdrawal from these agents may have serious medical consequences, including grand mal seizures, delirium, or death. A number of studies have shown that alcohol detoxification can be accomplished safely and effectively for carefully screened patients in selected outpatient settings (Hayashida et al. 1989; Soyka and Horak 2004; Wiseman et al. 1997). However, inpatient detoxification is still commonly used because of the risk of potentially serious medical sequelae of withdrawal and the potential unreliability of this patient population. For example, some patients undergoing outpatient alcohol detoxification may concomitantly use other drugs, such as cocaine, which lowers the seizure threshold. Although detoxification from therapeutic doses of benzodiazepines is frequently done on an outpatient basis, patients with mixed benzodiazepine and alcohol dependence and patients who have been abusing benzodiazepines are often detoxified as inpatients. Moreover, although opioid withdrawal is generally less medically dangerous than sedative-hypnotic or alcohol withdrawal, the discomfort that many opioid-dependent patients experience in attempting detoxification may lead to frequent relapses, which may diminish the effectiveness of outpatient treatment. Some patients who are unable to be successfully detoxified from opioids on an outpatient basis may thus be admitted as inpatients to complete the withdrawal process. Complicated detoxification regimens, such as those prescribed for patients who are dependent on two or more classes of drugs, should generally be administered in a hospital because of the need for frequent reevaluation and adjustment of such regimens. Similarly, patients with significant organ (e.g., cardiac, cerebral, hepatic) dysfunction should generally be detoxified in a hospital. As can be seen in the latter examples of indications for hospitalization, there is frequently an overlap between use of the hospital as a protective environment and use of the hospital to reap the benefits of a maximally intensive treatment program. Some individuals are treated as inpatients because of their actual or perceived inability to benefit from less intensive forms of treatment. Although hospitalization was frequently recommended as an initial treatment modality in the 1980s (Steenrod et al. 2001), patients currently are recommended for hospital care either in the case of imminent danger (as described earlier in this section) or after outpatient or partial hospital treatment efforts have failed. For patients who need to be in a structured and safe environment while undergoing rehabilitation, residential treatment programs may be appropriate; whereas patients who represent a more acute

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danger to themselves or others, who require intensive medical supervision to achieve detoxification, or who need psychiatric stabilization during detoxification require medically managed, hospital-based treatment. Studies comparing inpatients and outpatients typically show that the former have more severe substance use histories and a greater prevalence of medical, psychosocial, and vocational difficulties, including less social stability, more unemployment, and a greater preponderance of medical and psychiatric disorders (Harrison and Asche 1999, 2001; Tiet et al. 2007). Of course, these data in part reflect referral patterns and do not necessarily indicate which populations fare best in which settings. A number of early studies involved randomly assigning alcohol- or drug-dependent patients to inpatient treatment or a less intensive alternative. Although these studies generally showed little difference between inpatient treatment and other modalities (Longabaugh 1988; Miller and Hester 1986; Schneider et al. 1996), methodological flaws in some of these studies may have affected results (Craig et al. 1996; Nace 1990; Pettinati et al. 1993; Sell 1995). For example, in one frequently cited study, it was concluded that individuals treated as inpatients or in a partial hospital setting had similar outcomes (Longabaugh et al. 1983). However, the patients in each of the two groups in this study were initially treated as inpatients. In another classic study, it was concluded that a session of outpatient "advice" was as effective as inpatient treatment (Edwards et al. 1977). However, later analysis of the data from this study showed that patients with more severe alcohol dependence responded better to inpatient treatment than to outpatient treatment (Nace 1990). One of the difficulties with studies that compare inpatient and outpatient treatment for SUDs is related to the framing of a question that is frequently asked—namely, "Which is better: inpatient or outpatient treatment?" This type of head-to-head competition has been called "nonsensical" (Weddington and McLellan 1994) because the goals and structure of and overall approach to treatment of substance dependence problems are different in inpatient and outpatient settings. Asking about the place of inpatient treatment for SUDs is similar to asking about the use of inpatient treatment for other chronic illnesses such as diabetes or asthma. These are all lifelong, chronic, relapsing illnesses for which inpatient treatment is required for certain complications and to support long-term outpatient management of the conditions. Even in studies in which patients were randomly assigned to inpatient treatment or to intensive outpatient or partial hospital treatment, patients were systematically excluded if they had serious medical, psychiatric, or social comorbidity that might make random assignment to anything other than inpatient treatment hazardous (Weddington and McLellan 1994). For example, McKay et al. (1997) found that the psychosocial dimensions of the original ASAM Patient Placement Criteria (Hoffman et al. 1991) did not predict who would do well in inpatient compared with intensive outpatient substance abuse rehabilitation. However, these researchers did not study the two medical problem areas—acute intoxication/withdrawal and physical complications—in these patient placement criteria because random treatment assignment of patients meeting those criteria would not have been possible. Results of studies of randomized treatment have been conflicting with regard to the role of inpatient treatment. Walsh et al. (1991) showed inpatient treatment to be more effective than assignment to AA meetings for alcohol-dependent individuals referred for treatment by their employee assistance programs. However, intermediate-level options, such as partial hospitalization or intensive outpatient treatment, were not offered in this study. Alterman et al. (1994) found day hospital treatment of cocaine-dependent patients to be as effective as inpatient treatment at the 7-month follow-up, although the treatment completion rate among the inpatients was higher. Schneider et al. (1996) studied cocaine-dependent patients who, after completing a 5-day inpatient detoxification, were randomly assigned to 2 weeks of partial hospital day treatment or inpatient treatment. Although treatment outcome at the 3-month follow-up favored the inpatient participants, the difference between the two groups was not statistically significant at the 6-month follow-up. Pettinati et al. (1993) examined the role of psychiatric severity and level of social support in predicting the rate of early attrition from inpatient or intensive outpatient treatment. These investigators found that outpatients were more likely

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to experience early treatment failure, regardless of psychiatric severity. More recent research indicates that inpatient hospitalization may be preferable to outpatient treatment for subsets of patients with SUDs. In a longitudinal, naturalistic study, Harrison and Asche (1999) used admission data to examine factors associated with abstinence rates after treatment in different settings. Among patients with suicidal ideation at the time of treatment initiation, subsequent abstinence rates were higher among those who participated in an inpatient treatment program than among those who received outpatient treatment. In a follow-up analysis, patients with greater severity of pretreatment problems (e.g., alcohol or drug problems, psychological distress, social isolation, unemployment) were more likely to complete treatment and to remain abstinent if they received inpatient treatment rather than outpatient treatment (Harrison and Asche 2001). Similarly, Ilgen et al. (2005) found that patients who had made a suicide attempt in the last 30 days were more likely to remain abstinent 6 months after inpatient treatment than after outpatient treatment. In a study of 192 patients presenting to an SUD treatment center, Rychtarik et al. (2000) randomly assigned subjects to inpatient, intensive outpatient, or standard outpatient treatments. Patients with more severe baseline alcohol problems had more days voluntarily abstinent and fewer drinks per drinking day after inpatient treatment than outpatient treatment. The opposite was true for patients with less severe baseline problems (Rychtarik et al. 2000). Tiet et al. (2007) randomly surveyed a representative sample of 1,917 patients from 50 Department of Veterans Affairs (VA) SUD treatment programs, rating patients on a range of psychosocial and substance-related symptoms using the Addiction Severity Index. Again, patients with more severe problems experienced better alcohol- and drug-related outcomes following inpatient treatment than following outpatient treatment (Tiet et al. 2007). None of these studies demonstrated a difference in abstinence rates between inpatient and outpatient treatment among individuals with less severe problems at the time of treatment initiation.

OUTCOME OF INPATIENT TREATMENT General Findings A number of follow-up studies involving patients treated in hospital programs have yielded impressive success rates. For example, Stinchfield and Owen (1998) conducted 1-month, 6-month, and 12-month follow-up questionnaire assessments of patients who had been treated at Hazelden Foundation (a well-known Minnesota Model treatment center). These researchers found that 59% of patients who completed the questionnaires (approximately 70% of the total sample) were abstinent from drugs and alcohol at the time of the 6-month assessment, and 53% of respondents were abstinent 1 year after discharge (Stinchfield and Owen 1998). Wallace et al. (1988) presented similarly favorable results among patients treated at Edgehill Newport, a facility similar to Hazelden that has since closed. They found that 57% of patients interviewed had been continuously abstinent from alcohol and drugs after discharge for 6 months. In a 4-year follow-up of inpatients treated at Carrier Clinic, approximately half of the study sample had favorable outcomes (Pettinati et al. 1982). However, fluctuations in outcome status were common, and only one-fourth of patients were continuously abstinent for all 4 years. In a 1-year follow-up of patients treated in an integrated program for patients with SUDs and co-occurring psychiatric disorders, Moggi et al. (2002) described improvement in levels of substance use and severity of psychiatric symptoms; the 1-year abstinence rate in this sample was 25%. This lower abstinence rate may in part reflect a more severe case mix, although programmatic factors cannot be excluded (Moggi et al. 2002). In a study involving nearly 75,000 alcoholic men identified through the VA's computerized database, Bunn et al. (1994) found that patients who completed extended formal inpatient alcoholism treatment had lower mortality rates in the 3 years after discharge than did patients who had shorter inpatient stays (either because they entered a short-term detoxification program or because they did not complete a longer-term program) or patients who were hospitalized without receiving any formal alcoholism treatment. Unfortunately, all of the studies mentioned here were uncontrolled and were therefore subject to the

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biases inherent in uncontrolled research. It is because of these concerns that an increasing number of controlled studies have recently been undertaken. However, as explained earlier, controlled studies are also not immune to methodological limitations. For example, readmission rates are commonly used to measure the outcome of an episode of inpatient treatment. These data have the potential to miss patients who are hospitalized in a different health care system or treated in another setting. Furthermore, other measures may be more relevant to the outcomes of interest yet may not be available to researchers (Phibbs et al. 1997). On the other hand, readmission data are more easily available and so have made possible large studies of factors associated with repeat admissions.

Patient Characteristics in Inpatient Treatment Outcome Research Although some authors have written that inpatient treatment of substance-dependent individuals is often not superior to less intensive treatment, some subgroups of patients do appear to respond better than others to hospitalization. Most studies of inpatient treatment have found that the following groups have a better prognosis: patients who are older, patients who are married, patients who abuse alcohol rather than other drugs, and patients whose families participate in treatment (Harrison et al. 1991). Patients with more social support for sobriety and who are confident in their ability to maintain sobriety also appear less likely to resume use after discharge (Broome et al. 2002; Murphy et al. 2003). Individuals with histories of injection drug use or antisocial behavior tend to fare less well in inpatient treatment outcome studies (Harrison et al. 1991). However, these same patient characteristics are associated with a favorable prognosis in other forms of substance dependence treatment. Patients with greater psychosocial stressors and those with more severe SUDs may receive greater benefit from inpatient treatment than from outpatient treatment (Harrison and Asche 2001). Although much of this research has been conducted in VA programs with a preponderance of male patients, women appear to have similar risk factors for poor outcomes from inpatient detoxification (Callaghan and Cunningham 2002). The relationship of co-occurring Axis I and Axis II psychiatric disorders to the clinical course of SUDs is more complex. In general, patients with more severe psychiatric problems are likely to have worse outcomes following hospitalization than those without co-occurring major mental disorders. However, patients with mild to moderate levels of psychiatric symptoms may improve substantially after inpatient care (McLellan et al. 1986; Ouimette et al. 1999; Swindle et al. 1995). Similarly, one study of patients with co-occurring Axis II psychopathology showed similar degrees of global improvement in that group during inpatient substance use treatment when compared with those without Axis II diagnoses (Ross et al. 2003). The timing and persistence of psychiatric problems may play a significant role in their impact on SUDs. For instance, Read et al. (2004) assessed 133 patients over 6 months after inpatient SUD treatment. In this study, baseline posttraumatic stress disorder (PTSD) status did not predict substance use outcome, while persistent PTSD symptoms were associated with worse outcomes (Read et al. 2004). Similarly, Hasin et al. (2002) found that the timing of depressive episodes changed their impact on remission and relapse of substance dependence. They conducted follow-up evaluations for 18 months after treatment in a sample of 250 inpatients with cocaine, heroin, and/or alcohol dependence. Patients who were less likely to remit from substance dependence included 1) those with a lifetime history of major depressive disorder (MDD) prior to onset of an SUD and 2) those with baseline substance-induced MDD. Among patients who became abstinent after inpatient treatment, those who experienced MDD during sustained remission were three times as likely to relapse than patients who were not depressed during abstinence (Hasin et al. 2002). One mechanism by which depression may adversely affect drinking outcomes is by making patients more vulnerable to craving. In a study of 218 alcohol-dependent patients in residential care, Gordon et al. (2006) found that patients who were depressed on admission were more likely to experience craving for alcohol during treatment. Patients who experienced alcohol craving at the end of treatment were in turn more likely to be using alcohol at the 3-month follow-up. On the other hand, it has been found that patients with recent suicide attempts not only respond better to inpatient than to outpatient care but also may have better outcomes than those without a recent attempt. Greater baseline distress and greater likelihood of using psychiatric treatment may explain this paradoxical

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protective effect of recent suicide attempt history (Ilgen et al. 2005). Furthermore, depression itself may not negatively affect the outcome of SUD treatment if symptoms are identified early and integrated psychiatric care is provided (Charney et al. 2001). Beyond substance-related and psychosocial sequelae of substance use problems, patients with SUDs are at increased risk of premature death. Johnson et al. (2005) examined predictors of 5-year mortality after inpatient treatment for SUDs. Risk factors were examined at intake, at discharge, and at a 1-year follow-up for 3,698 male veterans. Independent predictors of 5-year mortality included 1) not having a spouse or partner at intake or at the 1-year follow-up, 2) depression at discharge, and 3) medical problems or more alcohol use on maximal drinking days at the 1-year follow-up.

Program Characteristics in Inpatient Treatment Outcome Research Although a number of studies have focused on the contribution of patient factors to substance abuse treatment outcome, there has been a relative paucity of research on inpatient treatment program characteristics that affect prognosis. Some authors have argued that programmatic variables are less important than patient characteristics in determining treatment outcome (Armor et al. 1976), but Cronkite and Moos (1978), who conducted a path analysis of treatment outcome among 429 alcoholic patients treated in five programs, concluded that program-related characteristics did influence treatment outcome substantially. Peterson et al. (1994) found that, while patient characteristics explained 36% of the variance in readmission rates between VA inpatient programs, characteristics of programs themselves also accounted for a substantial amount of this variance. Furthermore, higher levels of participation while attending residential treatment are associated with more favorable outcomes at discharge, independent of patient intake characteristics (Moos and King 1997). Several characteristics of inpatient substance abuse treatment have been examined to determine their effect on treatment outcome (Adelman and Weiss 1989), but many of these studies either were uncontrolled or did not include a carefully matched control group. Moreover, these studies were generally performed in the 1970s and 1980s, when hospitalization was often a first-line treatment for patients with SUDs. In a study of the effect of the referral process on outcome, employed alcoholic individuals who were forced by their employers to enter treatment fared better than individuals who volunteered for treatment (Chopra et al. 1979). Moberg et al. (1982) also found that involving a patient's employer during hospitalization had a beneficial effect on treatment outcome. Others have found that external incentives and compulsory treatment can improve substance-related outcomes of inpatient care (Moos and King 1997; Peterson et al. 1994). Another promising approach is motivational interviewing. This brief treatment approach, which is designed to foster internal motivation to change addictive behaviors, lends itself to the short lengths of stay typical in an inpatient setting (Miller and Rollnick 2002). Van Horn and Bux (2001) conducted a pilot study of group motivational interviewing among patients with dual diagnoses and reported that the intervention is feasible for implementation in an inpatient setting. Kahler et al. (2004) found that brief motivational enhancement for 12-step involvement during inpatient detoxification may lead to greater attendance at 12-step groups over 6 months of follow-up among those without much prior 12-step involvement, although the intervention was not beneficial for those with prior experience. Some evidence indicates that the level of emphasis on peer group interaction in a treatment center may affect treatment efficacy (Barnett and Swindle 1997). Stinson et al. (1979) randomly assigned 466 patients to two alcoholism treatment programs: one with an emphasis on intensive individualized treatment and a high staff-to-patient ratio and the other with a lower staff-to-patient ratio and an emphasis on peer group interaction. Patients who entered the latter program had better treatment outcomes, which suggests the potential importance of peer support in alcoholism treatment programs. Characteristics of staff members have been examined in several studies. Valle (1981) found that the interpersonal skills of alcoholism counselors in an inpatient treatment facility had a marked effect on

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treatment outcome. McLellan et al. (1988) obtained similar results in a study involving counselors working in an outpatient methadone maintenance treatment program. Likewise, Harris et al. (2006) found that clients in residential treatment programs who perceived staff as supportive were more likely to engage in continuing outpatient care after discharge. These findings add weight to the argument that characteristics of specific counselors may substantially affect treatment outcome within a given treatment setting. Potentially beneficial program characteristics may vary for different subgroups of patients. For instance, patients with more severe psychopathology or substance use problems may require different approaches to inpatient treatment. The recent development of psychological and pharmacological treatment approaches for specific subgroups of patients with coexisting SUDs and psychiatric illness (Busch et al. 2005) points to the importance of performing careful psychiatric evaluations in substancedependent patients. Several studies have examined the aspects of inpatient programs most likely to benefit these more severely ill patients. After controlling for the effects of case-mix in a study of 7,711 VA inpatients with both substance abuse and major psychiatric disorders, Swindle et al. (1995) found that patients treated in programs with greater tolerance of problem behaviors, higher rates of psychiatric aftercare, more 12-step groups, less varied treatment activities, and greater use of psychotropic medications had more favorable outcomes. Grella and Stein (2006) found that, among patients with co-occurring mental disorders and SUDs, those treated in residential programs that provided dual diagnosis groups and that had more staff trained in dual diagnosis treatment were more likely to subsequently use psychological services. In turn, those patients who used more psychological services showed improvements in measures of psychological symptoms and distress and in amount of heroin use (Grella and Stein 2006). Programs that use traditional "step-down" approaches in which patients are gradually moved from more intensive to less intensive levels of care, may also provide greater benefit for more severely ill patients. For instance, Moos et al. (2000) examined the effect of inpatient treatment as a precursor of community residential treatment. In this naturalistic study, 257 patients who underwent inpatient treatment immediately before admission to one of 44 community residential facilities were compared with 257 matched patients who underwent no inpatient treatment before receiving community residential treatment. Patients with co-occurring mental disorders and SUDs who received intensive inpatient treatment prior to treatment in community residential facilities fared better than those entering residential treatment directly from the community. These patients demonstrated more improvement on measures of clinically significant distress, psychiatric symptoms, and employment. Those defined as having environmental risk factors for poor outcomes (such as loved ones who were using drugs or alcohol) also showed better 1-year abstinence rates if first treated intensively as inpatients (Moos et al. 2000). Similarly, McKay et al. (2002) found that patients with higher baseline substance use severity showed greater improvements in alcohol, drug, and psychiatric problems when intensive outpatient treatment and follow-up care were preceded by a 21- to 28-day inpatient stay. Housing instability is generally considered a risk factor for poor outcomes from SUD treatment, and homeless individuals may respond optimally to programs with different characteristics than patients with stable housing. Kertesz et al. (2003) found that homeless individuals with SUDs who received brief residential treatment after inpatient detoxification had less than half the readmission rate of those not receiving residential treatment. In this study, nonhomeless persons did not benefit from stabilization in brief residential programs. The treatment of opioid-dependent patients has also received specific study. In one investigation of risk factors for premature discharge from brief hospital detoxification, patients treated with clonidine only were more likely to leave against medical advice than were patients treated with other medications for detoxification (Armenian et al. 1999). A national, open-label, community-based trial examined treatment completion in four groups of patients undergoing detoxification: 1) inpatients treated with buprenorphine, 2) inpatients treated with clonidine, 3) outpatients treated with buprenorphine, and 4) outpatients treated with clonidine. Inpatients and outpatients treated with buprenorphine were more

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likely to complete treatment and to provide an opiate-free urine sample on the last day of treatment. Furthermore, patients undergoing treatment in inpatient settings showed relatively higher rates of treatment completion (Ling et al. 2005). The decision as to whether to detoxify opioid-dependent patients at all in an inpatient setting has also received recent study. Inpatient initiation of buprenorphine maintenance rather than detoxification appears to be associated with better transition to and a longer stay in subsequent outpatient follow-up treatment (Caldiero et al. 2006). One of the major components of virtually all inpatient treatment programs is the emphasis on group therapy and attendance at AA meetings. Because of the near ubiquity of these aspects of inpatient treatment, little research has been done on their relative contribution to treatment outcome. However, some specific types of groups have been examined, and positive results have been reported for groups teaching social skills (Eriksen et al. 1986) or coping skills (Vogel et al. 1997). When specific theoretical orientations have been compared (i.e., 12-step or cognitive-behaviorally oriented relapse prevention), outcome has largely been similar (Moos et al. 1999). Nonetheless, having some clear treatment orientation appears to improve outcome (Moos et al. 1999; Swindle et al. 1995). Aftercare has long been considered an essential part of inpatient treatment, and several studies have shown the positive effect of aftercare on treatment outcome (Carroll 1997; Donovan 1998). Some researchers have questioned whether the continuing care program itself improves treatment outcome or whether the patients who are likely to have good treatment outcomes are the ones who also participate in continuing care more often. Two studies using cross-lagged analyses have supported the former hypothesis (Costello 1980; Vannicelli 1978). However, McLatchie and Lomp (1988) disputed this theory. These investigators randomly assigned 155 patients who had completed a 4-week inpatient alcoholism treatment program to one of three aftercare groups: 1) a mandated aftercare group; 2) a voluntary aftercare group, in which patients could decide on their own whether to participate; or 3) a group in which patients were dissuaded from participating in aftercare. No differences were found among groups with respect to relapse to drinking, lifestyle, satisfaction, or level of anxiety. However, 66% of patients in the voluntary aftercare group did request aftercare. Despite this controversy, the Work Group on Substance Use Disorders of the American Psychiatric Association recommends continuing care after intensive treatment in its clinical practice guidelines (Kleber et al. 2006). Case management augmentation strategies appear to be useful for linking patients to continuing care. Traditionally, inpatient case management has involved identifying referral sources and working with family members and outpatient providers. Some evidence suggests that augmenting these traditional case management services with additional services may enhance treatment outcome. These additional services include identifying adjunctive services for patients, encouraging patients to take the initiative for their own post-inpatient treatment, and providing additional structure to the continuing care referral process (for example, see Franco et al. 1995; Siegal et al. 1995). In one strategy that has been shown to be effective, the patient becomes familiar with the aftercare treatment by attending at least one meeting before discharge (Verinis and Taylor 1994), meeting a member of the outpatient team before discharge (Lash 1998), or being escorted from the inpatient unit to the outpatient facility (Chutuape et al. 2001). Other factors associated with continuing outpatient care after inpatient treatment include perceiving inpatient staff as supportive, higher patient motivation to change, financial incentives (including decreased direct costs to patients), and conveniently located aftercare programs (Harris et al. 2006; Mark et al. 2003; Schmitt et al. 2003; Stein et al. 2000). Hence, continuing outpatient care is more likely to take place when it is familiar, convenient, and economical and in the presence of high internal and external motivation for treatment. Finally, the correlation between length of stay and inpatient treatment outcome has long been controversial. Although some research has found that inpatient treatment offered no more benefit than a session of outpatient advice (Edwards et al. 1977), other studies have found a positive correlation between length of stay and treatment response (Barnett and Swindle 1997; Hubbard et al. 2003). However, many of these results are difficult to evaluate because of lack of randomization or poor comparability of study groups. One randomized study of two residential programs examined the effects

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of longer planned length of stay on outcomes (McCusker et al. 1997). Patients completing treatment in a residential relapse prevention program with a 6-month planned length of stay had better outcomes at 18 months than patients in a comparable 3-month program. However, these positive results were to some extent counterbalanced by worse outcomes among those who dropped out of the longer program than among dropouts from the shorter program (McCusker et al. 1997). Gottheil et al. (1992) examined 131 alcoholic male veterans who received inpatient treatment for the recommended period of 90 days. The authors found that patients with less severe impairment, as measured by the Addiction Severity Index, fared best. Moreover, in these patients, a longer hospital stay resulted in better treatment outcome. Patients with the most severe problems, on the other hand, did not benefit from an increase in length of stay. The results of this study are similar to those of Simpson (1979), who found that drug-dependent patients who received less than 90 days of treatment in either inpatient or outpatient programs did less well than patients who received 90 or more days of treatment. Gottheil et al. (1992) posited that the more severely psychiatrically ill patients may have failed to benefit from treatment because even 90 days of hospitalization was insufficient for their needs.

IMPLICATIONS FOR THE FUTURE The role of inpatient treatment for patients with SUDs remains a complex and controversial issue, with public health, political, philosophical, financial, and moral implications attached to its discussion. It is clear, however, that attempting to formulate simplistic guidelines about the use of this treatment modality is in the best interest of no one. Thus, the question should not be "Is inpatient treatment effective?" but rather "For which patients is inpatient treatment effective, at what time or times, and for how long?" To that end, the emphasis of current research in this area is on discerning which aspects of inpatient treatment are effective for which groups of patients. As future research helps to clarify these issues, it is hoped that inpatient treatment will have a more stable and defined place in the therapeutic approach to patients with SUDs.

KEY POINTS Inpatient treatment programs for substance use disorders (SUDs) are heterogeneous, taking place in an array of facilities with different theoretical orientations, planned durations, and immediate treatment goals (i.e., detoxification, formal rehabilitation, or both). Inpatient treatment of SUDs is indicated for particular patients unlikely to benefit sufficiently from less intensive levels of care. This may include patients with severe SUDs, co-occurring psychiatric problems, or medical complications that are best managed in an inpatient setting. Clinical guidelines have been developed to assist clinicians in determining the appropriate level of care. The evolving understanding of risk factors for poor outcomes from inpatient care can help clinicians to identify patients who may need additional interventions or who may be best treated in other settings. Emerging knowledge about program elements most likely to benefit specific groups of patients can inform clinicians in optimizing the care provided in inpatient/residential programs. More research is needed, particularly on identifying which subgroups of patients are most likely to benefit from inpatient treatment, as well as on how inpatient care best fits into the full continuum of treatment levels.

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SUGGESTED READING Brunette MF, Mueser KT, Drake RE: A review of research on residential programs for people with severe mental illness and co-occurring substance use disorders. Drug Alcohol Rev 23:471–481, 2004 Busch AB, Weiss RD, Najavits LM: Co-occurring substance use disorders and other psychiatric disorders, in Clinical Textbook of Addictive Disorders, 3rd Edition. Edited by Frances RJ, Miller SI, Mack AH. New York, Guilford, 2005, pp 271–302 Gastfriend DR (ed): Addiction Treatment Matching. Binghamton, NY, Haworth, 2003 Mark TL, Coffey RM, Vandivort-Warren R, et al: U.S. spending for mental health and substance abuse treatment, 1991–2001. Health Aff (Millwood) W5:133–142, 2005 Ross S, Dermatis H, Levounis P, et al: A comparison between dually diagnosed inpatients with and without Axis II comorbidity and the relationship to treatment outcome. Am J Drug Alcohol Abuse 29:263–279, 2003 Tiet QQ, Ilgen MA, Byrnes HF, et al: Treatment setting and baseline substance use severity interact to predict patients' outcomes. Addiction 102:432–440, 2007 Ziedonis DM: Integrated treatment of co-occurring mental illness and addiction: Clinical intervention, program, and system perspectives. CNS Spectr 9:892–904, 925, 2004 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 32. Therapeutic Communities

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George De Leon: Chapter 32. Therapeutic Communities, in The American Psychiatric Pub lishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.359790. Printed 1 0/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Therapeutic Communities George De Leon, Ph.D.

THERAPEUTIC COMMUNITIES: INTRODUCTION Therapeutic communities (TC) for substance abuse appeared a decade later than did therapeutic communities in psychiatric hospitals pioneered by Maxwell Jones and others in the United Kingdom (Jones 1953). The term therapeutic community evolved in the psychiatric hospital setting, although the two models arose independently. The TC for substance abuse emerged in the 1960s as a self-help alternative to existing conventional treatments. Recovering alcoholic and drug-addicted individuals were its first participants/developers. Although its modern antecedents can be traced to Alcoholics Anonymous and Synanon, the TC prototype is ancient, existing in all forms of communal healing and support. Contemporary TCs for addictions are sophisticated human services institutions. Today, the term therapeutic community is generic, describing a variety of short-term and long-term residential programs, as well as day treatment and ambulatory programs that serve a wide spectrum of drug-abusing and alcohol-abusing patients. Although the TC model has been widely adapted for different populations and settings, it is the traditional long-term residential prototype for adult substance abusers that has documented effectiveness in rehabilitating substance-abusing individuals. The last section of this chapter summarizes the adaptation and modifications of the traditional TC model for various special populations. This chapter is abstracted from a comprehensive account of the therapeutic community theory, model, and method provided elsewhere (De Leon 2000). Descriptive accounts of the therapeutic community for substance-abusing patients, which are less formal than the description presented here, are contained in the literature (e.g., Casriel 1966; Deitch 1972; Yablonsky 1965), as are formal accounts of the therapeutic community from sociological (Sugarman 1986), anthropological (Frankel 1989), and psychodynamic (Kooyman 1993) perspectives.

THE TRADITIONAL TC Traditional TCs are similar in structure, staffing pattern, perspective, and rehabilitative regimen, although they differ in size (from 30 to several hundred beds in a facility) and patient demographics. A TC staff is composed of TC-trained clinicians (with and without recovery experiences) and other human service professionals who provide medical, mental health, vocational, educational, family counseling, fiscal, administrative, and legal services. The recommended planned duration of stay for long-term TCs has gradually decreased through the years, from 15–24 months to 9–15 months. TCs accommodate a diversity of drug-abusing patients, and although they originally attracted individuals addicted to narcotics, most of the current TC patient populations are non-opioid-abusing persons, all with various lifestyles; various social, economic, and ethnic or cultural backgrounds; and drug problems of varying severity. In TCs, drug abuse is viewed as a deviant behavior, reflecting impeded personality development or chronic deficits in social, educational, and economic skills. Such behavior is often a result of socioeconomic disadvantage, poor family effectiveness, and psychological factors. Therefore, the principal aim of the TC is a global change in lifestyle, involving abstinence from illicit substances, the elimination of antisocial activity, and the development of employability and prosocial attitudes and values. The rehabilitative approach requires multidimensional influence and training, which can occur

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only in a 24-hour residential setting for most individuals. The traditional TC can be distinguished from other major drug treatment modalities in three general ways. First, the TC coordinates a comprehensive range of interventions and services in a single treatment setting: vocational counseling; work therapy; recreation, group, and individual therapy; and educational, medical, family, legal, and social services are all offered within the TC. Second, the primary therapist and teacher in the TC is the community itself, consisting of peers who serve as role models of successful personal change and staff members who serve as rational authorities and guides in the recovery process. Thus, the community as a whole provides a crucial 24-hour context for continued learning in which individual changes in conduct, attitudes, and emotions are monitored and mutually reinforced in the daily regimen. Third, the TC approach to rehabilitation is based on an explicit perspective of the substance use disorder, the patient, the recovery process, and healthy living. It is this perspective that shapes its organizational structure, staffing, and treatment process.

THE TC PERSPECTIVE The TC perspective consists of four interrelated views—the view of the disorder, person, recovery, and right living. Each of these is briefly outlined here.

View of the Disorder Drug abuse is viewed as a disorder of the whole person, affecting some or all areas of functioning. Cognitive and behavioral problems are often present, as are mood disturbances. Thinking may be unrealistic or disorganized; values may be confused, nonexistent, or antisocial. Frequently, the patient exhibits deficits in verbal, reading, writing, or marketable skills. Moral or even spiritual issues, whether expressed in existential or psychological terms, are apparent. The TC perspective considers the problem to be the individual, not the drug, and addiction is a symptom, not the essence of the disorder. In the TC, chemical detoxification is a condition of entry, and the goal of treatment is learning to maintain a drug-free existence.

View of the Person In TCs, individuals are distinguished along dimensions of psychological dysfunction and social deficits rather than according to drug use patterns. In many TC residents, vocational and educational problems are marked; middle-class, mainstream values are either missing or not sought. Usually these residents emerge from a socially disadvantaged sector, where drug abuse is more a social response than a psychological disturbance. Their TC experience is better termed habilitation, development of a socially productive, conventional lifestyle for the first time. Among patients from more advantaged backgrounds, drug abuse is more directly expressive of psychological disorder or existential malaise. For these, the term rehabilitation is more suitable, because the term emphasizes a return to a lifestyle previously lived, known, and perhaps rejected. Notwithstanding these social differences, substance-abusing individuals in TCs have important similarities. Either as a cause or as a consequence of their drug abuse, all such persons exhibit features of personality disturbance and impeded social function (see "Clinical Characteristics" section below). Therefore, all residents in the TC follow the same regimen. Individual differences are recognized in specific treatment plans that modify the emphasis, not the course, of their experience in the TC.

View of Recovery In the view of recovery employed in the TC, the aim of rehabilitation is global, involving both a change in lifestyle and a change in personal identity. The primary psychological goal is to change the negative patterns of behavior, thinking, and feeling that predispose the individual to drug use; the main social goal is to develop the skills, attitudes, and values of a responsible drug-free lifestyle. Stable recovery, however, depends on a successful integration of these social and psychological goals. Behavioral change is unstable without insight, and insight is insufficient without felt experience. Therefore, to ensure

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enduring change, conduct, emotions, skills, attitudes, and values must all be addressed.

Motivation Recovery depends on pressures to change, positive and negative. Some patients seek help, driven by stressful external pressures; others are moved by more intrinsic factors. For all, however, remaining in treatment requires continued motivation to change. Therefore, elements of the rehabilitation approach are designed to sustain motivation or to enable detection of early signs of premature termination.

Self-help and mutual self-help Strictly speaking, treatment is not provided; rather, it is made available to the individual in the TC through its staff and peers and the daily regimen of work, groups, meetings, seminars, and recreation. However, the effectiveness of these elements depends on the individual, who must constantly and fully engage in the treatment regimen. In self-help recovery, the individual makes the main contribution to the change process. In mutual self-help, the principal messages of recovery, personal growth, and right living are mediated by peers through confrontation and sharing in groups, by example as role models, and as supportive, encouraging friends in daily interactions.

Social learning A lifestyle change occurs in a social context. Negative patterns, attitudes, and roles were not acquired in isolation, nor can they be altered in isolation. Thus, recovery depends not only on what has been learned but also on how and where learning occurs. This assumption is the basis for the community's serving collectively as teacher. Learning is active, involving doing and participating. A socially responsible role is acquired by acting the role. What is learned is identified with the individuals involved in the learning process—supportive peers and staff members who are serving as credible role models. Sustained recovery requires a perspective on self, society, and life that must be continually affirmed by a positive social network of others within and beyond the TC.

Treatment as an episode Residence in the TC is a relatively brief period in an individual's life, and the influence of this period must compete with the influences of the years before and after treatment. For this reason, unhealthy outside influences are minimized until the individual is better prepared to deal with them on his or her own. As a result, life in the TC is necessarily intense, the daily regimen is demanding, and the therapeutic confrontations are continuous.

View of Right Living TCs adhere to certain precepts that constitute a view of healthy personal and social living. These precepts concern moral behavior, values, and a social perspective that are intimately related to the TC view of the individual and of recovery. For example, in TCs, unambiguous moral positions are held regarding social and sexual conduct. Explicit right and wrong behaviors are identified for which there are appropriate rewards and sanctions. These include antisocial behaviors and attitudes; the negative values of the street, jails, or negative peers; and irresponsible or exploitative sexual conduct. Feelings of guilt relating to self, significant others, and the larger community outside the TC are central issues in the recovery process. Although they are associated with moral matters, feelings of guilt are special psychological experiences that if not addressed maintain the individual's disaffiliation from peers and block the self-acceptance that is necessary for authentic personal change. Certain values are emphasized as being essential to social learning and personal growth. These values include truth and honesty (in word and deed), a work ethic, self-reliance, earned rewards and achievement, personal accountability, responsible concern (being one's brother's or sister's keeper), social manners, and community involvement. Treatment helps the individual to focus on the personal present (here and now) versus the historical

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past (then and when). Past behavior and circumstances are explored only to illustrate the current patterns of dysfunctional behavior, negative attitudes, and outlook. Residents are encouraged and trained to assume personal responsibility for their present reality and destiny.

WHO COMES FOR TREATMENT Most patients who enter TCs have histories of multiple drug use, including use of marijuana, cocaine, crack, opioids, alcohol, and prescription medications. However, research has documented that persons admitted to TCs have a considerable degree of psychosocial dysfunction in addition to their substance abuse.

Social Profiles Patients in traditional programs are usually men (70%–75%), but the number of admissions of women is increasing. Most community-based TCs are integrated across gender, race or ethnicity, and age, although the demographic proportions differ according to geographical regions and specific programs. In general, Hispanics, Native Americans, and patients younger than age 21 years represent smaller proportions of admissions to TCs. Increasingly there are dedicated programs for women and for juveniles under age 21 years. Most patients admitted are from broken homes or have ineffective families, have poor work histories, and have engaged in criminal activities. Among adults who are admitted to TCs, fewer than one-third have been employed full-time in the year before treatment, more than two-thirds have been arrested, and 30%–40% have drug treatment histories (e.g., De Leon 1984; Hubbard et al. 1997; Simpson and Sells 1982).

Psychological Profiles Patients differ in demographics, socioeconomic background, and drug use patterns, but psychological profiles obtained with the use of standard instruments appear relatively uniform, as has been shown in a number of TC studies (e.g., Biase et al. 1986; Brook and Whitehead 1980; Carroll and McGinley 2000; De Leon 1984; De Leon et al. 1973; Holland 1986; Kennard and Wilson 1979; Zuckerman et al. 1975). Typically, symptom measures of depression and anxiety are deviantly high, socialization scores are poor, and IQ is in the dull to normal range. Self-esteem is markedly low and Minnesota Multiphasic Personality Inventory scores are deviant, reflecting confusion (high F), character disorder (high Pd), and disturbed thinking and affect (high Sc). Smaller but still deviant peaks are seen on depression (D) and hypomania (Ma). The psychological profiles mirror features of both psychiatric and criminal populations. For example, the character disorder elements and poor self-concept of delinquent and repeat offenders are present, as are the elements of dysphoria and confused thinking seen in emotionally unstable or psychiatric populations. Therefore, in addition to their substance abuse, patients in TCs have considerable degrees of psychological disability.

Psychiatric Diagnoses In diagnostic studies in which the Diagnostic Interview Schedule was used, nearly three-fourths of patients admitted to TCs had a lifetime (i.e., beginning before the last 30 days) non-drug-related psychiatric disorder in addition to substance-related problems. One-third had a current (beginning within the last 30 days) mental disorder in addition to substance-related problems. The most frequent non-drug-related diagnoses were phobias, generalized anxiety, psychosexual dysfunction, and antisocial personality. There were few cases of schizophrenia, but lifetime affective disorders occurred in more than one-third of those studied (De Leon 1993; Jainchill 1994). That the psychological and psychiatric profiles reveal few psychotic features and relatively low variability in symptoms or personality characteristics reflects several factors: the TC exclusionary criteria, the common characteristics among all substance-abusing individuals, and to some degree the self-selection

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among those who seek admission to residential treatment programs.

Clinical Characteristics Regardless of drug preference or severity, most individuals admitted to TCs have shared clinical features that are directly addressed in the TC treatment. These characteristics center around immaturity or antisocial dimensions (De Leon 2000). For example, they include low tolerance for all forms of discomfort and delay of gratification; problems with authority; inability to manage feelings (particularly hostility, guilt, and anxiety); poor impulse control (particularly sexual or aggressive impulse control); poor judgment and reality testing concerning consequences of actions; unrealistic self-appraisal regarding discrepancies between personal resources and aspirations; prominence of lying, manipulation, and deception as coping behaviors; and personal and social irresponsibility (e.g., inconsistency or failures in meeting obligations). These clinical characteristics are not necessarily indicative of an addictive personality, although many of these features are typical of conduct disorder in younger substance-abusing individuals, which can later evolve into adult character disorder. Nevertheless, whether they are antecedent or consequent to serious involvement with drugs, these characteristics are commonly observed to be correlated with chemical dependency. More important, a positive change in these characteristics is considered to be essential for stable recovery in TCs.

Contact and Referral Approximately 25%–35% of adult admissions to community-based TCs have a legal status, in terms of being paroled, probated, or otherwise court ordered to treatment. Voluntary contacts with TCs occur through self-referral, social agencies, treatment providers, and active recruitment by TCs. For example, outreach teams (often trained graduates of TCs and selected caseworkers) recruit in hospitals, jails, courtrooms, and social agencies. Although most adult admissions to TCs are voluntary, many of these patients come to treatment programs under various forms of perceived pressures originating from conflicts with family members or significant others, employment difficulties, or anticipated legal consequences (De Leon 1988). Thus, a variety of perceived external pressures motivate abusers to enter TC treatment (Klag et al. 2006). In contrast with adults, a majority of adolescent admissions to TCs are legal referrals (e.g., Jainchill 1997, 2000; Pompi and Resnick 1987). Thus, for the younger substance abusers, actual legal pressure is a prominent form of external motivation to enter treatment. Their lower internal motivation to change reflects the shorter time-correlated negative consequences of their substance abuse (Melnick et al. 1997).

Detoxification Status With few exceptions, admission to residential treatment does not require medically supervised detoxification. Therefore, traditional TCs do not usually provide this service on the premises. Most individuals whose primary drugs of abuse are opioids, cocaine, alcohol, marijuana, barbiturates, or methamphetamines have undergone self-administered or medical detoxification before seeking admission to the TC. A small proportion of individuals require detoxification during the admission evaluation, and these persons are offered the option of detoxification at a nearby hospital. A minor percentage of patients admitted to TCs have been primarily involved with hallucinogens or phencyclidine (PCP). In the case of those who appear compromised, a referral is made for psychiatric service, after which the individuals can return for residential treatment.

Criteria for Residential Treatment Traditional TCs maintain an open-door policy with respect to admission for residential treatment. This understandably results in a wide range of treatment candidates, not all of whom are equally ready for, suited for, or motivated to face the demands of the residential regimen. Relatively few are excluded, because the TC policy is to accept individuals who elect residential treatment, regardless of the reasons

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influencing their choice. The main consideration for exclusion from the TC is community risk. Risk refers to the extent to which patients present a management burden to the staff or pose a threat to the security and health of the community. Specific exclusionary criteria most often include histories of arson, suicide attempts, and serious psychiatric disorder. Psychiatric exclusion is usually based on documented history of psychiatric hospitalizations or evidence of psychotic symptoms on interview (e.g., frank delusions, thought disorder, hallucinations, confused orientation, signs of serious affect disorder). An important differential diagnostic issue concerns drug-related mood or mental states. For example, disorientation, dysphoria, and thought or sensory disorders clearly associated with use of hallucinogens, PCP, and sometimes cocaine may not exclude an otherwise suitable individual from the TC. When diagnosis remains in question, most TCs will use a psychiatric consultation after admission. Referral, however, is based on the patient's suitability or risk rather than on diagnosis alone. In the past, patients on regular regimens of psychotropic medication were excluded from admission to TCs because these regimens are usually correlated with chronic or severe psychiatric disorders. However, psychotropic medication is now more widely used in TCs to accommodate increasing numbers of admissions with comorbid conditions. Patients taking medication for medical conditions can be admitted, as can disabled individuals or persons who require prosthetics, providing these patients can participate fully in the program. Physical examinations and laboratory workups (blood and urine profiles) are performed after admission. Because of concern about communicable disease in a residential setting, some TCs require tests for conditions such as hepatitis to be performed before patients enter the facility or at least within the first weeks of admission. Policies and practices concerning testing for HIV and management of AIDS and hepatitis C emphasize voluntary testing with counseling, special education seminars on health management and sexual practices, and special support groups for residents who are HIV-positive or who have a clinical diagnosis of AIDS or hepatitis C (e.g., Barton 1994; De Leon 1996b; McCusker and Sorensen 1994).

Suitability for the TC A number of those seeking admission to a TC may not be ready for treatment in general or may not be suited for the demands of a long-term residential regimen. Assessment of these factors at admission provides a basis for treatment planning in the TC or sometimes appropriate referral. Some indicators of motivation, readiness, and suitability for TC treatment are acceptance of the severity of the drug problem; acceptance of the need for treatment (the patient thinks he or she "can't do it alone"); willingness to limit contact with family and friends and halt one's current lifestyle while in treatment; and willingness to surrender a private life and meet the expectations of a structured community. Although motivation, readiness, and suitability are not criteria for admission to the TC, the importance of these factors often emerges after entry to treatment, and these factors, if not identified and addressed, are related to early dropout (De Leon et al. 1994).

THE TC APPROACH The TC approach can be summarized in the phrase "community as method" (De Leon 1997, 2000). The TC uses the diverse elements and activities of community to foster rehabilitative change. These can be organized in terms of the TC structure or social organization and the TC process in terms of the individual's passage through stages of change within the context of community life.

TC Structure The relatively small staff of the TC is complemented by resident peers at junior, intermediate, and senior levels. These groups constitute the community or family in the residence. This peer-tocommunity structure strengthens the patient's identification with a perceived ordered network of individuals. More important, it arranges relationships of mutual responsibility at various levels in the program.

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The daily operation of the community itself is the task of the residents, who work together under staff supervision. The broad range of resident job assignments illustrates the extent of the self-help process. Residents perform all house services (e.g., cooking, cleaning, kitchen service, minor repair); serve as apprentices; run all departments; and conduct house meetings, certain seminars, and peer encounter groups. The TC is managed by the staff, whose members monitor and evaluate patient status, supervise resident groups, assign and supervise resident jobs, and oversee house operations. The staff members conduct therapeutic groups (other than peer encounter groups), provide individual counseling, organize social and recreational projects, and confer with the significant others of the residents. They make decisions about resident status, discipline, promotion, transfers, discharges, furloughs, and treatment planning. The new patient enters a setting of upward mobility. The resident job assignments are arranged in a hierarchy according to seniority, clinical progress, and productivity. Residents are first assigned the most menial tasks (e.g., mopping the floor) and then work their way up to levels of coordination and management. In fact, individuals come in as patients and some can leave as staff members. This social organization of the TC reflects the fundamental aspects of its rehabilitative approach: work as education and therapy, mutual self-help, peers as role models, and staff members as rational authorities.

Work as education and therapy Work and job changes have clinical relevance for substance-abusing patients in TCs, most of whom have not successfully negotiated the social and occupational world of the larger society. Vertical job movements carry the obvious rewards of status and privilege. However, lateral job changes are more frequent and permit exposure to all aspects of the community. Job changes in the TC are singularly effective therapeutic tools, providing both measures of and incentives for behavioral and attitudinal changes. In the vertical structure of the TC, ascendancy marks how well a patient has assimilated what the community teaches and expects; hence, job promotion is an explicit measure of the resident's improvement and growth. Lateral or downward job movements also create situations that require demonstrations of personal growth. These movements are designed to teach new ways of coping with reversals and change that appear to be unfair or arbitrary.

Mutual self-help The essential dynamic in the TC is mutual self-help. In their jobs, groups, meetings, recreation, and personal and social time, residents continually transmit to one another the main messages and expectations of the community. Prominent examples of mutual self-help are verbal correctives and affirmations, described in the section, "Community and Clinical Management Elements."

Peers as role models Peers, serving as role models, and staff members, serving as role models and rational authorities, are the primary mediators of the recovery process. TC members who demonstrate the expected behaviors and reflect the values and teachings of the community are viewed as role models. Thus, all members of the community—roommates, older and younger residents, and junior, senior, and directorial staff—are expected to be role models. TCs require these multiple role models in order to maintain the integrity of the community and ensure the spread of social learning effects. Two main examples of how role models function in the community are given below. 1. Resident role models "act as if." The resident behaves as the person that he or she should be, rather than as the person that he or she has been. Despite resistances, perceptions, or feelings to the contrary, residents engage in the expected behaviors and consistently maintain the attitudes and values of the community, which include self-motivation, commitment to work and striving, positive regard for staff members as authorities, and an optimistic outlook toward the future. In the TC's view, acting as if is not merely an exercise in conformity it is an essential mechanism for

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more complete psychological change. Feelings, insights, and altered self-perceptions often follow rather than precede behavioral change. 2. Role models display responsible concern. This concept is closely akin to the notion of being one's brother's or sister's keeper. Showing responsible concern involves willingness to confront others whose behavior is not in keeping with the rules of the TC, the spirit of the community, or the community expectations of growth and rehabilitation. Role models are obligated to be aware of the appearance, attitude, moods, and performance of their peers and to confront negative signs in these areas. In particular, role models are aware of their own behavior in the overall community and the process prescribed for personal growth.

Staff members as rational authorities Staff members foster the self-help learning process through performance of the managerial and clinical functions described above and through maintenance of psychological relationships with the residents as role models, parental surrogates, and rational authorities. TC residents often have previously had difficulties with authorities who have not been trusted or who have been perceived as guides and teachers. Therefore, residents need a positive experience with an authority figure who is viewed as credible (recovered), supportive, corrective, and protective so that they may gain authority over themselves (personal autonomy). As rational authorities, staff members provide the reasons for their decisions and explain the meaning of consequences. They exercise their powers to teach, guide, facilitate, and correct rather than to punish, control, or exploit.

The TC Process: Basic Program Elements The treatment process may be defined as the interaction between the treatment interventions and patient change. Unlike other treatment approaches, however, the TC treatment intervention is the daily regimen of structured and unstructured activities and social intercourse occurring in formal and informal settings. The typical day in a TC is highly structured. It begins at 7:00 A.M. and ends at 11:00 P.M. During this time, residents participate in a variety of meetings, encounter and other therapeutic groups, and recreational activities; perform job functions (work therapy); and receive individual counseling. The interplay of these activities is part of the TC process. As interventions, these activities may be divided into three main groups: therapeutic-educative activities, community enhancement activities, and community and clinical management.

Therapeutic-educative activities Therapeutic-educative activities consist of various group processes and individual counseling. These activities provide residents with opportunities to express feelings, divert negative acting out, and resolve personal and social issues. They increase communication and interpersonal skills, bring about examination and confrontation of behavior and attitudes, and offer instruction in alternative modes of behavior. The four main forms of group activity in the TC are encounters, probes, marathons, and tutorials. These differ somewhat in format, objectives, and method, but all have the goal of fostering trust, personal disclosure, intimacy, and peer solidarity to facilitate therapeutic change. The focus of the encounter is behavioral. Its approach is supportive confrontation, and its objective is to modify negative behavior and attitudes directly. Probes and marathons have as their primary objectives substantial emotional change and psychological insight. In tutorials, the learning of concepts and specific skills is emphasized. Encounters are the cornerstone of group process in the TC. The term encounter is generic, describing a variety of forms that use supportive confrontational procedures as their main approach. The basic encounter group is a peer-led group composed of 12–20 residents in the community; it meets at least three times weekly, usually for 2 hours in the evening, and an additional 30-minute period for snacking and socializing follows each meeting. The basic objective of each encounter is to heighten individual

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awareness of specific attitudes or behavioral patterns that should be modified. Probes are staff-led group sessions that are conducted to obtain in-depth clinical information on patients early in their residence (in the first 2–6 months). They involve 10–15 residents, are scheduled when needed, and usually last 2–4 hours. Their main objectives are to increase staff understanding of individuals' backgrounds for the purposes of treatment planning and to increase openness, trust, and mutual identification. Unlike the encounter, in which confrontation is emphasized, the probe involves the use of support, understanding, and the empathy of the other group members. Probes go beyond the here-and-now behavioral incident, which is the material of the encounter, to past events and experiences. Marathons are extended group sessions whose objective is to initiate resolution of life experiences that have impeded individuals' development. During his or her months of residence, every patient participates in several marathons. All staff members conduct these sessions and are assisted by senior residents with marathon experience. Marathons usually include large groups of selected residents and last for 18–36 hours. Considerable experience, both personal and professional, is required to ensure safe and effective marathons. The intimacy, safety, and bonding in the marathon setting facilitate emotional processing ("working through") of a significant life event and encourage the individual to continue to deal with certain life-altering issues of the past. These issues are identified in counseling, probes, or other group sessions and may include issues of violence, sexual abuse, abandonment, illness, and deaths of significant others. A wide variety of techniques, including psychodrama, primal therapy, and pure theater, are employed to produce impact. The use of marathons has sharply declined commensurate with the decreases in planned duration of residential stay. However, a number of long-term TCs incorporate elements of the marathon into their other formats of group process. Tutorials are primarily directed toward training or teaching. Tutorial groups, usually staff led, consist of 10–20 residents. Tutorials are scheduled as needed and focus on certain clinical themes, including personal growth, recovery, and right-living concepts (e.g., self-reliance, maturity, relationships); and skills training (e.g., management of the department or the reception desk, training in the use of encounter tools). Additionally, cognitive-behavioral tutorials using manualized curricula are employed for targeted areas such as relapse prevention and criminal thinking. Other groups that convene regularly or as needed supplement the four main groups. These vary in focus, format, and composition. For example, weekly or biweekly "static" (caseload) groups are convened. These home groups consist of the same composition of peers who address and mutually monitor ongoing clinical progress. Special gender, ethnic, age-specific, or health theme groups may use encounter or tutorial formats. Dormitory, room, or departmental encounters may address issues of daily community living. In addition, sensitivity training, psychodrama, and conventional gestalt and emotionality groups are used to varying extents. One-to-one counseling balances the needs of the individual with those of the community. Peer exchange is ongoing and is the most consistent form of informal counseling in TCs. Staff counseling sessions may be formal or informal and are usually conducted as needed. The staff counseling method in the TC is not conventional, as is evident in its main features: transpersonal sharing, direct support, minimal interpretation, didactic instructions, and concerned confrontation. The focus of staff counseling is to address issues that may impede progress and to facilitate the patient's adjustment to and constructive use of the peer community.

Community enhancement activities Community enhancement activities include the four main facility-wide meetings: the morning meeting, the seminar, the house meeting (these three meetings are held each day), and the general meeting (which is called when needed). Though different in format, all meetings have the common objective of

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facilitating the individual's assimilation into the community. All residents of the facility and the staff on the premises attend the morning meeting, which takes place after breakfast and usually lasts 30 minutes. The purpose of the meeting is to instill a positive attitude at the beginning of the day, motivate residents, and strengthen unity. This meeting is particularly relevant because most residents of TCs have never adapted to the routine of an ordinary day. Seminars take place every afternoon and usually last 1 hour. Because it brings all residents together, the seminar in the afternoon complements the daily morning meeting and the house meeting in the evening. A clinical aim of the seminar is to balance the individual's emotional and cognitive experience. Residents lead most seminars, although some are led by staff members or less frequently by outside speakers. The seminar is unique among the various meetings and groups in the TC in its emphasis on listening, speaking, and conceptual behavior. Seminar topics directly or indirectly relate to the TC perspective on recovery and right living. House meetings take place nightly after dinner, usually last 1 hour, and are coordinated by a senior resident. The main aim of these meetings is to transact community business, although they also have a clinical objective. In this forum, social pressure through public acknowledgment of positive or negative behaviors is judiciously applied to facilitate individual change. General meetings take place only when needed and are usually called so that negative behavior, attitudes, or incidents in the facility can be addressed. All residents and staff members (including those not on duty) are assembled at any time and for an indefinite duration. These meetings, conducted by multiple staff members, are designed to identify problem individuals or conditions or to reaffirm motivation and reinforce positive behavior and attitudes in the community. Community enhancement occurs in a variety of nonscheduled, informal activities as well. These include activities related to rituals and traditions, celebrations (e.g., birthdays, graduations, phase changes), ceremonies (e.g., those relating to general and cultural holidays), and memorial observances for deceased residents, family members of residents, and staff members. These activities reflect humanistic reactions of the membership and increase cohesiveness of the community.

Community and clinical management elements Community and clinical management elements maintain the physical and psychological safety of the environment and ensure that resident life is orderly and productive. They protect the community as a whole and strengthen it as a context for social learning. The main elements, which are staff managed, are privileges, disciplinary sanctions, surveillance, urine testing, and peer confrontation.

Privileges In the TC, privileges are explicit rewards that reinforce the value of achievement. Privileges are accorded with overall clinical progress in the program. Displays of inappropriate behavior or negative attitude can result in loss of privileges, which can be regained through demonstrated improvement. Staff members deliver all privileges, which may range from telephone use and letter writing early in treatment to overnight furloughs later in treatment. Successful movement through each stage earns privileges that grant wider personal latitude and increased self-responsibility. Privileges acquire importance because they are earned through investment of time, investment of energy, and self-modification and because residents seeking them risk failure and face disappointment. Thus, the earning process establishes the value of privileges and gives them potency as social reinforcements. Although the privileges offered in the TC are quite ordinary, it is their social and psychological relevance to the patient that enhances their importance. Moreover, because substanceabusing patients often cannot distinguish between privilege and entitlement, the privilege system in the TC teaches that productive participation or membership in a family or community is based on an earning process.

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Finally, privileges are tangible rewards that are contingent on individual change. This concrete feature of privilege is particularly suitable for those with histories of performance failure or incompletion.

Disciplinary sanctions TCs have their own specific rules and regulations that guide the behavior of residents and the management of facilities. The explicit purpose of these rules is to ensure the safety and health of the community. However, their implicit aim is to train and teach residents through consequential learning. In the TC, social and physical safety are prerequisites for psychological trust. Therefore, sanctions are invoked against any behavior that threatens the physical safety of the therapeutic environment. For example, breaking one of the TC's cardinal rules (such as that of no violence or threat of violence) or a house rule (such as the unapproved borrowing of a book) is a threat that must be addressed. Loss of privileges or a speaking ban may be applied for less severe infractions. Job demotion or loss of accrued time may be invoked for more serious infractions. Expulsion may be appropriate for behavior that is incorrigible or dangerous to others. Sanctions may also be delivered for a resident's persistent failure in meeting community expectations. Examples are nonparticipation in community activities and repeated displays of negative attitudes toward the program. All sanctions are implemented by staff members, usually as written contracts with the resident. These agreements make explicit the behaviors addressed and the nature and duration of the consequences. Although contracts are often perceived as punitive, their basic purpose is to create a learning experience by compelling residents to attend to their own conduct, reflect on their own motivation, and consider alternative forms of acting under similar situations. The entire facility is made aware of all disciplinary actions. This helps to deter contract violations. Contracts thus create vicarious learning experiences for others, and as symbols of safety and integrity, they strengthen community cohesiveness.

Surveillance: the house run The TC's most comprehensive method for assessing the overall physical and psychological status of the residential community is the house run. Several times a day, staff members and senior residents walk through the entire facility, examining its overall condition. This single procedure has clinical implications as well as management goals. House runs provide global snapshot impressions of the facility: its cleanliness, planned routines, safety procedures, morale, and psychological tone. They also illuminate the psychological and social functioning of individual residents and peer groups.

Urine testing Most TCs use unannounced random urine testing or incident-related urine-testing procedures. Residents who deny the use of drugs or refuse to undergo urine testing on request are rejecting a fundamental expectation in the TC, which is to trust staff and peers enough to disclose undesirable behavior. The voluntary admission of drug use initiates a learning experience, which includes exploration of conditions precipitating the infraction. Denial of actual drug use, either before or after urine testing, can block the learning process and may lead to termination or dropout. When urine tests positive for drugs, the action taken depends on the drug used, the resident's time and status in the program, the resident's history of drug and other infractions, and the locus and condition of use. Actions may involve expulsion, loss of accrued time, radical job demotion, or rescinding of privileges for specific periods. Review of the triggers or reasons for drug use is also essential.

Peer confrontation In the TC, verbal affirmations and correctives are the main way that peers engage in community management. These verbal interactions illustrate examples of peer confrontation in that they provide face-to-face feedback to members as to whether they are meeting community expectations of program participation, recovery, and right living. Correctives aim to raise the individual's awareness of behaviors

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and attitudes that require changing. Correctives range in severity from mild reminders ("pull-ups") to stern conversations ("verbal reprimands"). Affirmations aim to encourage or reinforce positive clinical change or personal growth. Except as part of certain rituals (e.g., closing group sessions or meetings), affirmations are usually spontaneously offered as supportive expressions (e.g., "Yes, you can do it," "You're doing great," "You're my role model") or specific acknowledgments (e.g., "You have really changed"). Affirmations provide the crucial balance to verbal correctives and staff disciplinary sanctions. Peer confrontations are intended to facilitate learning by those delivering as well as those receiving them. Observing, affirming, reminding, and correcting others reciprocally reinforce self-learning through practice, rehearsal, or role modeling. Thus verbal affirmations and correctives are quintessential examples of the principle of mutual self-help (see Center for Substance Abuse Treatment 2005a, p. 169).

The TC Treatment Process: Program Stages and Phases Recovery in the TC is a developmental process, one that occurs in a social learning setting. The developmental process itself can be understood as a passage through stages of learning. The learning that occurs at each stage facilitates change at the next, and each change reflects movement toward the goal of recovery. Three major program stages characterize change in long-term residential TCs: orientation-induction, primary treatment, and reentry. Additional substages or phases are also discussed.

Stage 1: orientation-induction (0–60 days) The main goals of the orientation-induction phase of residence are further assessment and orientation to the TC. The aim of orientation in the initial phase of residence is for the individual to be assimilated into the community through full participation and involvement in all of its activities. Rapid assimilation is crucial at this point, when patients are most concerned about the amount of time they are required to spend in the TC. Formal seminars and informal peer instruction focus on reducing anxiety and uncertainty, which is accomplished through dissemination of information and instruction concerning cardinal rules (i.e., no use of drugs, no violence or threat of physical violence); house regulations (e.g., no leaving the facility, stealing, borrowing, or lending; the maintenance of manners) or expected conduct (e.g., punctuality, attendance, conduct relating to speaking and dressing); the program itself (e.g., TC structure, job functions, the privilege system, TC process stages, TC philosophy and perspective); and TC tools (e.g., encounter and other groups). Successful passage through the initial stage is reflected mainly in retention. The fact that patients have remained for 30–60 days indicates that they have adhered to the rules of the program well enough to meet the orientation objectives of this stage and have passed through the period of time when they are most vulnerable to dropping out.

Stage 2: primary treatment (2–12 months) The three phases of primary treatment roughly correlate with time spent in the program (2–4, 5–8, and 9–12 months). These phases are marked by plateaus of stable behavior that signal the need for further change. The daily therapeutic-educational regimen of meetings, groups, job assignments, and peer and staff counseling remains the same throughout the year of primary treatment. However, progress is reflected at the end of each phase in terms of three interrelated dimensions of change: community status, development or maturity, and overall psychological adjustment. The following brief description of residents who have completed 12 months of primary treatment serves to illustrate this concept. Twelve-month residents are established role models in the program. Privileges reflect the increasing degree of personal autonomy. These residents enjoy more privacy and can obtain regular furloughs. Although they cannot hold jobs outside the facility, their positions within the TC indicate that they

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effectively run the house. As senior coordinators, for example, they are responsible for arranging resident schedules, trips, and seminars—tasks they perform under staff supervision. Similarly, their status in terms of earning power is also increased; they are eligible to be staff-in-training in executive management offices, in special ancillary services, or as junior counselors. They are expected to assist the staff in monitoring the facility overnight and on weekends. Those beginning vocational-educational programs experience the pressures and challenges of academics or training. They accept responsibility for themselves and for other members in the community. The maturity of 12-month residents is most evident in their emotional self-management and increased autonomy. Job performance is consistent, and self-assessment is realistic, as is goal setting. Their social interactions with staff are more spontaneous and relaxed, and they socialize with positive peers during recreational activities and on furlough. Their movement past conformity is evident in their ability to adapt to new situations and teach others TC values. Twelve-month residents show some insight into their drug problems and personalities. These residents also display paradoxical signs of positive change. Although they are confident and eager to move forward, a certain degree of anxiety and insecurity emerges, associated with their uncertainty about the future. Their openness about anticipated problems is considered a positive psychological sign. After a year, residents are fully trained participants in the group process and often serve as facilitators. A high level of personal disclosure is evident in groups, in peer exchange, and in their increased use of staff counseling.

Stage 3: reentry (13–24 months) Reentry is the stage at which the patient must strengthen skills for autonomous decision making and the capacity for self-management and must rely less on rational authorities or a well-formed peer network. The two phases of the reentry process are early reentry and later reentry.

Early reentry phase (13–18 months) The main objective of the early reentry phase, during which patients continue to live in the facility, is to prepare patients for separation from the community. Emphasis on rational authority decreases, the assumption being that patients in this phase are sufficiently capable of self-management. This capability is reflected in more individual decision making about privileges, social plans, and life design. Particular emphasis is placed on life skills seminars, which provide training for life outside the community. Attendance is mandated for sessions on budgeting, job seeking, use of alcohol, sexuality, parenting, use of leisure time, and so on. During this phase, the development of plans for the individual is a collective task of the patient, a key staff member, and peers. These plans are comprehensive blueprints for long-term psychological, educational, and vocational efforts, which include goal attainment schedules, methods of improving interpersonal and family relationships, and counseling on social and sexual behavior. Patients may be attending school or holding full-time jobs, either within or outside the TC. Still, they are expected to participate in house activities when possible and to have some community responsibilities (e.g., monitoring of the facility at night).

Later reentry phase (18–24 months) The objective of the later reentry phase is successful separation from the community. Patients have a "live-out" status; they hold full-time jobs or attend school full-time, and they maintain their own households, usually with live-out peers. They may participate in Alcoholics Anonymous or Narcotics Anonymous or attend family or individual therapy sessions. Contact with the TC is frequent at first and is gradually reduced to weekly telephone calls and monthly visits with a primary counselor.

Graduation Completion marks the end of active program involvement. Graduation itself, however, is an annual

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event conducted in the facility for individuals who have completed the program, usually 1 year after their residence is over. Thus, the TC experience is preparation rather than a cure. Residence in the program facilitates a process of change that must continue throughout life, and what is gained in treatment are tools to guide the individual on a path of continued change. Completion, or graduation, therefore, is not an end but a beginning.

Aftercare TCs have always acknowledged the patient's efforts to maintain sobriety and a positive lifestyle beyond graduation. Until recently, long-term TCs addressed key clinical and life adjustment issues of aftercare during the reentry stages of the 2-year program. However, funding pressures have resulted in shorter planned durations of residential treatment and the stages and phases therein. This has underscored the necessity for aftercare resources to address both primary treatment as well as reentry issues. Thus, many contemporary TCs offer postresidential aftercare treatment and social services within their systems, such as intensive day treatment and step-down outpatient ambulatory treatment, or through linkages with outside agencies.

RESEARCH: EFFECTIVENESS AND RETENTION Success Rates A substantial amount of evaluation literature documents the effectiveness of the TC approach in rehabilitating drug-abusing individuals (see reviews in Anglin and Hser 1990; Condelli and Hubbard 1994; De Leon 1984, 1985, 2004; Institute of Medicine 1990; National Institute on Drug Abuse 2002; Simpson 1997; Simpson and Curry 1997; Simpson and Sells 1982; Tims and Ludford 1984; Tims et al. 1994). The findings of single-program and multiprogram studies regarding short- and long-term posttreatment outcomes are summarized in this section. Substantial improvements are noted on separate outcome variables (i.e., drug use, criminality, and employment) and on composite indices for measuring individual success. Maximally to moderately favorable outcomes (in terms of opioid, non-opioid, and alcohol use; arrest rates; retreatment; and employment) occur in more than half of the sample of patients who have completed programs and dropouts. There is a consistent positive relationship between time spent in residential treatment and posttreatment outcome. For example, in long-term TC programs, success rates (on composite indices of no drug use and no criminality) determined 2 years after completion of treatment are approximately 90% for graduates or completers, 50% for dropouts who remain in residential treatment for more than 1 year, and 25% for dropouts who remain in residential treatment for less than 1 year (e.g., De Leon et al. 1982). In studies that investigated psychological outcomes, results uniformly showed marked improvement at follow-up (e.g., Biase et al. 1986; De Leon 1984; Holland 1983). A direct relationship has been demonstrated between posttreatment behavioral success and psychological adjustment (De Leon 1984; De Leon and Jainchill 1981–1982). Since the early 1980s, most patients admitted to residential TCs have been multiple-drug–abusing individuals—primarily abusing cocaine, crack, marijuana, and alcohol—and there have been relatively smaller proportions of patients admitted whose primary drug of abuse is heroin (e.g., De Leon 1993). Several large-scale, federally funded evaluation efforts have documented the effectiveness of TCs for the changing population of substance-abusing individuals. These studies include the Drug Abuse Treatment Outcome Study (Hubbard et al. 1997; Simpson and Curry 1997) and the multisite program of research carried out in the Center for Therapeutic Community Research (De Leon 1997).

Retention Dropout is the general rule for all drug treatment modalities. For TCs, retention is of particular importance because research has established a firm relationship between time spent in treatment and

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successful outcome. However, most patients admitted to TCs leave the programs, with many leaving before treatment influences are presumed to be effectively rendered. Research on retention in TCs has been increasing. Reviews of the TC retention research are contained in the literature (e.g., De Leon 1985, 1991; Lewis and Ross 1994; Simpson and Curry 1997). The key findings from these are summarized here.

Retention rates Dropout rates are highest (30%–40%) for the first 30 days of residence but decrease sharply thereafter (De Leon and Schwartz 1984). This temporal pattern of dropout is uniform across TC programs (and other modalities). In long-term residential TC programs, completion rates range from 15% to 30% of all admissions. One-year retention rates range from 25% to 40%, although more recent findings suggest gradual increases in annual retention compared with earlier periods. Retention rates vary considerably across programs, implicating differences in organizational sophistication and fidelity of treatment delivery (Simpson and Curry 1997).

Predictors of dropout No patient characteristics reliably predict retention, with the exceptions of severe criminality and severe psychopathology, which are correlated with earlier dropout. Studies point to the importance of dynamic factors in predicting retention in treatment, such as perceived legal pressure, motivation, and readiness for treatment (e.g., Broome et al. 1997; Condelli and De Leon 1993; Condelli and Dunteman 1993; De Leon 1988; De Leon et al. 1994; Hubbard et al. 1988).

Enhancing retention in TCs Some attempts to enhance retention in TCs have involved supportive individual counseling, improved orientation to treatment by experienced staff members as "senior professors" (De Leon et al. 2000a), and family alliance strategies to reduce early dropout (e.g., De Leon 1991). Other efforts involve providing special facilities and programming for mothers and children (e.g., Coletti et al. 1997; Stevens et al. 1997) and teaching curriculum-based relapse prevention methods (Lewis and Ross 1994) to sustain retention throughout residential treatment. Recent studies in European TCs demonstrate the importance of a social network in sustaining retention in treatment (Soyez et al. 2006). An important evolution in TC research is studies that investigate the role of medications in retention. For example, the use of buprenorphine for opioid abusers significantly decreases short-term dropout from TCs (Amass et al. 2004). Although the findings of these various efforts to increase retention are promising, they require replication in multiple sites. While a legitimate concern, retention should not be confused with treatment effectiveness. TCs are effective for those who remain long enough for treatment influences to occur. Obviously, however, a critical issue for TCs is maximizing holding power to benefit more patients.

Treatment Process Recent developments have facilitated empirical studies into the hitherto underinvestigated area of treatment process. These developments include formulations of the perspective and essential elements of the TC approach and of the stages of recovery in the TC (e.g., De Leon 1995, 1996a, 2000). Findings based on these formulations illuminate some of the essential program elements, which may serve as the active ingredients in the treatment process. Several examples of process-related research are briefly summarized. Studies of criminal justice substance abusers underline the critical importance of client participation in community activities and treatment effectiveness. Inmates who fully engaged in a prison-based TC were more likely to enter aftercare and have better postrelease outcomes (Melnick and De Leon 1999; Melnick et al. 2001b). A recent report demonstrates that substance abusers who were more involved in providing verbal affirmations and corrections during their stay in a prison-based TC were significantly

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less likely to be reincarcerated 2 years after release (Warren et al. 2007). Another prospective study documents that among substance abusers treated in a prison-based TC, those with greater self-perceived change at 1 year postrelease were significantly less likely to be reincarcerated 3 years later (De Leon et al. 2006). Finally, an investigation of encounter group process in community-based TCs indicates that benefits occur to those who both deliver and receive confrontation (Broekaert et al. 2004).

THE EVOLUTION OF THE TC: MODIFICATIONS AND APPLICATIONS The traditional TC model described in this chapter is actually the prototype of a variety of TC-oriented programs. Today, the TC modality consists of a wide range of programs serving a diversity of patients who use a variety of drugs and present with complex social and psychological problems in addition to their chemical abuse. Patient differences as well as clinical requirements and funding realities have encouraged the development of modified residential TC programs with shorter planned durations of stay (3, 6, and 12 months) as well as TC-oriented day treatment and outpatient ambulatory models. Having become overwhelmed with alcohol and drug abuse problems, correctional facilities, medical and mental hospitals, and community residences and shelters have implemented TC programs within their settings. Highlighted in the following sections are some of the key modifications and applications of the TC approach for different patient populations in different settings.

Current Modifications of the TC Model Most community-based traditional TCs have expanded their social services or have incorporated new interventions to address the needs of their diverse residents. These changes and additions include family services; primary health care specifically geared toward HIV-positive patients and individuals with AIDS (e.g., Barton 1994; De Leon 1996b; McCusker and Sorensen 1994); aftercare, particularly for special populations such as substance-abusing inmates (e.g., Lockwood and Inciardi 1993); relapse prevention training (e.g., Lewis and Ross 1994); components of 12-step groups (De Leon 1990–1991); and mental health services (e.g., Carroll and Sobel 1986). These various modifications are mostly additions to the program activities and they enhance but do not alter the basic TC regimen. In some cases, these modifications substantially change the TC model itself.

The multimodal TC and patient–treatment matching Traditional TCs are highly effective for a certain segment of the drug-abusing population. However, those who seek assistance in TCs represent a broad spectrum of patients, many of whom may not be suited for a long-term residential stay. Improved diagnostic capability and assessment of individual differences have clarified the need for options other than long-term residential treatment. Many TC agencies are multimodality treatment centers that offer services in their residential and nonresidential programs, depending on the clinical status and situational needs of the individual. The modalities include short-term (less than 90 days), medium-term (6–12 months), and long-term (1–2 years) residential components and drug-free outpatient services (6–12 months). Some TC agencies have drug-free day treatment and methadone maintenance programs. Attempts are made to match the patient to the appropriate modality within the agency. For example, the spread of drug abuse, particularly cocaine use, in the workplace has prompted the development of short-term residential and ambulatory TC models for more socialized patients. Also, initial studies indicate better retention rates in patients matched to TC-oriented residential and outpatient settings on the basis of multiple domains of drug use severity and social and psychological functioning (Melnick et al. 2000, 2001a). To date, the effectiveness of TC-oriented multimodality programs has not been systematically evaluated. Several relevant studies indicate that positive outcomes are obtained in various shorter-term residential, day treatment, and outpatient programs (e.g., Bucardo et al. 1997; Karson and Gesumaria 1997; McCusker and Sorensen 1994). However, given what is known about the complexity of the recovery process in addiction and the importance of length of stay in treatment, there is little likelihood that shorter-term treatment alone will be sufficient to produce stable positive outcomes for individuals

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with serious substance-abuse and related lifestyle problems. This conclusion is supported by evidence in the national Drug Abuse Treatment Outcome Study showing that clients with the highest problem severity have better outcomes in long-term TCs than in other settings (Simpson and Curry 1997). Therefore, for serious substance abusers entering multimodality TC agencies, combinations of residential and outpatient services are needed for long-term treatment involvement and effectiveness.

Current Applications to Special Populations An important sign of the evolution of the TC is its application to special populations and special settings. It is beyond the purview of this chapter to detail the modifications of these adapted TC models. In the main examples of these models, the focus on mutual self-help is retained, along with basic elements of the community approach, meetings, groups, work structure, and perspective on recovery and right living. Examples of these adaptations are more fully described elsewhere (Center for Substance Abuse Treatment 2005a, 2005b; De Leon 1997, 2000). Modifications in practices and in program elements for special populations and settings center upon the treatment goals and planned duration of treatment, flexibility of the program structure to accommodate individual differences, and the intensity of peer interactions. Special services and interventions are integrated into the program as supplemental to the primary TC treatment. Successful implementation of TC program models within special settings requires accommodation to the goals, procedures, personnel, general practices, and restrictions of these settings. Recent research provides evidence for the effectiveness of modified TCs for special populations. These study populations include adolescents in various adaptations of the community-based TC (Hubbard et al. 1988; Jainchill 1997), inmates in prison-based TCs (Inciardi et al. 1997; Simpson et al. 1997; Wexler et al. 1999a, 1999b), mentally ill chemical-abusing individuals (De Leon et al. 2000b; Sacks et al. 1997), addicted mothers and their children (Coletti et al. 1997; Winick and Evans 1997), and (although not described here) patients receiving methadone in a day treatment TC (De Leon et al. 1995). The findings and conclusions from the research on TCs for special populations are reviewed elsewhere (De Leon 2005) and may be briefly summarized. Among mentally ill chemical abusers, inmates, adolescents, and homeless substance abusers treated in modified TC programs, drug use and criminality decline and improvements in employment and psychological status are seen; improvements were correlated with length of stay in treatment. Fiscal studies indicate that TC-oriented programs reveal favorable cost-benefit gains, particularly in reduction of expenditures associated with criminal activity in mental health services.

The TC in Human Services The modifications of the traditional model and its adaptation for special populations and settings are redefining the TC modality within mainstream human services and mental health services. Most contemporary TC programs adhere to the perspective and approach described in this chapter. However, the basic peer/social-learning framework has been enlarged to include additional social, psychological, and health services. Staffing compositions have been altered, reflecting the fact that traditional professionals—correctional, mental health, medical, educational, family, and child care specialists; social workers; and case managers—serve along with experientially trained TC professionals. These changes in patients, services, and staffing have also brought to the surface complex issues, particularly concerning divergence of the program from the proven TC model as well as staff divergence and integration. Program diversity has led to problems of maintaining treatment fidelity and effectiveness. The response to this issue has been the development of national standards of TC programming (Commission on Accreditation of Rehabilitative Facilities 2000 [cited in De Leon 2000, p. 390]; Therapeutic Communities of America 1999) and quality assurance models (Kressel et al. 2002) based on theory and clinical practice. Staff issues are related to the TC's philosophy of drug-free living and the TC's self-help perspective;

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other issues are related to differences in therapeutic concepts and terms, staff members' academic education, staff members' experience with addiction, and their roles and functions within the context of a peer community model. The issues of staff integration have been addressed through the development of TC training curricula based on theory and standards (Center for Substance Abuse Treatment 2006; Therapeutic Communities of America 1999). Vigorous training and orientation efforts are guided by a common perspective of recovery (Carroll and Sobel 1986; Deitch and Solit 1993; De Leon 1985; Galanter et al. 1991; Talboy 1998). Indeed, the cross-fertilization of personnel and methods between traditional TCs and mental health and human services portends the evolution of a new TC: a general treatment model applicable to a broad range of populations for whom affiliation with a self-help community is the foundation for effecting the process of individual change.

KEY POINTS The therapeutic community (TC) is a unique social-psychological approach to the treatment of substance abuse and related disorders. The primary "therapist" and teacher in the TC is the community itself, consisting of peers, who serve as role models of successful personal change, and staff members, who serve as rational authorities and guides in the recovery process. The TC serves the substance abusers with the highest severity of substance abuse disorder, social deviancy, and psychological problems. For some, treatment involves rehabilitation, or relearning a positive lifestyle. For most, treatment involves habilitation, or learning a positive lifestyle for the first time. Today, the term therapeutic community is generic, describing a variety of short-term and long-term residential programs, as well as day treatment and ambulatory programs that serve a wide spectrum of drug-abusing and alcohol-abusing patients. These modified TC programs retain the essential elements of "community as method," while incorporating other evidence-based psychological and pharmacological practices. The effectiveness and cost benefits of the TC have been documented in a number of studies, including those involving special populations of substance abusers, such as adolescents, individuals with co-occurring mental illness, criminal justice cases, and the homeless treated in special settings such as correctional facilities, halfway houses, and psychiatric hospitals. These studies demonstrate reductions in drug use, criminality, and psychiatric symptoms and increases in employment and prosocial behaviors. Research documents a consistent relationship between longer retention in treatment and positive outcomes. The cross-fertilization of personnel and methods between traditional TCs and mental health and human services portends the evolution of a new TC: a general treatment model applicable to a broad range of populations for whom affiliation with a self-help community is the foundation for effecting the process of individual change.

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as predictors of reincarceration following graduation from a corrections-based therapeutic community. Offender Substance Abuse Report, Vol 7, No. 3 Wexler HK, De Leon G, Thomas G, et al: The Amity Prison TC evaluation: reincarceration outcomes. Crim Justice Behav 26:147–167, 1999a Wexler HK, Melnick J, Lowe L, et al: Three-year reincarceration outcomes for Amity in-prison therapeutic community and aftercare in California. The Prison Journal 79:321–336, 1999b Winick C, Evans JT: A therapeutic community for mothers and their children, in Community as Method: Therapeutic Communities for Special Populations and Special Settings. Edited by De Leon G. Westport, CT, Greenwood, 1997, pp 143–160 Yablonsky L: Synanon: The Tunnel Back. New York, Macmillan, 1965 Zuckerman M, Sola S, Masterson J, et al: MMPI patterns in drug abusers before and after treatment in therapeutic communities. J Consult Clin Psychol 43:286–296, 1975 [PubMed]

SUGGESTED READING Center for Substance Abuse Treatment: Substance Abuse Treatment for Persons With Co-occurring Disorders. Treatment Improvement Protocol (TIP Series) #42 (DHHS Publ No SMA 05-3992). Rockville, MD, Substance Abuse and Mental Health Services Administration, 2005 De Leon G (ed): Community as Method: Therapeutic Communities for Special Populations and Special Settings. Westport, CT, Greenwood, 1997 De Leon G: The Therapeutic Community: Theory, Model, and Method. New York, Springer, 2000 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 33. Community-Based Treatment

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Jonathan I. Ritvo, Harvey L. Causey: Chapter 33. Community-Based Treatment, in The A merican Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.35 3945. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Community-Based Treatment Jonathan I. Ritvo, M.D. Harvey L. Causey III, M.D.

COMMUNITY-BASED TREATMENT: INTRODUCTION In this chapter we discuss community-based substance abuse treatment from two perspectives. The first perspective, the community's role in treatment, encompasses substance abuse identification and intervention, ranging from noncoercive brief interventions in medical care settings to coercive interventions through social service agencies and criminal and civil courts. The second perspective, specific non-hospital-based treatment services, encompasses outpatient treatment programs, community residential facilities, detoxification centers, and case management approaches.

COMMUNITY INTERVENTION Fifty-five percent of treatment referrals in the 2003 Treatment Episode Data Sets came from community sources such as the criminal justice system, schools, employers, and health care providers outside the substance abuse treatment system (Table 33–1).

Brief Interventions Table 33–2 lists the components of a typical brief intervention. Heavy drinking, as defined in studies demonstrating the effectiveness of brief intervention, ranges from 12 to 25 drinks per week for men and from 9 to 16 drinks per week for women (Fleming and Manwell 1999). Typically, these studies exclude individuals who have been treated for alcoholism or meet criteria for abuse or dependence. The heavy drinkers targeted for brief intervention are at risk both for excess alcohol–related morbidity and for developing an alcohol use disorder. These heavy drinkers represent a much larger population than drinkers who meet criteria for alcohol abuse or dependence, who would be candidates for more specialized intervention and treatment. Brief intervention research has profound implications for many health care fields, including public health, prenatal care, general medical practice, trauma care, student health services, health care economics, and the education of health professionals.

Primary care Several randomized controlled trials have demonstrated that brief intervention by primary care providers reduces heavy drinking and its health consequences (Fleming 2002). Fleming et al. (1997) and Manwell et al. (2000) studied 774 heavy drinkers screened in 10 primary care practices in southern Wisconsin. The brief intervention group received two 15-minute physician advice sessions and a telephone follow-up by a nurse. At 1-year follow-up, men in the brief intervention group showed significant (P <0.001) reductions in comparison with control subjects in number of drinks consumed, episodes of binge drinking, and frequency of excessive drinking in the previous month (Fleming et al. 1997). A subsequent study by Fleming et al. (2002) demonstrated the benefits of brief intervention in terms of alcohol use, health care utilization, and motor vehicle accidents after 48 months and calculated a total net benefit to society of $7,780 per patient for the study's 48-month follow-up period. Other studies have examined special populations. Women of childbearing age showed significant intervention effects in number of drinks and episodes of binge drinking, with the most dramatic decreases in those who became pregnant during the follow-up year (Manwell et al. 2000). Brief intervention in the elderly (65 or older) has shown benefits similar to those seen in younger people in

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reduction of alcohol use but has not shown a corresponding benefit in economic outcomes, including health care costs (Mundt et al. 2005).

Emergency and trauma care Physicians, other caregivers, and even the general public are aware that alcohol plays a central role in motor vehicle accidents and fatalities. However, the fact that 40% of motor vehicle fatalities in the United States are related to alcohol is truly sobering (Sommers et al. 2006). Studies in trauma centers find that the period immediately after a motor vehicle accident is a window of opportunity for brief intervention. Such interventions have been shown to reduce alcohol consumption, trauma recidivism (Gentilello et al. 1999), and future arrests for driving while intoxicated (DWI; Schermer et al. 2006). Gentilello et al. (2005) estimated that providing brief interventions routinely to intoxicated trauma patients nationwide could lead to an annual savings of $1.82 billion. Alcohol exclusion laws pose a significant barrier to brief intervention in trauma settings. In 1947, the National Association of Insurance Commissioners proposed a Uniform Accident and Sickness Policy Provision Law that allowed insurers to exclude from coverage any accidents and injuries resulting from intoxication. Thirty-two states and the District of Columbia have adopted statutes allowing this exclusion, and 10 additional states implicitly allow the exclusion. This exclusion creates a financial disincentive to identify and to intervene with substance use disorders in trauma settings. The association has recommended unanimously that states repeal these laws and require insurers to cover injuries resulting from intoxication (Fornili and Goplerud 2006).

Colleges High-risk drinking is a significant health problem in young adults (Grossberg et al. 2004). The College Alcohol Study conducted by the Harvard School of Public Health, which included more than 14,000 students in 119 four-year colleges, found that 31% of students met criteria for alcohol abuse and 6% for alcohol dependence in the past 12 months (Knight et al. 2002). An estimated 1,400 students ages 18–24 years died in 1998 from alcohol-related accidental injuries, including motor vehicle accidents (Hingson et al. 2002). Perkins (2002) found that peer norms were the strongest influence on student drinking and that students tended to dramatically overestimate the drinking of their peers, thus giving themselves permission to drink more. The brief intervention model described earlier has demonstrated effectiveness in young adults in terms of decreased emergency department visits, motor vehicle accidents, and arrests for controlled substance or alcohol violations (Grossberg et al. 2004). A literature review by Larimer and Cronce (2002) evaluated various modalities utilized for prevention and treatment of college drinking problems. They found that cognitive-behavioral skills-based interventions and brief motivational feedbacks were effective treatments, whereas educational/awareness programs were not effective. The authors suggested that interventions target high-risk students identified either through brief screening or through membership in a high-risk subpopulation such as Greek organizations or athletics. Marlatt et al. (1998) described programs at the University of Washington that target college students who drink heavily. These programs do not involve diagnosis of alcoholism, labeling of problem drinking, or prescribing of abstinence; instead, they present risks, benefits, choices, normative data, and personalized feedback as well as strategies and standards for moderate and safe drinking. Outcome analysis showed that first-year students identified as heavy drinkers who received a brief motivational intervention of this type demonstrated greater reductions in their drinking rates and problems related to drinking than did control subjects. Both the intervention and control groups, as well as peers who did not drink heavily, showed reductions in drinking over the study period, consistent with a maturational effect as students learn to drink moderately and responsibly. The National Institute on Alcohol Abuse and Alcoholism Taskforce on College Drinking has published a manualized brief intervention curriculum for training health care providers to identify and treat college students with drinking problems (Fleming 2002).

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Workplace Interventions The majority of individuals in the United States who abuse alcohol and drugs are employed. The National Household Survey on Drug Abuse for 1999 found that 77% of adult illicit drug users (approximately 9.4 million individuals) work and that 6.2% of full-time workers are heavy drinkers, whereas 38% of workers ages 18–25 years are binge drinkers (Substance Abuse and Mental Health Services Administration 2000). Substance abuse is costly to employers, particularly in terms of worker turnover, accidents, and increased health care costs (Reynolds and Lehman 2003). One percent of treatment referrals came from employers and employee assistance programs (EAPs; see Table 33–1).

Employee assistance programs In the United States, EAPs have constituted employers' primary response to the problem of workers' substance abuse. With regard to substance abuse, EAPs have two purposes: 1) protection of employers and their employees from the adverse consequences of coworkers' substance use and 2) protection of the employers' investment in their employees (Roman and Blum 2004). EAPs began in the 1940s as industrial alcoholism programs (Hartwell et al. 1996), often established and run by recovering alcoholics who encouraged involvement in Alcoholics Anonymous (Steele 1998). By the early 1970s, EAPs broadened their scope as it became clear that deterioration in job performance could be related to a number of problems other than alcoholism. Today, EAPs are usually multiservice programs that address a variety of issues affecting job performance, including mental health and family problems as well as substance use (Hartwell et al. 1996). A recent survey demonstrates this shift in focus, finding that non–substance users were more likely to utilize their EAP than were substance users (Reynolds and Lehman 2003). Since the late 1980s, the role of EAPs in the identification and referral of substance-abusing workers has declined because of both the shift in focus of EAPs (Roman and Blum 2004) and the advent of managed care (Nace et al. 2007).

Workplace drug testing As EAPs have broadened their focus to issues other than drugs and alcohol, employers have come to rely increasingly on drug testing to detect and deter substance problems. Guidelines for drug testing in the workplace began to emerge in the 1980s. Urinalysis is the most frequent test, but testing also can involve oral fluids, sweat, or hair (Cone 2001). DuPont et al. (1995) found that the establishment of random drug testing was associated with a decrease in workplace problems associated with illicit drug use. Although random testing was more effective at detecting daily users than infrequent users, DuPont and colleagues concluded that such testing was a deterrent to both frequent and casual drug use. Lawental et al. (1996) compared individuals coerced into treatment following a positive random drug screen with voluntary referrals for treatment from the same EAP. Coerced patients were more likely to remain in treatment than those who were self-referred, and levels of improvement in substance use, employment, and medical and psychiatric conditions were similar at 6-month posttreatment follow-up.

Interventions by Welfare Services Child protective services More than twice as many women as men are referred to treatment by social service agencies, a difference probably related to women making up the majority of single parents (Brady and Ashley 2005). MacMahon (1997) reviewed the cases of 53 mothers in San Mateo County, California, who were reported to child protective services (CPS) when their infants in the newborn nursery tested positive for illicit substances. All mothers were then court-ordered to participate in a drug rehabilitation program and to undergo monitoring through urine toxicology testing. The 44% who complied with treatment had repeatedly drug-free urine tests; these mothers regained custody of their infants. Mothers coerced into treatment by CPS are better served by specialized programs. Analyzing data collected from public drug and alcohol treatment programs in San Diego County, California, over a

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3-year period, Hohman et al. (2002) found that pregnant women mandated to treatment by CPS were more likely to end treatment unsatisfactorily than were patients in the same programs who were not involved with CPS. The authors considered the many demands placed on the patients by CPS and the treatment programs' difficulties in working with CPS clients as possible explanations for this finding. In Los Angeles, California, Nishimoto and Roberts (2001) found better treatment retention and better custody outcome for postpartum mothers who participated in a gender-specific intensive day treatment program compared with mothers assigned to a 1.5-hour/week, 6-month, mixed-gender program. The intensive program required 5.5-hour/day, 7-days/week participation for 6 months and also offered family therapy, child care, transportation, and infant care and assessment. Analyzing data from another intensive intervention program for mothers of drug-exposed infants, Mullins et al. (2005) found that termination status (a study variable that combined dose of services, duration of involvement, and progress toward treatment goals) was associated with lower rates of further CPS reports for child maltreatment.

Disability and public support Substance abuse by public disability beneficiaries has been the subject of political and scientific controversy. In 1994, Congress limited Supplemental Security Income (SSI) and Social Security Disability Income (SSDI) benefits arising from chemical dependence to 3 years and required recipients to participate in treatment and to have a payee manage their funds. Before this could be fully implemented, in 1996 Congress prohibited new SSI and SSDI benefits based on chemical dependence and terminated existing benefits as of January 1997 (Nace et al. 2007). The disqualification of beneficiaries for whom substance abuse contributed to disability had several unintended consequences. It made it more difficult to appoint payees for beneficiaries with substance use disorders (Rosen and Rosenheck 1999), and many of those who lost benefits had significant medical and psychiatric comorbidity for which they were less likely to receive treatment after losing benefits (McKay et al. 1998; Swartz et al. 2003). Some data and reports support the perception of misuse of disability funds for substance use. Shaner et al. (1995) documented increased cocaine use, psychiatric symptoms, and hospitalization among cocaine-dependent, disabled veterans with schizophrenia shortly after the first of the month, when they received their benefit payments (the "check effect"). Other reports have linked the receipt of large, lump-sum retroactive disability payments with negative treatment events such as premature, abrupt termination of long-term residential substance abuse treatment (Satel et al. 1997) and missed visits and positive urine tests during methadone maintenance treatment (Herbst et al. 1996). In contrast, Frisman and Rosenheck (1997) found no increased drug and alcohol use among homeless mentally ill veterans who received disability payments. Similarly, Rosen et al. (2005) found that individuals newly awarded benefits did not increase their drug use. In addition, although Swartz et al. (2003) found a check effect for cocaine use, increased drug use in the first 10 days of the month occurred equally in both recipients and nonrecipients of SSI in their study. Ries et al. (2004b) did not find the check effect in terms of substance use or hospitalizations in 44 cocaine-abusing schizophrenic patients for whom payeeship, or use of a representative payee, was integrated into their treatment program. Herbst et al. (1996) found that the use of a representative payee (an agency or individual appointed to receive and manage disability payments for the use and benefit of the disabled individual) protected against the negative effect on treatment of large lump-sum retroactive payments. Since the 1996 legislation eliminated SSI and SSDI benefits based on substance abuse, subsequent data on the effects of payees on substance abuse come mainly from populations of mentally ill substance abusers. Rosenheck et al. (1997) found that the use of representative payees for homeless mentally ill individuals decreased homelessness but not substance abuse. Rosen et al. (2007) failed to find a benefit from the use of payees in terms of drug use, but did find that participants assigned payees made greater use of psychiatric services. Ries et al. (2004b) concluded that use of representative payees who were an

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integral part of the treatment program had two main benefits: it limited drug binges and their resultant consequences and increased treatment participation in a population that is frequently nonadherent. Contingent management of the form and frequency of benefits disbursed by the integrated payees further reduced alcohol and drug use (Ries et al. 2004a). In the Veterans Administration (VA) system, departmental policy precludes such integration of payeeship by prohibiting its programs and clinicians from serving as representative payees (Satel 1995). Disability benefits for substance-abusing individuals may well be a mixed blessing. Certainly there are potential negative aspects to consider: disincentive to work, ineligibility for many rehabilitation programs, loss of the structuring of time and of the rewards for sobriety provided by work, and availability of money for addictive substances. However, the evidence suggests that receiving benefits does not cause a substantial increase in substance use and may, if administered by a payee, increase an individual's likelihood of utilizing treatment for comorbidities. Furthermore, a payee system integrated into the treatment program not only appears to improve treatment participation but also appears to reduce binges and the adverse consequences of heavy use. Given the importance of money in access to substances and in relapses, greater coordination of policy and practice regarding the representative payee mechanism between entitlement and support programs on the one hand and local treatment services on the other could add considerable leverage to substance abuse treatment.

Interventions by the Judicial System Thirty-six percent of treatment referrals in the 2003 Treatment Episode Data Sets comes from the criminal justic system. This includes referral stemming from DWI cases (see Table 33–1). In this section we dicuss the most effective criminal justice interventions for substance use problems—interventions for DWI and interventions by specialized drug courts—as well as civil commitment, a noncriminal court intervention.

Driving while intoxicated The enforcement of DWI laws and the management of the DWI offender in the legal system have evolved considerably in the past 40 years. Most importantly, at the same time, alcohol-related motor vehicle fatalities have declined significantly. (Preventive community interventions for DWI are discussed in Chapter 48, "Prevention of Substance Abuse.") In the late 1960s and early 1970s, the Alcohol Safety Action Programs of the National Highway Traffic Safety Administration expanded the interventions for DWI from jail and license actions to education and rehabilitation. In the 1970s and 1980s, the use of license sanctions progressed as many states adopted administrative per se laws that established administrative license revocation (ALR) procedures. ALR permits swift license suspension in the cases of drivers who fail or refuse sobriety tests, usually well before the often lengthy and contested criminal proceedings are resolved. Retrospective studies have shown decreases in recidivism and subsequent accidents involving offenders after initiation of ALR (McArthur and Kraus 1999). ALR laws exist in 40 states (Voas and Fisher 2001). A comprehensive meta-analysis by Wells-Parker et al. (1995) concluded that treatment of the DWI offender effected an 8%–9% reduction in both DWI recidivism and alcohol-related crashes. License sanctions led to a decrease in non-alcohol-related crashes, probably because they reduced driving by offenders. The authors concluded that the combination of therapy and license sanctions was more effective than either alone. Similarly, a large California study (DeYoung 1997) showed that combining treatment and license suspension was more effective than incarceration or license suspension alone in reducing recidivism. The meta-analysis (Wells-Parker et al. 1995) also found that multimodality treatment programs (e.g., programs combining education, psychotherapy/counseling, and follow-up) showed the most effectiveness, probably because these programs affected a larger proportion of a heterogeneous population than single-modality programs that tend to rely on education. This suggested that treatment effectiveness could improve with better treatment matching.

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In a later report, Wells-Parker and Williams (2002) demonstrated a specific treatment-matching effect for depressed offenders. Randomizing 4,074 participants in a Mississippi program for first-time DWI offenders, they added a brief intervention (two 20-minute individual counseling sessions with a 4- to 6-month follow-up session) to a standard education-based (10 hours over four sessions) group intervention. Counselors trained in motivational interviewing used self-assessment and motivational enhancement techniques in the individual sessions. Depressed offenders receiving the additional individualized brief intervention were 35% less likely to recidivate than those receiving only the standard group intervention. After controlling for depressed mood, the individualized brief intervention did not reduce recidivism for problem drinkers overall. The authors concluded that "[i]t is possible that mild depression and feelings of sadness enhance the 'window of opportunity' that a DUI [driving under the influence] arrest and conviction could open" (p. 662), making the offender particularly ready for brief motivational intervention. Most states require some assessment and screening of DWI offenders to determine both which offender is at high risk for recidivism and what type of education or treatment referral to require. Some states specify particular assessment tools and criteria to be used for treatment assignment. Theoretically, a diagnosis of an alcohol use disorder should lead to more intensive treatment for alcoholism. However, the screening process is complicated by the motivational issues of the coerced patient who may be interested in denying his drinking and avoiding self-disclosure. Therefore, to achieve maximum reliability, Cavaiola and Wuth (2002) recommended combining any standardized instruments with a comprehensive biopsychosocial assessment that remains open to data emerging over time and uses collateral information from family, significant others, and medical and legal records. Most states assign first offenders who do not screen positive for substance use disorders to 10- to 14-hour educational programs (e.g., the Mississippi program cited earlier). In general, educational programs have a harm-reduction orientation and tend to be moving away from purely didactic approaches that rely on lectures, films, and literature; many programs are moving toward greater use of interactive groups and skills training that focus on choosing, implementing, and assessing plans to avoid driving after drinking. Evaluations of educational programs have demonstrated attitude change, but the impact on recidivism is less clear (Hon 2003; Voas and Fisher 2001). In approaching the treatment of the DWI offender, Cavaiola and Wuth (2002) noted that many offenders fall midway between social drinkers and problem drinkers. Only 20% of offenders have the level of problem severity of alcoholics in treatment. The DWI charge is usually the offender's first experience with a major consequence related to substance use, as well as his or her first experience with arrest and adjudication. Cavaiola and Wuth recommend using the common goal of avoiding another DWI offense as the basis for an alliance with the resistant offender and using a nonconfrontational motivational enhancement approach to meet the offender at his or her stage of change and to examine his or her alcohol use in the context of current life goals and issues. Noncompliance with sentences is common with repeat ("hardcore") drunk drivers. Table 33–3 summarizes the variety of monitoring models and noncompliance sanctions that courts have developed for the hardcore drunk driver. Using the drug court model (Table 33–4), DWI courts (sometimes also called DUI courts) help judges and prosecutors to specialize in the issues of the DWI population, to coordinate sentencing with treatment providers, to keep the DWI cases from being lost in the general criminal court docket, and to improve monitoring of these cases for compliance. A recent evaluation of one such DWI court in Los Angeles, California, found cost savings for third-time offenders largely attributable to reduced incarceration without increased recidivism (Eibner et al. 2006). By the end of 2004, there were 90 pure DWI courts and 86 hybrid DWI courts (drug courts that also took DWI offenders) in the United States (Huddleston et al. 2005).

Drug courts

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Beginning in Miami, Florida, in 1989, drug treatment courts have provided a model for cooperation between the criminal justice system and addiction treatment services. By the end of 2004, there were 1,621 drug courts in the United States, serving more than 70,000 clients and graduating more than 16,200 clients that year (Huddleston et al. 2005). The drug court model outlined in Table 33–4 depends on the collaboration of judges, prosecutors, public defenders, and community treatment programs to apply the leverage of the criminal justice system to the treatment of the drug-abusing offender. The judge plays a key role by administering sanctions —which often consist of brief jail stays—for positive urine screenings or missed treatment appointments. Two drug court judges have called this "smart punishment" (Hora et al. 1999). Satel (1998) pointed out that these sanctions conform to basic principles of behavioral therapy by being "swift and sure but not necessarily severe" (p. 59). The drug court's use of sanctions can also be conceptualized as shoring up the offender's weakened ego with firm, consistent limits that better promote emotional growth and mature accountability than do traditional court sanctions, which more closely follow the model of the offender's rigid, harsh, and unpredictable primitive superego. A meta-analysis of drug court program outcome studies by the U.S. Government Accountability Office (GAO) reviewed 27 studies involving 39 different drug courts. It found lower re-arrest and conviction rates for drug court participants while in the program (GAO 2005). This reduction was observed for any felony as well as for all drug offenses (both felony and misdemeanor). More limited data suggested maintenance of the reduction in recidivism after completion of the drug court program and cost-effectiveness of the drug courts. The cost-effectiveness primarily resulted from the reduction in recidivism, which led to reduction of costs both to the judicial system and—importantly—to potential victims. Limited data on effectiveness in reducing relapse (from seven programs) were less clear, with drug test results, but not participant self-report, showing reductions in use. The GAO analysis could not determine which core ingredients of drug courts were associated with effectiveness. However, Marlowe et al. (2004) examined judicial supervision as a variable and found a significant matching effect. Offenders with antisocial personality disorder and/or prior drug treatment ("higher-risk") performed better with biweekly status hearings before the judge. Offenders without antisocial personality disorder and/or prior drug treatment ("lower-risk") performed better with case management monitoring, with the case manager petitioning for as-needed judicial status hearings in response to infractions. Performance measures included drug-free urine screenings and successful completion of the program. Drug courts increasingly focus on higher-risk offenders. Originally, drug court programs tended to follow diversionary models (also called pre-plea, or deferred prosecution models), in which charges would be dropped with successful completion of the program. By 2004, 69% of adult drug courts had probationary conditions (post-plea, deferred sentencing), and there were also 16 reentry (parole) drug courts that combined judicial monitoring, treatment, community supervision, regular drug testing, and specialized ancillary services to reintegrate drug-involved offenders being released from correctional facilities (Huddleston et al. 2005). The Drug Treatment Alternative to Prison Program (DTAP) in Brooklyn serves a higher-risk population and changed from deferred prosecution to deferred sentencing in 1998 in order to improve retention. DTAP admits addicted, repeat, nonviolent felony offenders (typically involved in drug sales) to long-term (15- to 24-month) residential treatment in therapeutic communities with vocational training. With deferred sentencing, the offender enters a guilty plea and upon successful completion of the program the plea is withdrawn and the charge dismissed. If the defendant absconds from the program, he is picked up by a special "warrant enforcement team" and as a repeat offender faces a mandatory 4.5- to 9-year sentence. The district attorney has some leeway to allow return to the program based on circumstances such as voluntary return or family upheaval. Deferred sentencing makes the consequence of imprisonment for absconding swifter and more certain than with deferred prosecution. Since the change to deferred sentencing, DTAP's 2-year retention rates have risen from 49% to 64% (National

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Center on Addiction and Substance Abuse at Columbia University 2003). Ninety-two percent of DTAP's graduates are employed (versus 26% in the year prior to arrest). Two years after leaving the program, DTAP participants had lower re-arrest, reconviction, and returnto-prison rates than a matched comparison group had 2 years after leaving prison. DTAP's costs for residential drug treatment, vocational training, and other services were about 50% of the cost of imprisoning the offender (National Center on Addiction and Substance Abuse at Columbia University 2003). Although DTAP is a highly successful model, full realization of the potential of the probation and parole systems to offer surveillance, monitoring, and contingencies for treatment will require considerable investment in substance abuse training for probation and parole officers and immediate access to comprehensive treatment services that can also address issues of poverty, employment, health, and drug-free housing (National Center on Addiction and Substance Abuse at Columbia University 1998).

Civil commitment Thirty-one states and the District of Columbia have statutes allowing the civil commitment of individuals with serious substance-related disorders. Other states permit commitment for substance-related disorders under mental health commitment laws. However, these procedures are not widely utilized, partly because insurance plans usually do not cover court-ordered treatment (Nace et al. 2007). Olson et al. (1997) found an overall positive outcome in 21 of 38 veterans civilly committed for substance abuse treatment in Minnesota. Most were committed initially to residential treatment, and the duration of commitment averaged 6 months. Beane and Beck (1991) found that in Massachusetts in 1989, judges frequently initiated civil commitment as an alternative to criminal prosecution for low-level crimes related to drug abuse, even though the statute did not authorize judicial initiation. This seems to have been an attempt to solve the problem of overcrowding of courts, jails, and prisons that led to the development of drug courts at the same time. In Colorado, we have found civil commitment procedures clinically useful as an intervention mechanism for concerned families: this extricates them from enabling positions and allows them to apply appropriate therapeutic pressure to a substance-abusing relative (J. I. Ritvo, personal observations, 1989–2007).

NON-HOSPITAL-BASED SERVICES The 1990s saw a major change in the chemical dependence treatment paradigm. In the 1980s, the Minnesota Model of 28-day residential treatment followed by aftercare and participation in Alcoholics Anonymous was standard and was supported by generous insurance coverage of inpatient treatment. The pressure to provide less costly, less restrictive treatment led to increased interest in community-based (as opposed to hospital-based) treatment and led to limiting inpatient and intensive residential (Minnesota Model) treatment to cases involving more severe complications or in which "life is in danger or other forms of treatment have failed" (Book et al. 1995). The new standard promoted individualized treatment determined through the matching of a patient's biopsychosocial needs to a continuum of levels of care and a spectrum of specific services (Gastfriend and McLellan 1997). In this section we discuss the portion of the continuum of care that is based in the community. (Other community-based treatment settings and modalities are discussed in Chapter 32, "Therapeutic Communities," and Chapters 34, 35, and 36 of this volume, "Psychological Mechanisms in Alcoholics Anonymous," "The History of Alcoholics Anonymous and the Experiences of Patients," and "Outcome Research on 12-Step and Other Self-Help Programs.")

Day Hospital and Intensive Outpatient Services Day or partial hospital programs evolved from inpatient programs through the subtraction of the costly overnight residential component. In the 1980s, comparisons of day and inpatient programs for alcoholic patients who were physically and psychiatrically stable demonstrated equivalent outcomes and a 50% cost savings for day programs (Longabaugh et al. 1983; McLachlan and Stein 1982). With cocainedependent patients, day programs have had more difficulty with retention in early treatment, whereas

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inpatient programs have had more difficulty with the transition to aftercare. The net result is equivalent outcomes at 6–7 months (Alterman et al. 1994; Schneider et al. 1996). Two factors—the intense cue reactivity associated with cocaine use and the lack of an aversive pharmacotherapy such as disulfiram—may explain why community-based settings are more problematic for the cocainedependent patient than for the alcohol-dependent patient. Wallace and Weeks (2004) evaluated a single VA substance abuse intensive outpatient program (IOP). Graduation from the program required attending 20 four-hour sessions (three to five sessions per week). At 6-month follow-up, treatment graduates were more likely to be abstinent and less likely to be incarcerated than were dropouts. In the year after treatment, the graduates used fewer psychiatric inpatient bed days in comparison with both program noncompleters and their own prior use. At 3 years, graduates had lower death rates. Alterman et al. (1994) compared the outcomes of 56 cocaine-dependent patients in the Philadelphia VA day hospital program with the outcomes of 55 patients undergoing 28-day inpatient treatment at another Pennsylvania VA hospital located 35 miles away in Coatesville. After 28 days of inpatient treatment at Coatesville, patients returned to the twice-weekly aftercare program of the Philadelphia VA day program. Although the inpatient program had better treatment retention than did the day hospital in the first 28 days, the difference between the groups largely disappeared when the inpatients returned to Philadelphia for aftercare. At 7 months, there was no difference in outcome. The distinction between intensive outpatient and day or partial hospital programs is not always precise. McKay et al. (1997) used the term intensive outpatient to refer to the 27-hours/week Philadelphia VA day program (described in the previous paragraph as a day hospital). Guidelines published by the American Society of Addiction Medicine (2001) require 9 hours/week of structured programming for IOPs and 20 hours/week for partial hospital programs, which are described as having more immediate access to medical and psychiatric services. McLellan et al. (1997) used a similar minimum criterion of 9 hours/week (three sessions per week) to define 10 intensive outpatient programs. They then compared these programs with 6 "traditional" outpatient programs that offered no more than two 2-hour sessions a week. All programs were non-hospital-based and were oriented toward abstinence. Patients in the intensive outpatient programs engaged in more severe substance use and had more social and health problems. They received more addiction-focused treatment but not more comprehensive services related to medical, employment, family, or social problems. After 6 months, patients in both kinds of programs showed notable improvement in substance use, personal health, and social functioning. These research findings should prompt referring clinicians to examine individual intensive outpatient programs before assuming that they are intensive in terms of providing comprehensive services. Day or partial hospital programs may better serve patients who have a substantial need for comprehensive services. Intensive outpatient programs, which frequently have evening schedules, may better serve patients for whom continued employment or attendance at school is important during treatment.

Community Residential Treatment Facilities Community residential facilities (CRFs), often called halfway houses, typically receive patients from inpatient treatment or detoxification services. Patients may be referred to CRFs because they are not yet ready for independent living, because they need the supervision and support of a living environment committed to sobriety, and/or because they are homeless. In general, CRFs can address both the residential and treatment needs of many substance-abusing individuals with limited sober social supports or limited sober housing resources. For one VA hospital, CRF placement improved involvement in aftercare for patients returning from out-of-town inpatient treatment (Hitchcock et al. 1995). Moos et al. (1995) studied the 127 CRFs receiving the most VA referrals in 1991. Facilities generally had a 12-step orientation and averaged 30 residents and a 42-day length of stay. Longer lengths of stay were associated with lower rates of readmission to inpatient facilities. CRFs vary considerably in the amount and nature of treatment they provide, ranging from limited

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counseling to highly structured programs. Moos et al. (1999) reported that CRFs offering structured, coherent treatment approaches had better retention and substance abuse outcomes than CRFs with an undifferentiated approach. No differences in retention or outcome were found among three types of treatment approach (therapeutic community, psychosocial rehabilitation, or 12-step programs). In a study of 2,376 CRFs, Forys et al. (2006) found that life skills training, 12-step groups, and enhancement of supportive relationships during CRF treatment were all related to healthier coping strategies after treatment and that these healthier strategies were associated with decreased alcohol and drug use and fewer drinking-associated problems. Patient characteristics affect participation and outcomes from CRF treatment. Moos and King (1997) found that motivation for treatment, psychological distress, prior involvement in self-help, and social resources predicted engagement in CRF services and positive outcomes postdischarge. Conversely, history of a psychiatric disorder and prior inpatient treatment were associated with diminished engagement. Independent of other factors, CRF treatment participation was associated with positive outcomes, such as program completion and finding a stable residence, and counteracted the negative predictive effects of other patient characteristics. Similarly, Ilgen et al. (2007) found that a patient's confidence in his or her ability to maintain abstinence was associated with positive outcomes and was not only related to a patient's pretreatment characteristics but also could be augmented by more engagement in skills training activities during CRF treatment. Age was not related to treatment outcomes (Lemke and Moos 2003).

Detoxification Centers The Uniform Alcoholism and Intoxication Treatment Act promulgated by the National Conference of Commissioners on Uniform State Laws in 1971 sought to replace the criminal justice solution to public drunkenness with medical alternatives. Persons incapacitated by alcohol were to be taken home or to health care or treatment facilities instead of being arrested and held in "drunk tanks." By 1980, more than half of the states had implemented major provisions of the act (Finn 1985). This legislation led to the development of detoxification centers as a medical alternative to jail. Detoxification centers developed according to two major models, medical and nonmedical/social; the latter relied on rest, comfort, and support, with minimal use of medication or medical examination and supervision (Whitfield et al. 1978). The social model initially predominated because of its low cost and the refusal of some hospitals to provide detoxification services (Finn 1985). Over time, the distinctions between the two models blurred. As benzodiazepine therapy became the standard treatment for alcohol withdrawal, some nonmedical detoxification centers were medicalized, adopting protocols whereby nurses could administer benzodiazepines. Although the Uniform Alcoholism and Intoxication Treatment Act encouraged voluntary, community-based treatment through a continuum of services, Finn (1985) concluded that it did little to rehabilitate the so-called skid row alcoholic and that it replaced one revolving door with another. The detoxification center is certainly more hospitable and humane than the "drunk tank," but it does little to address the conditions that perpetuate the problem, such as inadequate shelter, poverty, and vocational and social handicaps. In the 1990s the demographics of detoxification centers shifted away from a predominance of older, white, male alcoholic persons to include more minorities, women, and heroin and cocaine addicts (McCarty et al. 2000). Outpatient alcohol detoxification is addressed in Chapter 9, "Clinical Management of Alcohol Abuse and Dependence," in this volume.

Case Management Case management developed from traditional social casework and emerged as a professional service in the 1970s to help connect clients who had multiple needs with increasingly complex social service delivery systems (Monchick et al. 2006). The goals of case management are to ensure continuity of care and to integrate other functions of the treatment system (Institute of Medicine 1990). Table 33–5 lists a range of case management activities, and Table 33–6 lists persons who may perform case management

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functions. Community institutions that perform case management functions for substance abusers include drug courts, EAPs, and physician health programs (discussed in Chapter 43 of this volume, "Substance Use Disorders Among Physicians") and similar programs for dentists, nurses, and other health professionals. Multiple factors help determine whether patients will require case management to achieve optimal therapeutic results. On the patient's side, these factors include motivation or resistance, experience, knowledge, intelligence, socioeconomic status, housing status, and other internal and external resources or deficits. On the system's side, relevant variables include the complexity of the system, the accessibility of the relevant components, and how well the components are integrated with one another and match the patient's needs. Perhaps the most important factor is the need for an individualized, caring, long-term relationship that may not be met elsewhere in treatment. Given the variations in the types of case management and in the settings, populations, and systems in which they are applied, it is not surprising that the literature on the efficacy of case management for substance-abusing patients is inconsistent. Monchick et al. (2006) considered case management the essential framework of the drug court process because drug court teams are highly complex systems that bring together "judges, clinicians, defense attorneys, prosecutors, program coordinators, probation officers, police officers, vocational rehabilitation counselors, housing and education officials and other treatment and justice representatives who provide important services in facilitating a participant's recovery" (p. 1). Case management "is the force that holds the varied and many drug court elements together, ensuring that: 1) clients are linked to relevant and effective services; 2) all service efforts are monitored, connected, and in synchrony; and 3) pertinent information gathered during assessment and monitoring is provided to the entire drug court team in real time" (p. ix). The most intensive case management approaches have been used in the treatment of substance abusers with severe and chronic mental illness (i.e., the dually diagnosed). Assertive community treatment (ACT) was originally developed to manage the severe and chronically mentally ill in the community. Table 33–7 lists standard features of ACT. ACT intensive case management teams that integrate mental health and substance abuse counseling and services through the same staff and also use stepwise motivational approaches to substance abuse have shown better treatment retention and better long-term outcomes than have either short-term intensive dual-diagnosis programs or programs that provide mental health and substance abuse treatment and services separately (Drake et al. 1998). Management of disability funds by a payee (as discussed earlier) can be readily integrated into the ACT model. Case management approaches less intensive than ACT have been effective in engaging and helping substance-abusing individuals who are not seeking treatment. Rhodes and Gross (1997) found that noncoerced case management offered to arrestees who were using illicit drugs other than marijuana decreased drug use and recidivism and increased use of substance abuse treatment. It is noteworthy that this study attributed its case management effect more to the personalized, supportive relationships it provided than to referral activity. Other evaluations of case management for substance-abusing patients have shown mixed results, with some indication that case management services may be most valuable for indigent, substance-abusing patients who need housing. A survey of a nationally representative sample of drug treatment programs found that case management services did correlate with utilization of housing assistance and financial services (Friedmann et al. 2000). However, in this survey, transportation and on-site location of ancillary services were more important than case management as correlates of ancillary service utilization. A positive outcome was found in a study of the "chronic public inebriates" who were the most frequent users of the King County Detoxification Center (Seattle, Washington). In this study, intensive outreach-oriented case management improved financial and residential stability and reduced alcohol and detoxification center admissions in this "revolving door" population (Cox et al. 1998). However, for

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homeless, substance-abusing persons seeking treatment, less intensive case management approaches that are more office based, more time limited, and more directed toward arranging rather than directly providing services have not demonstrated a differential effect on substance abuse outcome (Braucht et al. 1995; Stahler 1995; Stahler et al. 1995).

CONCLUSION In this chapter, we reviewed substance abuse identification and intervention in a variety of community settings and examined both the community-based portion of the continuum of levels of care and the case management approaches that serve to integrate the complex treatment system for the individual patient. We described instances, such as in drug courts and child protective services, in which the relationship between community institutions and treatment services has been fruitful. We highlighted promising brief interventions in primary and emergency care settings, colleges, and DWI programs, and we identified community institutions, such as the criminal justice system and public disability programs, in which much of the potential for community-based substance abuse treatment remains to be realized.

KEY POINTS Brief intervention has proved effective for reducing drinking and/or its consequences in primary care, emergency care, and college settings and with depressed first-time driving while intoxicated (DWI) offenders. Specialized programs for drug-abusing mothers improve outcomes such as treatment completion and maintenance of custody. The substance-abusing patient with chronic mental illness may be best managed by an assertive community treatment case management approach, with the case manager serving as payee for the patient's benefits. Treatment mandated through drug courts and through sentencing for DWI reduces recidivism in the criminal justice system. Treatment participation in community residential facilities and "graduation" from an intensive outpatient program predict positive outcome.

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SUGGESTED READING Cavaiola AA, Wuth C: Assessment and Treatment of the DWI Offender. New York, Haworth, 2002 Dill PL, Wells-Parker E: Court-mandated treatment for convicted drinking drivers. Alcohol Res Health 29:41–48, 2006. Hon J: Employee Assistance Programs: Workplace Opportunities for Intervening in Alcohol Problems. Washington, DC, The George Washington University Medical Center, 2003. Available at http://www.ensuringsolutions.org/usr_doc/Primer5_EAPs.pdf. Accessed February 26, 2007. Huddleston CW, Freeman-Wilson K, Marlowe DB, et al: Painting the Current Picture: A National Report Card on Drug Courts and Other Problem Solving Courts in the United States. Alexandria, VA, National Drug Court Institute, 2005. Available at http://www.ndci.org/publications/10697_PaintPict_fnl4.pdf. Accessed March 2, 2007. Monchick R, Scheyett A, Pfeifer J: Drug Court Case Management: Role, Function, and Utility. National

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Drug Court Institute, 2006. Available at http://www.ojp.usdoj.gov/BJA/pdf /Drug_Court_Case_Management.pdf. Accessed March 2, 2007. Nace EP, Birkmayer F, Sullivan MA, et al: Socially sanctioned coercion mechanisms for addiction treatment. Am J Addict 16:15–23, 2007 Ridgely MS, Willenbring ML: Application of case management to drug abuse treatment: overview of models and research issues. NIDA Res Monogr 127:12–33, 1992. Available at http://www.nida.nih.gov.ezproxy2.library.usyd.edu.au/pdf/monographs/127.pdf. Accessed March 2, 2007. U.S. Government Accountability Office: Adult Drug Courts: Evidence Indicates Recidivism Reductions and Mixed Results for Other Outcomes (GAO-05-219). Washington, DC, U.S. Government Accountability Office, 2005. Available at http://www.gao.gov/new.items/d05219.pdf. Accessed February 26, 2007. Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 34. Psychological Mechanisms in Alcoholics Anonymous

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J. Scott Tonigan, Gerard J. Connors: Chapter 34. Psychological Mechanisms in Alcohol ics Anonymous, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.354343. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Psychological Mechanisms in Alcoholics Anonymous J. Scott Tonigan, Ph.D. Gerard J. Connors, Ph.D.

PSYCHOLOGICAL MECHANISMS IN ALCOHOLICS ANONYMOUS: INTRODUCTION Alcoholics Anonymous (AA) is the most popular self-help program for alcohol-related problems, and 12-step therapy, based on AA doctrine and practice, is the prevailing alcohol treatment model in the United States (Morgenstern et al. 2002). Studies of 12-step therapy indicate that it is as effective as therapies that are more research supported, such as cognitive-behavioral approaches, and that it may actually be superior when total abstinence is the goal (Ouimette et al. 1997; Project MATCH Research Group 1997, 1998). A primary objective of 12-step therapy is to facilitate AA participation, and evidence suggests that this aim contributes to its overall success (e.g., Moos and Moos 2005; Tonigan 2005). To date, significant gains have been made both in identifying the individual characteristics predictive of AA affiliation (e.g., Emrick et al. 1993; Tonigan et al. 1996, 2006) and in developing effective clinical strategies to promote AA affiliation (e.g., Nowinski 2006; Nowinski et al. 1992). Furthermore, we now have a clearer picture regarding the nature and magnitude of benefits associated with AA attendance (e.g., Gossop et al. 2003; Kelly et al. 2006; Tonigan 2001). Understandably, then, high priority now has been assigned to investigation of what actually occurs in AA, with a special focus on identifying how prescribed AA behaviors and beliefs mobilize drinking reduction. This chapter focuses on the psychological mechanisms explaining how and why AA is beneficial for many substance abusers. Our goal is to provide readers with an evidence-based review of what is currently understood about AA-related change and to highlight some associated clinical recommendations. Early efforts to understand AA-related behavior change can be traced as far back as a paper delivered in 1943 by Dr. Harry Tiebout at the annual meeting of the American Psychiatric Association (Tiebout 1943). Based on case studies, Dr. Tiebout concluded that the spiritual experience sought by AA members countered the extreme egotism of alcoholic persons. According to Dr. Tiebout, ego reduction was essential to eliminating problematic drinking and, as such, was the pivotal psychological process in AA to mobilize to recovery from alcoholism. Today, clear themes explaining how AA-related change occurs have begun to emerge in the empirical literature, often based on large clinical samples in rigorous longitudinal studies. Interestingly, several of these psychological processes are counterintuitive to AA prescriptions about powerlessness over alcohol and the role of spirituality in recovery from addiction. At the outset it is important to acknowledge that a large body of research has investigated the social and environmental mechanisms that contribute to AA-related benefit. This includes findings that go beyond the scope of this chapter. There is strong evidence, for example, that AA contributes to the establishment of a social network that is supportive of abstinence (Humphreys and Noke 1997) and that this support can be more effective in helping the substance abuser than may be the support that is offered by concerned family members and friends (Kaskutas et al. 2002). Although these investigations direct attention to valuable external mechanisms in AA that contribute to remission of substance abuse, they offer little insight into the internalized processes that occur in response to AA participation and the role such psychological processes play in sustaining improved functioning. This chapter addresses this gap, and it does so in three sections. The first section provides the analytical perspective necessary to conceptualize psychological mechanisms of change and highlights the importance of context when judging the empirical literature. The second section identifies and discusses the primary psychological mechanisms that have been evaluated in AA-related research. Finally, the third section offers practical recommendations to practitioners who are interested in effectively engaging substance abusers in 12-step programs.

DEFINITIONS AND CONTEXT FOR UNDERSTANDING AA-RELATED 1 of 9

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PSYCHOLOGICAL PROCESSES A large body of literature has documented how specific AA-prescribed behaviors and beliefs predict later improvement. It is relatively clear, for instance, that acquiring a mentor or sponsor in AA as a guide to lead one through the 12 steps is predictive of increased abstinence (Emrick et al. 1993) and reduction in drinking intensity (Pagano et al. 2004). Also clear, however, is that the act of acquiring a sponsor does not, in itself, increase abstinence. For this particular example, the focus of this chapter is on what occurs within the individual who has acquired and nurtured a relationship with a sponsor that explains reductions in substance use. As displayed in Figure 34–1, four conditions must be met before declaring that a psychological process explains why a prescribed behavior produces a desired outcome. Thus the declaration that a psychological process is both catalyzed by prescribed AA behaviors and in turn accounts for later improvement must follow these analytical guidelines, initially described by Baron and Kenny (1986) and later elaborated upon by De Los Reyes and Kazdin (2006). Careful review of these criteria is important, with an additional requirement (not explicit in the figure) that the measurement of the three constructs be temporally arranged in order to infer causality (e.g., behavior occurs at time 1, psychological process at time 2, and outcome at time 3). FIGURE 34–1. Four conditions to establish statistical mediation in identifying processes of psychological change.

Note. AA = Alcoholics Anonymous. The context for studying AA-related psychological processes is as important as how one conceptualizes and then establishes the presence of curative psychological processes. In general, AA-related psychological processes have been studied in three contexts, each having particular strengths and weaknesses. On the one hand, 12-step–specific psychological processes have been investigated within the narrow context of therapy, often manual-guided 12-step therapy. Here, the manipulation and fidelity of therapist behaviors to mobilize AA-specific cognitions are carefully monitored, and desired changes in patient cognitions are reliably and temporally arranged to predict later substance use behavior. Although it has strong internal validity, this approach may lack ecological validity, stemming from a host of factors, including contrived settings not reflecting community-based AA. On the other hand, a few single-group, naturalistic longitudinal studies of AA-related processes are now under way that, although high in ecological validity, may fail to control for threats to internal validity, such as participant self-selection and attrition. Finally, investigators have applied a hybrid model in which interest focuses on posttreatment AA-related experiences of a treatment-seeking sample. These investigations can involve 8- and 10-year follow-up interviews, and they benefit from extensive assessment batteries from the parent clinical studies. Participants recruited into these randomized clinical trials, however, may differ systematically from substance abusers who refuse participation or directly enter AA without the aid of formal treatment. Ultimately, the reader is cautioned to place and judge findings

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within the context from which they are generated, paying careful attention to the limitations of each model.

SPECIFIC PSYCHOLOGICAL MECHANISMS Cognitive-Based Psychological Processes Several studies have investigated "AA-specific" cognitive psychological mechanisms in 12-step therapy, arguably replicating the mechanisms of change in community-based AA. Morgenstern et al. (2002), for example, investigated how effectively 12-step therapy promoted desired changes in 12-step cognitions by patients (N = 370) and, in turn, how these shifts in attitudes and beliefs predicted drinking at discharge and at 6- and 12-month follow-up. Somewhat unexpectedly, at intake patient endorsement of 12-step cognitions such as commitment to AA and abstinence, disease attribution, and a belief in powerlessness over alcohol (e.g., loss of control) was already high, with most patients already "in agreement" with these prescriptions. Nevertheless, significant gains in these beliefs and attitudes were achieved during treatment, although, in general, these gains faded during the follow-up phase of the study. Several 12-step cognitions at treatment discharge did not predict 12-month abstinence, including powerlessness over alcohol, belief in a higher power, and disease attribution. Commitment to AA and to abstinence, however, significantly predicted increased abstinence at both 6- and 12-month follow-up. As noted by Morgenstern et al. (2002), commitment to abstinence is not unique to 12-step therapy, and AA referral across different kinds of therapy is common (Humphreys and Noke 1997). In this light, it is unclear whether 12-step specific cognitions (or more general and shared psychological mechanisms) accounted for later abstinence. I also investigated 12-step emphasis on abstinence and how such emphasis may explain AA-related benefit (Tonigan 2005). This investigation was made in the context of Project MATCH, which was a large (N = 1,726), randomized clinical trial that investigated whether different types of patients fared better in different types of alcoholism treatment, in this case motivational enhancement therapy (MET), cognitive-behavioral therapy (CBT), and 12-step facilitation therapy (TSF). Based on videotapes of client–therapist sessions, I reported that TSF therapists endorsed the goal of abstinence significantly more than either CBT or MET therapists (Tonigan 2005). In turn, at week 2 of therapy, TSF clients reported significantly higher endorsement of treatment goals relative to CBT and MET clients, suggesting agreement with the goal of total abstinence. Although TSF clients reported significantly higher rates of abstinence at 12-month follow-up than did CBT and MET clients, I did not find that endorsement of abstinence among TSF patients accounted for this advantage. It appears, then, that although 12-step therapy differentially endorses the goal of abstinence, this increased emphasis did not produce or account for higher rates of abstinence among substance abusers receiving 12-step therapy. Finney et al. (1998) investigated desired cognitive shifts among patients in 12-step therapy (n = 970) relative to changes in patient cognitions in eclectic (n = 1,067) and cognitive-behavioral (n = 1,191) therapies in a Veterans Affairs hospital population. Like me, Finney's group found significantly larger gains in endorsement of the disease model of alcoholism, alcoholic identity, and the goal of abstinence among veterans receiving 12-step therapy. Unexpectedly, no difference in cognitive shifts specific to CBT were reported by veterans receiving 12-step and cognitive-behavioral therapies. Here, all patients reported at discharge significant and relatively equal increases in self-efficacy to remain abstinent and decreases in positive expectancies surrounding the use of substances. Although relationships between intended and unintended cognitive shifts and substance use were not investigated by these authors, for the first time with a comparison group the study raised the question of whether common, nonspecific therapeutic mechanisms operate in 12-step programs. A second contribution made by Finney et al. (1999) was their effort to identify the associations between 12-step cognitions and practices with more general and substance-specific coping strategies to increase abstinence. Based on the same veteran sample of substance abusers as in the 1998 study, for example, they found that 12-step cognitions (e.g., powerlessness over alcohol) and practices (e.g., AA meeting attendance) at treatment discharge were significantly and positively related to 1-year substance-specific coping strategies. These coping strategies included such cognitions as stimulus control (e.g., "I remove things from home that remind me of drinking"), counterconditioning (e.g., "Instead of drinking I engage in some physical activity"), and self-liberation (e.g., "I tell myself I can choose to drink or to not drink"). Notably, although 12-step cognitions and practices at treatment discharge were modestly and positively related with increased abstinence at 1-year follow-up, it was the general and substance-specific coping strategies that primarily

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accounted for 1-year abstinence rates. It appears then, that 12-step cognitions and practices may exert both a main and indirect effect on substance use behavior, with the indirect influences mobilizing powerful and well-understood coping mechanisms.

Confidence To Remain Abstinent Self-efficacy, or confidence to remain abstinent, is an important causal mechanism explaining substance use behavior change (e.g., Project MATCH Research Group 1997, 1998). To date, 11 studies have investigated AA exposure and abstinence self-efficacy, and one firm conclusion to be made is that 12-step members do experience increased self-efficacy to remain abstinent and that, in turn, such changes predict later drinking reduction. Table 34–1 provides the summary statistics derived from a meta-analysis combing the results of these 11 studies. As shown, rw summarizes the direction and magnitude of a relationship between two temporally ordered variables. We see, for example, that the relationship between AA exposure at time 1—typically measured as frequency of AA meeting attendance—and later self-efficacy measured at time 2 is positive and modest (rw = 0.21). Concordant with the larger substance abuse research literature we also see that, on average, the relationship between increased self-efficacy to remain abstinent and later abstinence is also positive and of a moderate magnitude (rw = 0.33). Outwardly, self-efficacy to remain abstinent and self-control over alcohol would appear to be positively associated and at odds with AA prescriptions about powerlessness over alcohol. Unfortunately, the factors accounting for increased self-efficacy among AA-exposed individuals are unclear and have yet to be empirically investigated. Parsimoniously, it may simply be the case that with increases in the duration of abstinence, one gains confidence in remaining abstinent in the future. Alternatively, specific yet unidentified AA-prescribed behaviors may contribute to or account for increased self-efficacy. Current speculation is that increased self-efficacy and powerlessness over alcohol may be reconciled by AA members by acknowledging a loss of control after taking the first drink of alcohol but having some personal control or responsibility in taking the first drink. Closely associated with confidence to avoid drinking is the construct of readiness or motivation not to drink. Surprisingly, few studies have investigated how AA attendance and engagement may mobilize and sustain motivation for abstinence in spite of the centrality of motivation for drinking reduction. In a unique study of adolescent substance abusers and AA, Kelly et al. (2006) investigated how several measures of AA exposure and reductions in substance use were mediated by abstinence-focused coping, self-efficacy, and motivation for abstinence. Kelly and colleagues found that higher rates of AA meeting attendance (during treatment) were associated with higher levels of motivation to be abstinent (at treatment discharge). Consistent with the adult research, the authors also reported that frequency of AA meeting attendance predicted higher self-efficacy to remain abstinent.

Spirituality The core AA literature (Alcoholics Anonymous 1981, 2001) posits that as a result of working the 12 steps one will have a spiritual awakening and that continued practice of spiritual principles will lead to sustained abstinence. This is a clear and direct statement that spirituality mediates AA involvement and later abstinence. Given the centrality of spirituality to AA, however, it is surprising how little systematic attention has been paid to the spiritual development of AA members and how, if at all, such psychological processes relate to prescribed AA practices and may explain improved functioning. In a series of three studies, for instance, spirituality was uniformly discussed in mainstream AA meetings regardless of differences in perceived AA group social dynamics (Horstmann and Tonigan 2000; Montgomery et al. 1993; Tonigan et al. 1995). In each of these studies, spirituality was defined using items asking to what extent God, spirituality, or a higher power was discussed in meetings and to what extent prayer and meditation were discussed. Some have adopted a commonsense approach for documenting the presence of spiritual content in AA meetings by simply asking individuals about the extent they feel affected by it. In Project MATCH, for example, 27.6% (n = 108) of the outpatient clients who attended AA during the 12 weeks of treatment (N = 391) also reported having had a spiritual awakening as a result of their AA attendance. In the aftercare sample, 74% reported attending some AA during treatment (569 clients), of which 29.3% (n = 167) reported a spiritual awakening in connection to AA attendance (Connors et al. 2001). Strong evidence across diverse measures of religiousness and spirituality documents spiritual increases among AA members. It is uncertain,

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however, whether these changes are specific to AA-exposed individuals or simply reflect maturation processes and are secondary and unintended consequences of achieving abstinence (for those with or without AA attendance). Figure 34–2 depicts self-reported God consciousness and formal religious practices (Connors et al. 1996) among three groups of AA-exposed individuals in Project MATCH over the course of 10 years (Tonigan 2003). The no-AA group showed maturation and associated increases in spirituality, but consistent AA attendance over 10 years was associated with significantly higher rates of formal religious practices (e.g., church attendance) and higher God consciousness relative to those who disaffiliated with AA or who never attended AA. It is reasonably clear, therefore, that spirituality is widely discussed in AA meetings and that exposure to AA is associated with increased spirituality, increases that are larger than those expected by maturation or the alleviation of substance abuse problems. FIGURE 34–2. Comparison of three Alcoholics Anonymous (AA)–exposed groups of treatmentseeking individuals on religious practices and God consciousness over a 10-year period.

Source. From Connors et al. 1996. Evidence is mixed at best about the utility of changes in spirituality in predicting later reductions in substance use. Discounting cross-sectional studies on spirituality and substance use because of irretraceable problems with self-selection, the weight of 17 prospective studies suggests that spirituality is only negligibly related with later abstinence. In particular, combining the estimates of the predictive utility of spirituality on later frequency of abstinent days across 17 studies, we found a correlation of r = 0.09 (standard deviation = 0.06), which in essence accounted for less than 1% of the variance in substance use. Thus, although religiousness and spirituality appear to serve as a protective factor against the development of substance use—and in spite of the centrality of spiritual growth in AA's self-described program of recovery—we find little support at this time for suggesting that such changes among AA members account for later reductions in substance use.

CLINICAL RECOMMENDATIONS Knowledge regarding the benefits associated with involvement in AA and the mechanisms by which these benefits occur has increased markedly over the past 20 years. Although there is still much to be further explored and learned, we nevertheless are in a position to offer several recommendations to practitioners that may be applicable to the conduct of their clinical practice. As a foundation, practitioners should be familiar with the core AA literature and should experience firsthand the environment and fellowship of AA by attending several meetings. In terms of core AA literature, probably the most relevant text is Alcoholics Anonymous (Alcoholics Anonymous 2001) and commonly referred to as the "big book." The volume is freely accessible online at the AA Web site (http://www.alcoholicsanonymous.org). Another relevant publication is Twelve Steps and Twelve Traditions (Alcoholics Anonymous 1981), which details the principles through which members recover and the fellowship of AA functions.

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Beyond reading these educational materials, we recommend that practitioners also attend several AA meetings, ideally in different locations so as to observe how home groups can vary in both context and culture. AA groups typically hold open and closed groups, with all interested individuals welcome at open groups. Attendance at open AA groups will expose the clinician to the experiences and beliefs described by members of AA. Taken together, the written materials of AA and attendance at meetings will better position the practitioner to describe and facilitate patient exposure to AA and to understand more fully patients' perceptions of AA meetings both before and after actual attendance. We further recommend that clinicians routinely assess at intake patients' prior experiences with self-help groups. A significant proportion of patients seeking clinical services for alcohol and other substance abuse have previously attended self-help groups. Most commonly, such attendance will have been at AA meetings. Patients may recall positive, negative, or mixed experiences. Patients with positive or mostly positive previous experiences may be particularly good candidates for reviving such involvement. For those with negative or fewer positive experiences, gathering information on those experiences, particularly in the context of the person's situation at that previous point in time, will be central to evaluation of whether, how, and to what extent subsequent attendance might now be recommended or encouraged. For patients holding negative perceptions of self-help groups independent of any actual previous self-help group experience, it often is helpful to negotiate attendance at several meetings (perhaps four or five) in order to obtain that experience or to reassess such involvement. It will be of benefit to practitioners to remain current on knowledge regarding AA and other self-help groups. The association of 12-step participation and positive drinking-related outcomes has long been recognized and documented, mostly based on correlational research. This association has been found among AA members not involved in other forms of treatment and among patients attending AA adjunctive to professional treatment. Recent research, including that reviewed in this chapter, has provided some insights into processes that may account for the changes observed among individuals involved in AA. As an example, it appears that the social support for abstinence provided in AA plays an important contributory role in achieving and maintaining alcohol abstinence. Research on psychological processes reviewed in this chapter has indicated a positive relationship between AA participation and increased efficacy to remain abstinent, which in turn is associated with better outcomes. Such relationships will position practitioners to outline for patients some of the ways self-help groups appear to help people recover from substance use disorders. There also may be opportunities in the future to align or complement focus on mechanisms of change that operate in treatment and those in self-help groups. Finally, practitioners may wish to consider different options, as warranted, for facilitating the patient's actual getting to AA. Some patients may be readily poised to attend and follow through with attendance. Other patients may need more encouragement or in some cases practical assistance in getting connected to AA. This has led to the development of several helpful clinical strategies that entail arranging for a current AA member to speak with the patient and arrange to bring the patient to the meeting or to meet the patient at the meeting to guide him or her through the meeting process.

CONCLUSION There is a firm empirical foundation indicating the nature and magnitude of benefits associated with AA participation. At present, there is increasing focus on study of what actually occurs in AA and the impact of prescribed AA behaviors and beliefs on changes in drinking behavior. A major component of these efforts is study of the psychological processes of AA-related change, including cognitive-based psychological processes (e.g., endorsement of 12-step cognitions such as commitment to AA and to abstinence; adoption of an alcoholic identity), confidence to remain abstinent, motivation, and spirituality. This line of research has considerable potential for explicating those psychological factors with greatest relevance to process and outcome evaluation of AA and of 12-step programs. Commitment to, and practice of, AA-prescribed behaviors and beliefs involves more than just attending AA meetings. Although evidence indicates that engagement in AA is a stronger predictor of positive outcome than mere AA attendance (e.g., Montgomery et al. 1993), less is known about which specific prescribed behaviors catalyze therapeutic psychological mechanisms described in this chapter. At this time, therefore, we believe that it is prudent for clinicians to encourage patients to become committed to AA practices that encompass both AA program and fellowship domains.

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KEY POINTS Alcoholics Anonymous (AA) is the most popular self-help program for alcohol-related problems. Much is known about the nature and magnitude of benefits associated with participation in AA attendance and participation, and researchers are focusing now on identifying and understanding the mechanisms of AA behavior. AA participation is associated with increases in self-efficacy, which is a consistent predictor of subsequent clinical improvement. Spirituality is a cornerstone of the philosophy and practice of AA, and many AA-exposed individuals report increases in their religious beliefs and practices. However, the evidence is mixed on the importance of such changes for later abstinence. It is important that practitioners be familiar with the core AA literature and experience the environment and fellowship of AA by attending several meetings. In the clinical setting, practitioners should routinely assess patients’ prior experiences with AA and/or other self-help groups, which will be helpful in determining whether, how, and to what extent subsequent attendance can or should be recommended, encouraged, and/or facilitated.

REFERENCES Alcoholics Anonymous: Twelve Steps and Twelve Traditions. New York, Alcoholics Anonymous World Services, 1981 Alcoholics Anonymous: Alcoholics Anonymous, 4th Edition. New York, Alcoholics Anonymous World Services, 2001 Baron RM, Kenny DA: The moderator–mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. J Pers Soc Psychol 51:1173–1182, 1986 [PubMed] Connors G, Tonigan JS, Miller WR: The Religious Background and Behavior instrument: psychometric and normed findings. Psychol Addict Behav 10:90–96, 1996 Connors G, Tonigan JS, Miller WR: Religiosity and responsiveness to alcoholism treatments: matching findings and causal chain analyses, in Project MATCH: A Priori Matching Hypotheses, Results and Mediating Mechanisms. Edited by Longabaugh R, Wirth PW. Rockville, MD, U.S. Government Printing Office, 2001, pp 166–175 De Los Reyes A, Kazdin AE: Conceptualizing changes in behavior in intervention research: the range of possible changes model. Psychol Rev 11:554–583, 2006 Emrick CD, Tonigan JS, Montgomery HA, et al: Alcoholics Anonymous: what is currently known? in Research on Alcoholics Anonymous: Opportunities and Alternatives. Edited by McCrady BS, Miller WR. New Brunswick, NJ, Rutgers Center on Alcohol Studies, 1993, pp 41–76 Finney JW, Noyes CA, Coutts AI: Evaluating substance abuse treatment process models, I: changes on proximal outcome variables during 12-step and cognitive behavioral treatment. J Stud Alcohol 59:371–380, 1998 [PubMed] Finney JW, Moos RH, Humphreys K: A comparative evaluation of substance abuse treatment, II: linking proximal outcomes of 12-step and cognitive behavioral treatment to substance use outcomes. Alcohol Clin Exp Res 23:537–544, 1999 [PubMed] Forcehimes A, Tonigan JS: Self-efficacy to remain abstinent and substance abuse: a meta-analysis. Alcohol Treat Q, in press Gossop M, Harris J, Best D: Is attendance at Alcoholics Anonymous meetings after inpatient treatment related to improved outcomes? a 6-month follow-up study. Alcohol Alcohol 38:421–426, 2003 [PubMed] Horstmann MJ, Tonigan JS: Faith development in Alcoholics Anonymous: a study of two AA groups. Alcohol Treat Q 18:75–84, 2000 Humphreys K, Noke JM: The influence of posttreatment mutual help group participation on the friendship

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networks of substance abuse patients. Am J Community Psychol 25:1–16, 1997 [PubMed] Kaskutas LA, Bond J, Humphreys K: Social networks as mediators of the effect of Alcoholics Anonymous. Addiction 97:891–900, 2002 [PubMed] Kelly JF, Stout R, Zywiak W, et al: A 3-year study of addiction mutual-help group participation following intensive outpatient treatment. Alcohol Clin Exp Res 30:1381–1392, 2006 [PubMed] Montgomery HA, Miller WR, Tonigan JS: Differences among AA groups: implications for research. J Stud Alcohol 54:502–504, 1993 [PubMed] Moos RH, Moos BS: Sixteen-year changes and stable remission among treated and untreated individuals with alcohol disorders. Drug Alcohol Depend 80:337–347, 2005 [PubMed] Morgenstern J, Bux D, Labouvie E, et al: Examining mechanisms of action in 12-step treatment: the role of 12-Step cognitions. J Stud Alcohol 63:665–672, 2002 [PubMed] Nowinski J: The Twelve Step Facilitation Outpatient Program. Center City, MN, Hazelden Press, 2006 Nowinski J, Baker S, Carroll K: Twelve Step Facilitation Therapy Manual: A Clinical Research Guide for Therapists Treating Individuals With Alcohol Abuse and Dependence (DHHS Publ No ADM-92-1893). Washington, DC, NIAAA Project MATCH Monograph 1, Department of Health and Human Services, 1992 Ouimette PC, Finney JW, Moos RH: Twelve-step and cognitive-behavioral treatment for substance abuse: a comparison of treatment effectiveness. J Consult Clin Psychol 65:230–240, 1997 [PubMed] Pagano ME, Friend KB, Tonigan JS, et al: Sponsoring others in Alcoholics Anonymous and avoiding a drink in the first year following treatment: findings from Project MATCH. J Stud Alcohol 65:766–773, 2004 [PubMed] Project MATCH Research Group: Matching alcoholism treatments to client heterogeneity: Project MATCH posttreatment drinking outcomes. J Stud Alcohol 58:7–29, 1997 Project MATCH Research Group: Matching alcoholism treatments to client heterogeneity: Project MATCH three-year drinking outcomes. Alcohol Clin Exp Res 22:1300–1311, 1998 Tiebout HM: Therapeutic mechanisms of Alcoholics Anonymous. Presented at the 99th annual meeting of the American Psychiatric Association, Detroit, MI, May 1943 Tonigan JS: Benefits of Alcoholics Anonymous attendance: replication of findings between clinical research sites in Project MATCH. Alcohol Treat Q 19:67–78, 2001 Tonigan JS: Spirituality and AA practices three and ten years after Project MATCH (abstract). Alcohol Clin Exp Res 26(suppl):660A, 2003 Tonigan JS: Examination of the active ingredients of twelve-step facilitation (TSF) in the Project MATCH outpatient sample. Alcohol Clin Exp Res 29:240–241, 2005 Tonigan JS, Ashcroft F, Miller WR: AA group dynamics and 12-step activity. J Stud Alcohol 56:616–621, 1995 [PubMed] Tonigan JS, Toscova R, Miller WR: Meta-analysis of the Alcoholics Anonymous literature: sample and study characteristics moderate findings. J Stud Alcohol 57:65–72, 1996 [PubMed] Tonigan JS, Bogenschutz MP, Miller WR: Is alcoholism typology a predictor of both Alcoholics Anonymous affiliation and disaffiliation after treatment? J Subst Abuse Treat 30:323–330, 2006 [PubMed]

SUGGESTED READING Alcoholics Anonymous: Twelve Steps and Twelve Traditions. New York, Alcoholics Anonymous World Services, 1981 Alcoholics Anonymous: Alcoholics Anonymous, 4th Edition. New York, Alcoholics Anonymous World Services, 2001 Emrick CD, Tonigan JS: Alcoholics Anonymous and other 12-step groups, in American Psychiatric Publishing Textbook of Substance Abuse Treatment, 3rd Edition. Edited by Galanter M, Kleber HD. Washington, DC,

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American Psychiatric Publishing, 2004 Emrick CD, Tonigan JS, Montgomery HA, et al: Alcoholics Anonymous: what is currently known? in Research on Alcoholics Anonymous: Opportunities and Alternatives. Edited by McCrady BS, Miller WR. New Brunswick, NJ, Rutgers Center on Alcohol Studies, 1993, pp 41–76 Morgenstern J, Bux D, Labouvie E, et al: Examining mechanisms of action in 12-step treatment: the role of 12-step cognitions. J Stud Alcohol 63:665–672, 2002 Tonigan JS: Examination of the active ingredients of twelve-step facilitation (TSF) in the Project MATCH outpatient sample. Alcohol Clin Exp Res 29:240–241, 2005 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 35. The History of Alcoholics Anonymous and the E...

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Edgar P. Nace: Chapter 35. The History of Alcoholics Anonymous and the Experiences of Patients, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.354487. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

The History of Alcoholics Anonymous and the Experiences of Patients Edgar P. Nace, M.D.

THE HISTORY OF ALCOHOLICS ANONYMOUS AND THE EXPERIENCES OF PATIENTS: INTRODUCTION On June 10, 1935, an Akron, Ohio, surgeon named Bob Smith took his last drink, a beer, to steady his nerves prior to performing surgery. This date is considered the founding date of Alcoholics Anonymous (AA; White 1998). Bob Smith and Bill Wilson, the cofounders of AA, had met in May 1935 in Akron. Bill, a New York stockbroker who was newly sober, was about to drink while on business in Akron. He desperately sought an Oxford Group meeting, realizing that he might stay sober if he had another alcoholic person to talk to. In the course of his search he was introduced to "Dr. Bob," a struggling alcoholic surgeon. Followers of AA and most students of alcoholism are familiar with the names Bill Wilson and Dr. Bob Smith. Their inauspicious yet fateful meeting in Ohio spawned the formation of the most successful grassroots self-help movement known. As this chapter demonstrates, however, this movement derived from processes that had been evolving for decades.

FORERUNNERS OF AA In 1840, nearly 100 years before the meeting of Bob Smith and Bill Wilson, six members of a drinking club in Baltimore, Maryland, inspired to turn from drink after attending a lecture on temperance, decided to quit their club and form what they would call the Washingtonian Total Abstinence Society. The men resolved to meet nightly, just as they previously had drunk nightly. These meetings involved sharing experiences. Drama was valued, and debates and formal speeches were avoided. Local alcoholic persons were encouraged to attend and to say a few words. Later, dues were assessed. The Washingtonians started with private meetings, but because of increasing public interest they began holding public meetings as well. Their slogan—"Let every man be present, and every man bring a man"—conveys the zeal this organization had for recruiting new members; they have since been described as "secular missionaries." They formed ward committees to recruit more alcoholic individuals and required that members sign a pledge of abstinence (Tyrell 1979). The Washingtonians, named after George Washington in honor of his character—and not the fact that he distilled liquor—grew at an impressive rate. Their numbers increased more rapidly in their first few years than did AA a century later. (In fact, by mid-1841, an organization for women was established, known as the Martha Washington Society [Maxwell 1950]; however, their momentum was not sustained.) Individuals who were not alcoholic could also attend the meetings, and soon they began to outnumber the alcoholic members. The message of the Washingtonians was carried largely by a few charismatic speakers who pursued their own independent agendas. Debates about alcohol prohibition divided the Washingtonians, and no central organizational structure was sustained (Maxwell 1950). By 1847 most Washingtonian societies had ceased to exist (White 1998). Nevertheless, the Washingtonian Total Abstinence Society laid the groundwork for several features that would eventually characterize AA: mutual self-help, sharing of the drinking experience and the recovery experience, focus on the welfare of the alcoholic person, the power of personal shared commitment to abstinence, and the use of religious and/or spiritual foundations for recovery.

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Fraternal temperance societies and reform clubs soon emerged. These organizations tended to emphasize anonymity and secrecy, which allowed alcoholic members to seek support without public acknowledgment. (The importance of anonymity would later be adopted by AA.) Some of these societies and clubs focused only on the reform of the alcoholic person, whereas others joined the political debate on prohibition. The Independent Order of Good Templars, founded in 1851, claimed to have 400,000 alcoholic persons in their membership by 1876, half of whom were purported to have kept their pledge of abstinence (Fahey 1996). These societies emphasized maintenance of sobriety, and breaks of abstinence could lead to expulsion. Some were racially integrated. Similar societies were formed for women. Reform clubs later overtook the fraternal temperance societies. These groups did not have restrictive membership, were less inclined to participate in prohibition issues, and were more informal. No particular religion was endorsed, but personal change was expected to include prayer and church attendance. Their ability to recruit members was impressive; 50,000 members were reported in Philadelphia, Pennsylvania, alone by 1870 (White 1998). By the turn of the twentieth century, a variety of mutual aid organizations had arisen to assist alcoholic persons who were willing to try to quit drinking. White (1998) described many of these groups, most of whose legacies have fallen into the cracks of social, religious, or medical histories: the Keeley Leagues, the United Order of Ex-Boozers, and the Emmanuel Clinic are little remembered today. However, one movement, now also out of existence, avoided obscurity by its seminal role in the origin of AA: the Oxford Group. Founded by a Lutheran minister in the early 1900s, the Oxford Group hoped to reestablish the fervor and enthusiasm of first-century Christianity: the group was not founded to address alcoholism but became active in helping alcoholic persons largely through the leadership of a New York City Episcopal priest, Rev. Sam Shoemaker. The Oxford Group emphasized personal spiritual change as a solution to man's problems. It endorsed "four absolutes": absolute honesty, absolute purity, absolute unselfishness, and absolute love. It also endorsed the "five C's": confidence, confession, conviction, conversion, and continuance (White 1998). To better appreciate the role of the Oxford Group as the immediate forerunner of AA, we must briefly divert our attention to Roland H. Roland H. was from a wealthy Connecticut family and had exhausted his family fortune through drinking. He sought treatment with Dr. Carl Jung and spent an uncertain amount of time in Zurich under analysis with Jung. Confident that his obsession for alcohol was resolved, he returned to the United States and promptly became drunk (Thomsen 1975). He then returned to Zurich. Jung explained that medicine and psychiatry could do no more for him. A spiritual or religious conversion, Jung explained, had brought recovery for some alcoholic persons, and this was Roland's only remaining hope, albeit somewhat unlikely (Kurtz 1979). Roland joined the Oxford Group, which was also very active in Europe at that time. He underwent a "conversion experience," returned to New York City, and never drank again. He became active at the headquarters of the Oxford Group, at the Calvary Episcopal Church in New York, which was headed by Rev. Sam Shoemaker. Rev. Shoemaker has been described as erudite, enthusiastic, eager, and honest. He was known to discuss his own shortcomings in preference to faulting others. People from all walks of life were drawn to him (Thomsen 1975). Under the auspices of the Oxford Group, Roland shared his conversion experience with those in need. This "mission" of Roland's led him to intervene with an old friend, Edwin Thacher, or Ebby T., who in 1934 was about to be committed to a long-term institution. Roland, along with another alcoholic, reached out to Ebby and led him to the Oxford Group, whereupon Ebby established his first period of sobriety and found "friendship and fellowship of a kind he had never known" (Kurtz 1979, p. 10). Ebby sought out another hopeless alcoholic, his friend Bill Wilson. As Kurtz (1979) described it, Ebby and Bill were talking over the kitchen table at Bill's house in Brooklyn. Bill was drinking that November afternoon and offered Ebby the same. Ebby refused Bill's repeated offers, finally explaining that he had

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found religion. Bill is described as being "not exactly insulted, but embarrassed, and somehow strangely betrayed" (Thomsen 1975, p. 207). Ebby explained that he had joined the Oxford Group; that had it originated on the Princeton campus and had later moved to Oxford and beyond. Bill had heard of the group but considered them too zealous for Christ, too social, and too rich. Ebby explained that he was not "on the wagon"; that this time, it was different. He had learned to pray, maintain an open mind about the benefit of prayer, and he felt that the desire to drink had been lifted from him. Ebby must have sensed that religious terms were averse to Bill; according to Thomsen (1975), instead of repeating the word God in their conversation, Ebby used terms such as "another power" and "higher power" (p. 209). Perhaps this is the origin of AA's embracement of the concept of a higher power in lieu of more precise religious terminology. Bill continued his drinking. Ebby stopped by a few days later with another Oxford Group member who was newly sober. They reiterated the power of prayer and meditation, giving of oneself, and a new sense of purpose. Bill remained disparaging of the religious promptings of these men, but he could not deny that his friend Ebby was different. Days later Bill decided to investigate the Oxford Group and found his way to a meeting while intoxicated. The dregs of the city were there. The odor was repulsive. The talk was of prayer, Jesus, and the possibility of a new life. Bill apparently spoke a few words himself, although he was not able to recall what he said (Thomsen 1975). At home he tried to taper off alcohol but was unsuccessful. His fear of brain damage and his uncontrollable drinking led him, again, to Towns Hospital, where he sought the help of Dr. William D. Silkworth. Silkworth was a neurologist whose dream of building his own hospital had collapsed along with his savings during the Depression. He had a compassionate interest in helping alcoholic persons and is estimated to have treated over 50,000 during his career (Thomsen 1975). Bill was admitted to Towns Hospital for what was probably the fourth time. On the second day Ebby visited and at Bill's request explained the "formula" for sobriety: "Realize you are licked, admit it, and get willing to turn your life over to the will of God" (Kurtz 1979, p. 19). What happened to Bill Wilson in that hospital bed was not fully described by him until two decades later (Wilson 1957). He was deeply depressed, but he fought the notion that there was a power greater than himself and reported that in his despair [I cried out,] if there is a God, let him show himself! I am ready to do anything, anything! Suddenly the room lit up with a great white light. I was caught up into an ecstasy which there are no words to describe. It seemed to me, in the mind's eye, that I was on a mountain and that wind not of air but of spirit was blowing. And then it burst upon me that I was a free man. Slowly the ecstasy subsided. I lay on the bed, but now for a time I was in another world, a new world of consciousness. All about me and through me there was a wonderful feeling of Presence, and I thought to myself, "So this is the God of the preachers!" A great peace stole over me and I thought, "No matter how wrong things seem to be, they are all right. Things are all right with God and His world." (Kurtz 1979, pp. 19–20) Bill asked a nurse to find Dr. Silkworth. He feared and wanted to know if this experience represented brain damage. Silkworth listened to Bill's experience, asked questions, and responded that Bill was "Perfectly sane, in my opinion" (Thomsen 1975, p. 224). Silkworth explained that he had read about such things and that they could produce profound changes. He encouraged Bill to "hang on to it. . . .It is so much better than what you had a couple of hours ago" (p. 224). After discharge from Towns Hospital, Bill returned to the Oxford Group—this time, he was sober. He and his wife, Lois, attended the meetings, and Bill would go after the meeting with other members to a local cafeteria. Three postconversion experiences strengthened Bill's sobriety and his determination to carry the message to other alcoholic persons: the support of Rev. Sam Shoemaker, the exchange of experiences with other alcoholic persons at Steward's Cafeteria, and the counseling of Dr. Silkworth. Silkworth provided a medical explanation for the alcoholic's plight: an "allergy." Of course, alcoholism is not an allergy, but the term was a useful analogy. Furthermore, Silkworth avoided focusing on the past

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and emphasized positive aspects of the individual's life and struggle with recovery. In this regard, his approach may have been a forerunner of motivational interviewing. The informal meetings of the alcoholics at the cafeteria, with their natural inclination to share experiences in a setting that was nonjudgmental, clearly convinced Bill Wilson that one alcoholic talking to another was a tool—a profound dynamic—for moving forward into a life free of alcohol. Rev. Shoemaker, the Episcopal priest, gave Bill and others a new perspective on prayer; namely, listening or meditating on what God wants for you as an alternative or in addition to requests and petitions (Thomsen 1975). Over the 6 months after leaving Towns Hospital, Bill is described as fervently telling his story to other alcoholic persons. He stayed sober, but they did not. He was frustrated that Oxford Group members were lukewarm at best with the idea of alcoholism being a disease. They were interested in moral regeneration. Discouraged, Bill spoke with Dr. Silkworth, who told him to stop preaching and to emphasize the physical destruction of alcohol (Thomsen 1975). Bill continued to struggle with whether to emphasize sin or sickness. Meanwhile, he was back working as a broker, which is what took him to Akron, Ohio, in May 1935. Bill was involved in a proxy fight to take over a small machine tool factory. He and his colleagues lost; the colleagues left Akron shortly thereafter, and Bill was left alone on the Saturday before Mother's Day. Dejected, he began to rationalize the desire to drink. A bar was down the hall, and he walked toward it, but in near panic about what he was about to do he went back to the lobby instead. In his telling of this years later, Bill said he knew he had to talk to someone, preferably another alcoholic person. He called a minister whose name was listed in the church directory located in the lobby. Rev. Walter Tunks received Bill's call and responded to his request for help, giving him 10 names. After numerous calls, Bill reached an Oxford Group member, Ms. Henrietta Seiberling. Ms. Seiberling, the daughter-in-law of the president of Goodyear Tire, understood Bill's plight and graciously asked him to her house. She was not alcoholic herself, but had been trying to help a local surgeon, Dr. Bob Smith, with his alcoholism. She arranged for Dr. Bob and Bill to meet at her home the next day (Thomsen 1975). Dr. Bob had attempted many treatments and had a strong connection with the local Oxford Group. He was considered hopeless. Bob and his wife, Anne, met Bill at Ms. Seiberling's on that Sunday. Dr. Bob was tremulous, stooped over, and haggard looking. Bill reassured him that their visit could be brief. It is likely that Bill shifted gears as he spoke with Dr. Bob—that is, Bill did not warn the doctor about the consequences of heavy drinking, nor did he emphasize his own turnaround as experienced during detoxification at Towns Hospital. Instead, Bill opened up about his past promises, failed hopes, and drunken despair. He reviewed his many detox stays and the visits from Ebby. He did not talk down to Dr. Bob, and in turn Dr. Bob, who was apparently very taciturn and self-reliant, saw himself in Bill's story. They knew that they understood each other (Kurtz 1979). Although Bill continued sober after their meeting, Dr. Bob soon thereafter went to a medical convention in Atlantic City and came back to Akron drunk. With assistance from his wife and Bill, however, he acquired lasting sobriety on June 10, 1935. Kurtz's (1979) definitive history of AA identifies what he has called four "founding moments" in the development and evolution of the group. These moments, mentioned previously, are highlighted again here because of their salience: 1. The relationship between Carl Jung and Roland H. This was a failed therapeutic experience, as acknowledged by Jung. However, Jung's discussion with Roland about the possibility of spiritual change or awakening was critical to Roland's joining the Oxford Group. Roland's successful conversion followed. Bill Wilson, in 1961, wrote to Jung: "The conversations between you [and Roland] were to become the first link in the chain of events that led to the founding of Alcoholics Anonymous" (Kurtz 1979, p. 8). 2. Ebby T.'s 1934 visit with Bill Wilson in Wilson's kitchen in New York City. Ebby had been guided by Roland to "get religion." Bill was drinking when Ebby visited. Ebby turned down Bill's offers of alcohol. Bill couldn't shake the image of his former co-drinker sober and resolute. Ebby's example and his kind, patient encouragement spawned Bill to try once again—that is, to readmit himself to

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Charles B. Towns Hospital. (Unfortunately, Ebby later relapsed and died from the consequences of alcoholism.) 3. Bill's spiritual experience at Towns Hospital. Either Roland or Ebby (it is not known which) directed Bill to William James' (1902/1985) famous work The Varieties of Religious Experience. This text enabled Bill to further understand and value the spiritual experience he had undergone in December 1934. 4. The conversation and the subsequent interaction between Bill and Dr. Bob Smith in Akron, Ohio, in May and June 1935. Their initial conversation captures the power of AA's eventual strategy of one alcoholic person talking to another. Kurtz (1979, p. 29) describes the conversation as follows: Here was someone who did understand, or perhaps at least could. This stranger from New York didn't ask questions and didn't preach; he offered no "you musts" or even "let's us's." He had simply told the dreary but fascinating facts about himself, about his own drinking. And now, as Wilson moved to stand up to end the conversation, he was actually thanking Dr. Smith for listening. "I called Henrietta because I needed another alcoholic. I needed you, Bob, probably a lot more than you'll ever need me. So, thanks a lot for hearing me out. I know now that I'm not going to take a drink, and I'm grateful to you." While he had been listening to Bill's story, Bob had occasionally nodded his head, muttering "Yes, that's like me, that's just like me." Now he could bear the strain no longer. He'd listened to Bill's story, and now, by God, this "rum hound from New York" was going to listen to him. For the first time in his life, Dr. Bob Smith began to open his heart.

GROWTH OF AA: A SLOW, PATIENT PROCESS Bill Wilson and Dr. Bob Smith spent the summer of 1935 meeting with alcoholic persons at Dr. Bob's home. When Bill returned to New York City at the end of the summer, there were four newly sober alcoholics, including Dr. Bob, in Akron. Bill Wilson was ambitious. He tirelessly recruited alcoholics at the Oxford Group meetings in New York. He sought funding and soon faced a major temptation: in 1936, Charles Towns, the owner of Towns Hospital, wanted Bill to bring his program into that hospital. Bill would receive a portion of the profits, which would solve Bill's growing financial problems and provide an organizational structure for the growth of his group (White 1998). Fellow members (the name Alcoholics Anonymous had not yet been coined) discouraged the arrangement, however, and Bill yielded to their influence. AA since has continued to avoid affiliation with other entities. There was no certain AA identity in the mid-1930s. The members met within the structure of the Oxford Group. Strains in this relationship soon emerged: the Oxford Group valued publicity, whereas the members preferred anonymity. The Oxford Group was Protestant; many of the alcoholics were Catholic. Oxford Group members were zealous about the strictness of their beliefs, whereas the early members of Bill's group wanted to accept any alcoholic—believer or not, Catholic, Protestant, or otherwise. The AA identity began to take shape through the formulation of the 12 steps (originally only six), which Bill Wilson credited to three sources: the Oxford Group, Dr. William Silkworth, and William James. The "big book," formally known as Alcoholics Anonymous, was written by Bill Wilson beginning in 1938. The book was published in 1939, and initial reviews in medical circles were derogatory, saying the book had "no scientific merit or interest" ("Book Reviews: Alcoholics Anonymous" 1940). Twenty thousand direct mail notices of the big book were sent to physicians, but only two orders were made (Thomsen 1975). Later, through articles in popular magazines such as The Saturday Evening Post, sales of the book took off and national publicity developed. The group that we now know as Alcoholics Anonymous officially adopted their name in 1939, at which time it is estimated there were 100 members. A rapid growth of the group occurred as members spread the word about AA beyond New York City and Ohio and as radio shows and newspaper articles publicized AA. Sales of the big book greatly increased, and Bill Wilson and Bob Smith were rumored to have split

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the royalties. An audit dispelled this rumor, but the growing pains continued. Critics complained of a lack of rules, too little authority, and insufficient organizational structure. Ultimately, "AA committed itself to corporate poverty, group authority rather than personal authority and leadership, and the lowest level of organization necessary to carry AA's message of recovery" (White 1998, p. 137). By 1946, AA's 12 traditions were formulated. The 12 traditions provide the guideline for AA organizational behavior and provide principles to protect the group life of AA (Alcoholics Anonymous 1978). A central office was established in New York City in 1945. In 1950, Dr. Bob, the cofounder of AA, died. He had lived long enough to witness AA's explosive growth, which was nearly 90,000 members at the time of his death. Bill Wilson died on January 24, 1971.

AA SURVEY DATA Since 1968, the General Service Office of AA in New York City has conducted a membership survey about every 3 years. No formal membership lists are maintained, and some local groups do not list themselves with the General Service Office. Table 35–1 lists AA membership and group information as of January 1, 2007. A 2004 membership survey (Alcoholics Anonymous 2004) documented increasing collaboration among physicians, other health care providers, and AA. Thirty-nine percent of current members reported being referred to AA by a health care professional; 64% of current members received treatment or some formal counseling prior to their joining AA; and 75% of these stated that such treatment played an important part in their decision to go to AA. The increasing transparency between AA and medicine is reflected further by a report stating that 77% of members' physicians know they are in AA.

How Do Members Discover AA? As mentioned, 39% of members in a 2004 survey were referred by a health care provider. Another 30% were self-motivated, 31% were referred through an AA member, 23% by family, 11% by court order, 5% by an employer or fellow employee, and 1% by clergy.

Length of Sobriety According to the latest AA survey, 26% of members report less than 1 year of sobriety, 24% report 1–5 years, 14% report 5–10 years, and 36% report more than 10 years. These data document that newcomers to AA can expect to meet alcoholic persons with long-term sobriety (Alcoholic Anonymous 2004). Occasionally, the newcomer is envious of those with long-term success in the program. Envy can be defused by the reminder that one stays sober "one day at a time" and that the old-timer may be as close to a next drink as the newcomer.

Current Demographics Table 35–2 presents the demographic makeup of AA as of 2004.

THE AA PROGRAM The program of AA is considered a fellowship. A fellowship is a "mutual association of persons on equal and friendly terms; a mutual sharing, as of experience, activity, or interest" (Webster's New Twentieth Century Dictionary of the English Language 1980). The fellowship of AA is structured to sustain the primary focus of AA, which is "to stay sober and help other alcoholics to achieve sobriety" (Alcoholics Anonymous 1992). Structured features of AA include meetings, AA literature, and the 12 steps and 12 traditions.

Meetings AA meetings may be open or closed. An open meeting welcomes guests and those attempting to recover from alcoholism. Closed meetings should be attended only by those who consider themselves AA members or are contemplating membership. There are several types of meetings: 1. Speaker meetings. During a speaker meeting, a member tells his or her story to the group in

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attendance, putting emphasis on what happened (e.g., the effect of alcohol in that person's life), what was done about it (how the person got sober), and what the person is doing now to stay sober. Experienced AA members often assess the quality of one's sobriety by how much emphasis is placed on the "drunkalogue" or the "war stories" versus how much the speaker emphasizes his or her current focus on remaining sobriety. (Quality is related to current recovery activities and not the gory details of drunkenness.) 2. Step meetings. During step meetings, one of the 12 steps is introduced by a group leader and discussed by the members. This is an effort to more fully appreciate the importance of each step and to develop a deeper understanding of the same for one's life. 3. Discussion meetings. Discussion meetings involve a group discussion focused on a salient aspect of recovery; for example, the group might discuss humility or resentments and learn from each other's experience of trying to apply the former or overcome the latter.

The AA Literature Each AA meeting starts with the leader of the meeting reading the AA preamble. The preamble concisely reviews what AA is and is not: Alcoholics Anonymous is a fellowship of men and women who share their experience, strength, and hope with each other that they may solve their common problem and help others to recover from alcoholism. The only requirement for membership is a desire to stop drinking. There are no dues or fees for AA membership; we are self-supporting through our own contributions. AA is not allied with any sect, denomination, politics, organization, or institution; does not wish to engage in any controversy, neither endorses nor opposes any causes. Our primary purpose is to stay sober and help other alcoholics to achieve sobriety. (Alcoholics Anonymous 1992) The General Service Office (Box 459, Grand Central Station, New York, NY, 10163) publishes a variety of pamphlets and books that describe what AA is, share AA wisdom, and guide recovering alcoholic persons. The AA literature is available in several different languages and can be ordered through the AA Web site, http://www.alcoholics-anonymous.org.

The 12 Steps and the 12 Traditions The 12 steps (Table 35–3) and the 12 traditions (Table 35–4) summarize the principles of AA and are widely printed in formats ranging from wallet cards to placards. One gains sobriety, in part, by working through the 12 steps. The 12 traditions reinforce the integrity of the AA approach. Sponsorship is another structured feature of AA. Each new member is encouraged to have a sponsor. The sponsor is an experienced member of AA with a respectable track record of sobriety. Typically, one would be expected to be sober at least 1 year before becoming a sponsor. A sponsor is a mentor. He or she is available for phone calls and works the steps with the newcomer—especially steps 4 and 5, in which the new member makes "a fearless moral inventory" (step 4) of him- or herself and shares the same (step 5) with his or her sponsor. AA emphasizes "principles before personalities"—that is, individuals are encouraged to choose a sponsor who will best allow them to grow within the program. The sponsor does not have to be the best friend you ever had or be socioeconomically or temperamentally similar. Some sponsors are very easygoing and put few demands on the fellow member, whereas others require daily readings and daily contact. AA is not effective simply by having established the structures outlined here. The process of AA is a powerful but not fully understood dynamic. This process includes spiritual growth, a tempering of pathological narcissism, empathy, interpersonal support, group adhesion, and variables perhaps as unique as each individual participant. (Psychological mechanisms are discussed in Chapter 34 of this volume, "Psychological Mechanisms in Alcoholics Anonymous," as well as by Nace [2005]).

THE EXPERIENCES OF PATIENTS

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Clinicians will find that patients in AA feel understood. They feel accepted. They are not judged or expected to change their personalities. They are encouraged to "keep coming back" and not told what to do but rather are told what worked for others. Rachel As an infant, Rachel would hold her breath when her mother left the room. This protest over separation led, at times, to loss of consciousness. Later, Rachel dreaded school and recalls daily anxiety at the start of class each day, including through graduate school. She obtained her Ph.D. in spite of escalating alcohol use. Her teaching career was checkered with unexplained absences (related to binge drinking) and eventually with episodes of rehabilitation and hospitalization. Brief periods of sobriety were punctuated with binge drinking, which often involved having 24 beers per day. By her 30s Rachel had gained control over her lifelong severe anxiety disorder through use of a variety of medications, but the drinking continued. Rachel grew up in a middle-class home free of alcohol or drug problems. Her mother was "nervous" but not formally diagnosed. Rachel, her two siblings, and her parents had no religious affiliation. This was a home indifferent to spirituality, religion, or ultimate concerns. Her psychiatrist continually urged her to try AA. Her discomfort with the "religiosity" kept her away. The tedious pattern of frequent (once or twice per week) heavy binge drinking, her growing social isolation, and a developing depression resulted in a return to a 30-day rehabilitation program. She found fault with much of the program, but gradually and unexpectedly felt early promptings of an inner peace. Early one morning she saw a deer on the grounds of this rural rehabilitation center. The deer paused, fixed its gaze on Rachel, and then cantered across the field. Her delight in this natural scene was followed by an unfolding acceptance—an acceptance of who she was, her powerlessness over many things in her life, and her powerlessness over alcohol. She heard the AA message differently now. It was comforting; it made sense. Her natural intellectual curiosity prompted her to read widely the big book, Twelve Steps and Twelve Traditions, and, eventually, Christian texts provided by her sponsor. Rachel's commitment to sobriety is firm. She is pensive about the years she lived in spiritual indifference. She is seeking to know God, and her mother and sister are joining her. Periodic intense cravings occur. The cravings have reduced her to tears at times, but she has learned to reach out to others and is gaining confidence without complacency. The absence of alcohol has diminished her anxiety. She is taking less medication, and psychotherapy with her psychiatrist has shifted in depth. Rachel's case is illustrative in several ways: the ease with which religion and ultimate concerns can be ignored in a comfortable materialistic culture; the transmission of this indifference from one generation to another; the eventual discovery of a drug (in her case, alcohol) to relieve dysphoria and transform (however briefly) her sense of self. Furthermore, the dependency on alcohol secondary to her anxiety disorder led to occupational and social dysfunction, loss of control, and despair. A concerned physician steered her back to an intensive recovery program. From there, a transforming spiritual reality was experienced. Rachel did not ignore this experience but embraced it, undeterred by cognitive dissonance. The AA program, the gentle mentoring of a sponsor, and the surprising support of her family opened the future for Rachel—a future where her considerable talents can be realized. Hope, cohesiveness, acceptance, and other positive aspects of the AA experience bind many fledgling members to the fellowship. The incentive to drink remains powerful for many, even some who successfully engage in the program. Relapses are accepted—indeed, they are expected—and no one is turned away or dismissed from AA as a result of relapse. A drunken participant may be asked to leave a meeting but is encouraged to return the following day. Roger

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Roger, a 48-year-old internist, returned from his third inpatient rehabilitation treatment for alcohol dependence. His response to treatment over the past 6 years had been poor. AA attendance had been sporadic. Psychotherapy had been provided by a variety of professionals. Now he faced major changes: his wife had filed for divorce while he was in residential treatment. He was not allowed to return to his home, was not permitted by his wife to accompany their 18-year-old daughter to the university she was about to attend, and had a hostile relationship with his 20-year-old son, who was also alcoholic. After 1 week of trying to reengage with his family, Roger began drinking. He called his previous psychiatrist on a Sunday night and was seen the next morning and started on disulfiram and an antidepressant. The psychiatrist, who was familiar with Roger's extensive treatment history, encouraged him to try to turn things around on an outpatient basis. Roger was relieved that he could continue his work, which was largely administrative rather than clinical. After the Monday appointment he was seen on Wednesday of the same week and again on that Friday morning. The preceding Thursday night was sleepless. Roger, a person without a commitment to religion or spirituality, had an inchoate sense of God and was what is often referred to as a "cultural Christian"—in contrast to a "believer." Yet on that Thursday night, something changed. Roger reported that he prayed to God that he would either stop craving alcohol or be allowed to drink himself to death. The constant tension between wanting/needing a drink and the obvious consequences had become intolerable. Roger showed up to his appointment that Friday morning reporting that he had lost the desire to drink. He did not know how; there had been no "white light" experience. He knew that he had felt desperate and prayed desperately. Neither his psychiatrist nor Roger knew quite what to make of this, but at least Roger seemed safe to remain on outpatient status. A week later he stopped taking Antabuse, confident that the tension over alcohol was over. It was. Six years later he remains sober and married. He and his son conduct an AA meeting at a halfway house for newly released prisoners. He still has not become "religious," but he remains grateful for a transformation that reversed his downward spiral. In addition to the craving or incentive to return to alcohol, many people encountering AA have personal reactions that deter their participation. The clinician should be alert to these common responses and motivate the patient to overcome them. "I wasn't as bad as that." Patients often find differences between themselves and the people they meet at AA. The patient may never have been in jail nor lost a job. Regardless of specific experiences, the AA wisdom is to look for similarities, not differences. "I can't identify with that group." Perhaps the participants seem too young, too old, or not up to one's social standards. Such responses often serve a defensive function. Other groups could be visited or a deeper understanding of the patient's resistances explored. "They're too religious" or "It's a cult." Further exposure is always necessary. These invalid responses are serving (more often than not) as a defense against relinquishing the dependency on alcohol. Repeated exposure to AA, including visiting different meetings, is likely to vitiate these initial problematic reactions. "Someone tried to hit on me." It is possible, but not very common, that an AA member will use the group as a potential source for sexual companionship. Other meetings may be chosen. Furthermore, the newcomer may use such an experience to learn how to set boundaries and to develop his or her priorities. Our exhortations to patients to attend meetings as part of their recovery will tap into some patients' pathology beyond the expected denial and defensive efforts listed here. Two categories stand out: those with anxiety disorders and those with paranoid or schizoid features. Jack

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Jack was brought home from his university after a near suicide attempt—Jack had been drunk while making preparations to overdose. His fraternity brothers called his parents. This was his third suicide attempt (all of which had occurred while drunk) in 12 months. Jack knew he was alcoholic, feared drinking because of the subsequent severe depression, and wanted help. He wanted to try AA again. The anxiety that built up as he thought of attending meetings was more than he wanted to endure. He would probably have to drink just to get there. Jack had a severe pervasive social phobia. Sertraline gradually began to dampen his symptoms, and injectable naltrexone lessened alcohol cravings. With encouragement as well as pressure from his parents, he reluctantly agreed to try AA again. Emphasis was placed on not letting his symptoms control his life but to move out into a venue that would assist him in his goal of sobriety. Jack built on his earlier success in attending classes, because he knew that as he became familiar with group members, attendance would be easier. George George had tried several rehabilitation programs over the past 10 years. Now in his mid-50s, he was living alone, alienated from his siblings, and trying to maintain a family apartment rental business. He called his doctor to get chlordiazepoxide (Librium). George did not trust people. There was a woman he thought he might marry. Although she was a "chronic liar," he figured that she could help take care of him, he figured. Alcohol withdrawal seizures were occurring more frequently. George ranted against AA, rehabilitation, and so on. He was inclined to give his views on God, religion, and the evils he saw in these concepts rather than focus on his increasingly acute alcohol-related complications. He was haughty and always disdainful of what his doctor and others advised. George's mixed personality disorder included schizoid, paranoid, and narcissistic traits. He remained noncompliant except during the most acute crisis, which typically took place during his efforts to taper his drinking. There have been no indications of a change in attitude for George and his prognosis would seem poor. Physicians who treat alcoholic persons encounter resistance in most patients. Often efforts at working on denial with the patient lead to movement along a continuum of change, from precontemplation ("It never occurred to me that I would quit") to contemplation ("Maybe I need to do something about drinking") to decision (formulating a plan) and then action (e.g., entering a treatment program or attending AA meetings) (DiClemente et al. 1999). Other circumstances involve comorbid conditions, as the two case vignettes here illustrate. Specific attention to comorbidity in synchrony with addressing the substance use disorder is essential.

THE REACH OF ALCOHOLICS ANONYMOUS Since AA's founding in 1935, its reach to alcoholic individuals has been monumental, extending to more than 2 million members in more than 100,000 groups across at least 150 countries. These numbers portray only one facet of AA's reach, however. AA's influence is found in many facets of today's efforts to address substance use disorders. Marty Mann, a woman who recovered from alcoholism in the early 1940s (with the help of AA) had a vision of educating the public about alcoholism. She shared her vision with Bill Wilson, but Bill, in accord with AA tradition, did not want to directly affiliate AA with a public educational campaign. Ms. Mann sought advice from Dr. E. M. Jellinek, who was affiliated with the Yale Center for Alcohol Studies. Jellinek, a scientist, found funding for Mann, whose primary "credentials" were her personal recovery and her zeal to educate the public. Mann founded a National Committee for Education on Alcoholism in 1944. In 1954, the group became known as the National Council on Alcoholism, and Mann served as director of this committee from 1954 to 1968. She lectured across the country for 35 years and influenced legislation to formulate a public health response to alcoholism (White 1998). A second sphere of influence has been the infusion of AA tenets in professionally based treatment programs. The Minnesota Model exemplifies the changed attitudes toward alcoholic persons that

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were emerging in the mid-twentieth century. This model has dominated the alcoholism treatment industry and still survives to some extent in the era of managed care. The model asserts that alcoholism is involuntary and a primary disease; it is chronic and progressive; a multidisciplinary team with recovery counselors is the optimal approach; and AA stepwork and follow-up are part of the model (Anderson 1981). The Minnesota Model integrated professionally managed treatment with the grassroots model of AA. Spirituality became a component of professional treatment, and the model has been extended to the treatment of drug abuse. Most self-help groups today borrow, with modifications, the 12-step approach of AA. Narcotics Anonymous, Cocaine Anonymous, Gamblers Anonymous, and Overeaters Anonymous are examples. Al-Anon is an additional example that provides a 12-step formulation for family members of an alcoholic person.

CONCLUSION AA was preceded by temperance societies, fraternal organizations, and religious groups that had an interest in arresting the destruction of alcoholism. The commitment of two recovered alcoholic men led to the founding of the most successful approach to alcoholism to date—Alcoholics Anonymous. AA has skillfully avoided extending its reach beyond helping alcoholic persons. It has a clear structure to follow for the individual desiring not to drink. The success of the AA program is reflected in the number of participants and its spread across the world. Furthermore, the AA approach has influenced modern rehabilitation efforts and most self-help groups.

KEY POINTS The founding of Alcoholics Anonymous (AA) was the culmination of decades of effort to help alcoholic persons by religious organizations, secular groups, and physicians. The integrity of the AA organization has been sustained by avoiding any affiliation with outside entities and by remaining faithful to its mission to help alcoholic individuals. The fellowship of AA provides a structure for daily living through appreciation of the 12 steps and 12 traditions that foster sobriety and personal maturity. The efficacy of AA is reflected by its growth, its influence on substance abuse treatment programs, and the increasing referral to AA by health care providers.

REFERENCES Alcoholics Anonymous: Twelve Steps and Twelve Traditions. New York, Alcoholics Anonymous World Services, 1978 Alcoholics Anonymous: Grapevine. New York, The AA Grapevine, 1992 Alcoholics Anonymous: Alcoholics Anonymous Membership Survey. 2004. Available at: http://www.aa.org/en_media_resources.cfm?PageID=75. Accessed October 4, 2007. Alcoholics Anonymous: Estimates of AA Groups and Members. 2007. Available at: http://www.aa.org /en_media_resources.cfm?PageID=74. Accessed October 4, 2007. Anderson D: Perspectives on Treatment: The Minnesota Experience. Center City, MN, Hazelden Educational Materials, 1981 Book Reviews: Alcoholics Anonymous. J Nerv Ment Dis 92:399, 1940 DiClemente CC, Bellino LE, Neavins TM: Motivation for change and alcoholism treatment. Alcohol Res Health 23:86–92, 1999 [PubMed] Fahey DM: Temperance and Racism: John Bull, Johnny Reb, and the Good Templars. Lexington, KY, Lexington University Press, 1996 James W: The Varieties of Religious Experience (1902). Cambridge, MA, Harvard University Press, 1985

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Kurtz E: Not-God: A History of Alcoholics Anonymous. Center City, MN, Hazelden, 1979 Maxwell M: The Washingtonian movement. Q J Stud Alcohol 2:410–451, 1950 Nace EP: Alcoholics Anonymous, in Substance Abuse: A Comprehensive Textbook, 4th Edition. Edited by Lowinson JH, Ruiz P, Millman RB, et al. Philadelphia, PA, Lippincott Williams & Wilkins, 2005, pp 587–599 Thomsen R: Bill W. New York, Harper & Row, 1975 Tyrell I: Sobering Up. Westport, CT, Greenwood Press, 1979 Webster's New Twentieth Century Dictionary of the English Language, Unabridged, 2nd Edition. New York, William Collins Publisher, 1980 White WL: Slaying the Dragon: The History of Addiction Treatment and Recovery in America. Bloomington, IL, Chestnut Health Systems/Lighthouse Institute, 1998 Wilson WG: Alcoholics Anonymous Comes of Age. New York, Alcoholics Anonymous Publishing, 1957

SUGGESTED READING Alcoholics Anonymous: Twelve Steps and Twelve Traditions. New York, Alcoholics Anonymous World Services, 1978 Alcoholics Anonymous: Alcoholics Anonymous, 4th Edition. New York, Alcoholics Anonymous World Services, 2001 Kurtz E: Not-God: A History of Alcoholics Anonymous. Center City, MN, Hazelden, 1979 Thomsen R: Bill W. New York, Harper and Row, 1975 White WL: Slaying the Dragon: The History of Addiction Treatment and Recovery in America. Bloomington, IL, Chestnut Health Systems/Lighthouse Institute, 1998 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 36. Outcome Research on 12-Step and Other Self-He...

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Rudolf H. Moos, Christine Timko: Chapter 36. Outcome Research on 12-Step and Other S elf-Help Programs, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.354949. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Outcome Research on 12-Step and Other Self-Help Programs Rudolf H. Moos, Ph.D. Christine Timko, Ph.D.

OUTCOME RESEARCH ON 12-STEP AND OTHER SELF-HELP PROGRAMS: INTRODUCTION Twelve-step self-help groups (SHGs), often called mutual help or support groups, are an important component of the system of informal care for patients with substance use disorders (SUDs). Individuals make more visits to SHGs for help with their own or family members' substance use and psychiatric problems than to all mental health professionals combined. As many as 9% of adults in the United States have been to an Alcoholics Anonymous (AA) meeting at some time in their lives, and more than 3% have been to a meeting in the prior year (Room and Greenfield 1993). Moreover, many SUD treatment service providers have adopted 12-step techniques in treatment, and most of them refer patients to SHGs. SUD patients have high rates of posttreatment relapse and additional episodes of specialized care; SHGs may improve the likelihood of achieving and maintaining remission and reduce the need for further professional care. SHGs provide continuing support, goal direction, and structure; exposure to abstinent role models and rewarding, substance-free activities; a forum wherein individuals can express their feelings in a safe setting; and a focus for building self-confidence and coping skills. The American Psychiatric Association (2000) recommends referrals to SHGs as an adjunct to the treatment of patients with SUDs. Department of Veterans Affairs Health Services Research and Development Service funds and NIAAA grant AA15685 supported preparation of the manuscript. We thank Bernice Moos for help in reviewing the literature. The views expressed here are the authors' and do not necessarily reflect the views of the Department of Veterans Affairs.

PARTICIPATION IN SELF-HELP GROUPS AND SUBSTANCE USE OUTCOMES Individuals with SUDs who participate in 12-step SHGs tend to experience better alcohol and drug use outcomes than do individuals who do not participate in these groups. The most common index of participation has been attendance at group meetings; however, recent attention has focused on aspects of involvement, such as reading 12-step literature, working the steps, obtaining and interacting with a sponsor, becoming a sponsor, and doing service work.

Attendance and Substance Use Outcomes Several prospective studies have shown that SHG attendance is associated with good substance use outcomes. Project MATCH was a large clinical trial that compared the outcome of 12-step facilitation, cognitive-behavioral, and motivational enhancement treatment for patients with alcohol use disorders. Patients who attended AA more often in each 3-month interval after treatment were more likely to maintain abstinence from alcohol in that interval. In addition, more frequent AA attendance in the first 3 months after treatment was related to a higher likelihood of abstinence and fewer alcohol-related consequences in the subsequent 3 months; these findings held for patients in each of the three types of

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treatment (Tonigan et al. 2003). Comparable findings have been obtained in several other studies. For example, inpatients with alcohol use disorders who attended AA at least weekly reported more reductions in alcohol consumption and more abstinent days at a 6-month follow-up than did individuals who attended AA less frequently or those who did not attend at all (Gossop et al. 2003). Alcohol-dependent individuals who participated in SHGs in the first and second years after intensive outpatient treatment were more likely to be abstinent in the second and third years, respectively; attendance at two or more meetings per week was associated with less severe relapses (Kelly et al. 2006). Although there is much less empirical evidence, these findings apply to participation in Narcotics Anonymous (NA), as would be expected given the commonalities between AA and NA, which follow the same 12 steps and have similar literature, speaker and step meetings, and home groups and sponsors. Individuals who consistently attended NA at least weekly during a 12-month interval had lower levels of alcohol and marijuana use at follow-up than did those who attended NA less consistently (Toumbourou et al. 2002). Among individuals with drug use disorders, those who participated only in AA, only in NA, or both in AA and NA had comparable 1-year abstinence rates, all of which were higher than the rate for individuals who did not participate in AA or NA (Crape et al. 2002). Individuals who continue to attend SHGs over a longer interval are more likely to maintain abstinence than are individuals who stop attending. Patients with drug use disorders who participated in 12-step groups at least weekly at 6-month and 24-month follow-ups were more likely to maintain abstinence from both drugs and alcohol (Fiorentine 1999). In another study, continuous attendance at baseline and at 6- and 30-month follow-ups was associated with better substance use outcomes at each follow-up; in addition, 6-month attendance was associated with better 30-month outcomes. Individuals who discontinued attendance or attended intermittently had substance use levels that were similar to those of individuals who reported no regular attendance (Kissin et al. 2003). A prospective study of individuals with alcohol use disorders showed that a longer duration of attendance in AA in the first year after help seeking was associated with a higher likelihood of 1-year, 8-year, and 16-year abstinence and freedom from drinking problems. Moreover, after controlling for the duration of AA attendance in year 1, the duration of attendance in years 2–3 and 4–8 was related to a higher likelihood of 16-year abstinence. Thus, individuals who continued to attend AA regularly over the long term experienced better substance use outcomes than those who did not (Moos and Moos 2006). In addition, the combination of a longer duration of AA attendance and better drinking outcomes at the 1-year follow-up was associated with a lower mortality rate in the subsequent 15 years (Timko et al. 2006b). These findings hold for SUD patients with different diagnoses. According to Witbrodt and Kaskutas (2005), individuals who attended more 12-step group meetings in the first 6 months after seeking treatment were more likely to be abstinent at a 6-month follow-up; those who attended more meetings in the subsequent 6 months were more likely to be abstinent at a 12-month follow-up. Comparable findings were obtained for patients with alcohol use disorder diagnoses only, patients with drug use disorder diagnoses only, and patients with both drug and alcohol use disorder diagnoses. In general, the duration of SHG attendance is more strongly related to substance use outcomes than is the frequency of attendance. The benefits of SHGs do not appear to be dependent on attending 90 meetings in 90 days.

Involvement and Substance Use Outcomes Attendance is an important indicator of participation, but it may not adequately reflect an individual's level of group involvement, as shown by such indices as number of steps completed, acceptance of 12-step ideology, and self-identification as a group member. These and related aspects of involvement are relatively highly correlated with indices of attendance; nevertheless, aspects of group involvement may be associated with substance use outcomes independent of the duration and frequency of attendance per se.

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In support of this idea, individuals who were more accepting of 12-step ideology, especially belief in the need for lifelong attendance at 12-step meetings and the need to surrender to a higher power, were more likely to attend 12-step meetings at least weekly. Belief in 12-step ideology, specifically the idea that nonproblematic drug use was not possible, was associated with abstinence independent of 12-step group attendance (Fiorentine and Hillhouse 2000b). In Project MATCH, AA attendance, the number of steps completed, and self-identification as an AA member were most closely associated with abstinence. The composite of these three items was more highly related to abstinence than was attendance by itself (Cloud et al. 2004). In a study of treatment for individuals with cocaine use disorders, active 12-step involvement in a given month predicted less cocaine use in the next month. Moreover, patients who increased their 12-step involvement in the first 3 months of treatment had better cocaine and other drug use outcomes in the next three months. Patients who regularly engaged in 12-step activities but attended meetings inconsistently had better drug use outcomes than did patients who attended consistently but did not regularly engage in 12-step activities (Weiss et al. 2005). Maintaining passive attendance may indicate reluctance to fully embrace 12-step group ideology and the goal of abstinence. Individuals who attend SHGs but are unable to embrace key aspects of the program are less likely to benefit from it.

Delay in Participation and Dropout Compared with individuals who begin to participate in SHGs either soon after initiating help seeking or during treatment, those who delay entering SHGs do not appear to benefit as much from them. For example, individuals who delayed participating in AA for more than a year after recognizing that they had an alcohol-related problem and initiating help seeking were more likely to have drinking problems and dependence symptoms 8 years later than were individuals who entered AA in a timely fashion. Moreover, these individuals experienced no better 8-year alcohol-related outcomes than did individuals who did not participate in AA at all. Individuals who entered AA but then dropped out also were more likely to relapse or remain nonremitted (Moos and Moos 2006). In support of these findings, Fiorentine (1999) noted that patients who continued to participate in AA after a 6-month follow-up were more likely to maintain abstinence at 24 months than were patients who dropped out of AA. Patients who did not enter AA until after the 6-month follow-up were no more likely to be abstinent at 24 months than patients who did not attend AA at all. According to Kelly and Moos (2003), 91% of patients with SUDs attended at least one 12-step group meeting either during treatment or in the year after treatment; however, 40% of these individuals had dropped out by a 1-year follow-up. Compared with patients who continued to attend, those who dropped out were less likely to be abstinent or in remission and more likely to report substance-related problems at a 1-year follow-up. Individuals who delay participating in SHGs may develop more severe substance use problems before they are motivated to obtain help and thus may have poorer prognoses than individuals who enter SHGs quickly. Most individuals who seek formal help for SUDs enter treatment and/or SHGs relatively soon. Accordingly, individuals who hesitate to join these groups may be less motivated for recovery, find it harder to establish a relationship with a sponsor, and drop in and out of SHG groups or attend only intermittently, a pattern that is associated with poorer outcomes.

CONNECTIONS BETWEEN SELF-HELP GROUPS AND TREATMENT Many individuals participate in both treatment and SHGs; in general, these two sources of help appear to strengthen or bolster each other. For example, compared with help-seeking individuals who initially entered only AA, individuals who entered both treatment and AA participated in AA as much or more in the subsequent 15 years. Individuals who stayed in treatment longer in the first year after initiating help-seeking subsequently showed more sustained participation in AA. More extended treatment later in individuals' help seeking careers was not associated with later participation in AA, which suggests that treatment providers' referrals to AA have more influence in the context of an initial treatment episode (Moos and Moos 2005).

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There also is a more specific link in that individuals who participate in 12-step treatment, which introduces patients to 12-step philosophy and encourages them to join a group and get a sponsor, are more likely to affiliate with 12-step SHGs than are individuals who participate in treatment that is not oriented toward 12-step principles. Patients with cocaine use disorders who received individual drug counseling based on 12-step philosophy were more likely to attend and participate in SHGs than were comparable patients who received supportive-expressive or cognitive treatment (Weiss et al. 2000). Similarly, patients and their partners in marital therapy that included AA/Al-Anon facilitation attended more AA and Al-Anon meetings during treatment than did patients in two other marital therapy conditions that did not include such facilitation (McCrady et al. 1996). In Project MATCH, patients who developed a stronger alliance in treatment were more likely to attend AA during and after treatment. In addition, patients in 12-step facilitation treatment were more likely to attend and affiliate with AA after treatment than were patients in cognitive-behavioral or motivational enhancement treatment (Tonigan et al. 2003). In another study, patients with SUDs treated in 12-step facilitation and eclectic programs (which also emphasized 12-step principles) participated more in 12-step SHGs after treatment than did patients treated in cognitive-behavioral programs. Specifically, these patients were more likely to attend meetings, talk to a sponsor, read 12-step literature, incorporate the steps into their daily life, and talk to friends in 12-step groups (Humphreys et al. 1999a). These findings suggest that referral and alliance processes in treatment contribute to participation in SHGs. The development of a treatment alliance may enhance patients' motivation for recovery and underlie the impact of counselors' recommendations to affiliate with SHGs and the overall duration of continuing to obtain help. Moreover, treatment that specifically emphasizes the value of SHGs in recovery encourages more SHG involvement than treatment that does not have this emphasis.

Treatment, Self-Help Groups, and Substance Use Outcomes Participation in treatment and participation in SHGs have independent effects on substance use outcomes and tend to augment each other. Compared with patients who participated only in 12-step SHGs or only in outpatient mental health care after discharge from residential care, patients who participated in both outpatient care and SHGs experienced better 1-year substance-related outcomes (Ouimette et al. 1998). Similarly, among clients with drug use disorders, longer episodes of treatment and weekly or more frequent SHG attendance during and after treatment were each independently associated with 6-month abstinence (Fiorentine and Hillhouse 2000a). Moreover, findings obtained in a nationwide sample of alcohol-dependent individuals showed that those who participated in 12-step SHGs in addition to treatment were more than twice as likely to achieve an abstinent recovery as were individuals who obtained formal treatment alone (Dawson et al. 2006). Among patients dependent on cocaine, participation in individual drug counseling and 12-step SHGs each had unique benefits; patients who received the counseling and increased their 12-step SHG participation in the first 3 months of treatment had the best drug use outcomes at the end of treatment (Weiss et al. 2005). In the long-term study of individuals with alcohol use disorders described earlier, individuals who participated in both treatment and AA were more likely to be remitted at both 1-year and 16-year follow-ups than were individuals who received only treatment in the first year (Moos and Moos 2005). These findings counter the concern that entry into treatment might reduce motivation to affiliate with SHGs; in fact, they suggest that participation in treatment tends to strengthen SHG affiliation and thereby to bolster the effects of treatment.

Support and Intensity of Treatment A supportive and spiritually oriented treatment environment can enhance participation in 12-step activities. In this vein, patients in more supportive treatment environments increased more in 12-step involvement during treatment—that is, they were more likely to acquire a sponsor and 12-step friends and to read 12-step literature. Moreover, when patients who had a high risk of dropping out of SHGs

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after treatment were treated in a more supportive environment, their risk of dropout declined (Kelly and Moos 2003). A stronger spiritual orientation in treatment also has been related to more posttreatment SHG involvement (Mankowski et al. 2001). In contrast, participation in SHGs may compensate for the lack of services provided in treatment. In a study of dually diagnosed patients in residential programs, more attendance at 12-step SHGs was associated with better substance use and psychiatric outcomes both at discharge and 1-year follow-up. Importantly, the benefits of 12-step SHG attendance depended on the intensity of services provided during treatment. More 12-step SHG attendance during treatment was associated with better alcohol and drug outcomes at discharge only among patients treated in low-service intensity programs; also, more attendance after discharge was associated with better psychiatric and family/social functioning at 1 year only among patients receiving low-service intensity care (Timko and Sempel 2004).

Mediation of Treatment Effects Participation in SHGs may mediate or explain part of the effects of treatment on substance use outcomes. According to Humphreys et al. (1999a), the orientation of treatment influenced the outcome of SHG participation: as the treatment emphasis on 12-step approaches increased, the positive relationship of SHG participation to better substance use outcomes became stronger. More specifically, there was a stronger relationship between 12-step SHG participation and better substance use outcomes among patients from 12-step treatment programs than among patients from cognitive-behavioral or eclectic programs. Posttreatment SHG involvement partially mediated higher rates of abstinence and freedom from substance use problems in patients from 12-step than in patients from cognitivebehavioral treatment programs. Essentially comparable findings were obtained in the National Institute on Drug Abuse Collaborative Cocaine Treatment study. Patients in individual drug counseling that emphasized 12-step principles changed more in 12-step beliefs and behaviors than did patients in supportive-expressive therapy and cognitive therapy, which placed less emphasis on 12-step ideology. These patients also experienced better end-of-treatment substance use outcomes; changes in patients' 12-step beliefs and behaviors explained or mediated part of this effect (Crits-Christoph et al. 2003). However, changes in 12-step involvement did not precede changes in drug use, suggesting that increases in 12-step involvement may occur together with or after improvements in drug use. For example, individuals might attribute reductions in their drug use to the 12-step approach and then increase their commitment to 12-step SHGs in the expectation that this will help them maintain abstinence. Thus, declines in substance use may precede and motivate subsequent changes in 12-step beliefs and behaviors.

SELF-HELP GROUPS AND HEALTH CARE UTILIZATION AND COSTS Two prospective studies have highlighted the potential for SHG involvement to reduce the use and costs of health care. Compared with individuals who initially obtained professional outpatient care, individuals who entered AA had less income and education and experienced more adverse consequences of drinking at baseline, suggesting somewhat worse prognoses. Nevertheless, individuals who initially sought help from AA had alcohol-related and psychosocial outcomes comparable with those who initially obtained outpatient treatment and had 45% lower alcohol-related health care costs over a 3-year period (Humphreys and Moos 1996). By increasing their patients' reliance on SHGs, professional treatment programs that emphasize 12-step approaches may lower subsequent health care costs. In this vein, compared with patients treated in cognitive-behavioral programs, patients treated in 12-step programs were more involved in SHGs at both 1-year and 2-year follow-ups after discharge from acute treatment. In contrast, patients treated in cognitive-behavioral programs received more inpatient and outpatient care after discharge, resulting in 64% higher 1-year and 30% higher 2-year annual health care costs. Substance use and psychiatric symptom outcomes were comparable across treatments, except that 12-step patients had higher rates of abstinence at both the 1-year and 2-year follow-ups (Humphreys and Moos 2001, 2007).

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PERSONAL FACTORS, PARTICIPATION, AND SELF-HELP GROUP OUTCOMES In a search to identify individuals who may be especially well-suited for participation in SHGs, researchers have examined a range of personal factors, including severity and impairment related to substance use, psychiatric disorders, and disease model beliefs and religious/spiritual orientation. In addition, some studies have focused on the suitability of SHGs for individuals who are court mandated to attend as well as for women and youth and older adults.

Severity and Impairment Individuals who are heavier substance users and have more substance-related problems, are more dependent on substances, and lack control over their substance use are more likely to affiliate with SHGs. More-impaired clients also are more likely to continue SHG attendance and less likely to drop out after treatment than are less impaired clients (Connors et al. 2001; Tonigan et al. 2006). Compared with individuals with less severe substance use problems, those with more-severe problems may benefit more from SHG involvement. Morgenstern et al. (2003) found that patients with more-severe substance use and psychosocial problems who had high levels of SHG affiliation had better 6-month substance use outcomes; outcomes were poor when group affiliation was low. For patients who had less severe problems, levels of SHG affiliation were not related to outcomes. Individuals with more-severe problems may benefit more from the support and structure of SHGs because it helps to alleviate their distress and increase their self-control and interpersonal and coping skills.

Psychiatric Disorders Many patients with SUDs also have co-occurring psychiatric disorders. With the exception of patients with psychotic disorders, these dually diagnosed patients are as likely to attend 12-step SHGs as are patients with only SUDs (Jordan et al. 2002). More importantly, some dually diagnosed patients appear to benefit as much from substance use–focused 12-step SHGs as do patients with only SUDs. A study of patients discharged from hospital-based residential treatment showed that dually diagnosed patients attended a comparable number of 12-step SHG meetings in the 3 months before 1-year, 2-year, and 5-year follow-ups as did patients with only SUDs. SHG attendance was similarly associated with a higher likelihood of 1-year and 5-year remission for both groups of patients (Ouimette et al. 1998; Ritsher et al. 2002a, 2002b). A few studies have focused on patients with specific psychiatric disorders. Patients with SUDs and posttraumatic stress disorders who were more involved in 12-step SHGs during treatment relied more on approach and less on avoidance coping at discharge; they also had fewer psychological symptoms. In contrast, there was little or no relationship between SHG involvement during treatment and these discharge outcomes among patients who had only SUDs. Patients with SUDs and posttraumatic stress disorder participated as much in 12-step SHGs in the first 2 years after discharge from treatment as did patients with only SUDs. The dually diagnosed patients who participated more in SHGs were more likely to be abstinent and experienced less distress; they also were more likely to maintain stable remission (Ouimette et al. 2000). The situation may be different for patients who have SUDs and co-occurring major depression. Compared with patients with only SUDs, those who also have major depression were less likely to become involved in 12-step SHGs in the year after treatment. At a 2-year follow-up, the association between SHG involvement and abstinence was stronger for patients who had only SUDs than for patients who also had major depression, who did not benefit as much from contact with a sponsor, 12-step friends, reading 12-step literature, and working the steps. Depressed individuals may have interpersonal problems that make it harder to develop friendships and acquire a sponsor; thus, they may need more support to become involved in and benefit from 12-step SHGs (Kelly et al. 2003). Traditional 12-step SHGs may have some limitations for dually diagnosed individuals because these individuals may bond less with other members who do not share the experiences associated with

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psychiatric problems. The guidance dually diagnosed individuals obtain from other members, although well-intentioned, may be misinformed; other members also may have equivocal or negative attitudes about the use of medications to prevent relapse or alter mood. Given these issues, some dually diagnosed individuals, especially those with Axis I psychiatric disorders, may do better in dual-focused 12-step SHGs, such as Double Trouble in Recovery (DTR). DTR is a mutual aid program adapted from the 12-step method of AA to focus specifically on dually diagnosed individuals' needs. Individuals who experience more psychiatric symptoms and more severe consequences of substance use are more likely to maintain attendance in DTR, which is associated with better adherence to medication regimens. Two processes that are closely related to group support involve assuming a helping role by providing support to other members and reciprocal learning, or the opportunity to learn new attitudes and skills from role models and share information at meetings. DTR members who assumed a helping role and engaged more in reciprocal learning were more likely to be abstinent at a 1-year follow-up (Magura et al. 2003). Members who had more sustained participation in DTR over a 1-year interval were less likely to use substances at a 2-year follow-up; this effect was partially explained by their higher levels of group-related social support (Laudet et al. 2004).

Disease Model Beliefs and Religious/Spiritual Orientation Individuals whose beliefs are more consonant with the 12-step orientation are more likely to affiliate with 12-step SHGs. More specifically, patients who believe in the disease model of substance use and have an abstinence goal and an alcoholic or addict identity tend to become more involved in SHGs and are less likely to drop out (Kelly and Moos 2003; Mankowski et al. 2001). Patients with both SUDs and posttraumatic stress disorder whose identity matched 12-step philosophy participated more in SHG activities; more participation was associated with less distress for these patients but with more distress for patients who did not have a 12-step identity (Ouimette et al. 2001). Because of the emphasis on spirituality in 12-step SHGs, there has been speculation that less religious or less spiritually inclined individuals may participate and benefit less from these groups. In fact, individuals with stronger religious beliefs are more likely to attend and become involved in 12-step SHGs and are less likely to drop out (Kelly and Moos 2003; Timko et al. 2006a). In a 3-year study that examined the role of religiosity in AA, more spiritually oriented individuals reported attending more meetings than did secular individuals; in addition, secular and uncommitted individuals had a sharper decline in AA involvement than spiritual and religious individuals did. These findings suggest that 12-step SHGs are accessible but somewhat less engaging for more secular individuals (Kaskutas et al. 2003). Importantly, when they do become involved in SHGs, less religious individuals appear to derive as much or more benefit from them as more religious individuals do (Kaskutas et al. 2003). In two large multisite studies, participation in SHGs was associated with better substance use outcomes, irrespective of the strength of individuals' religious beliefs or belief in God (Tonigan et al. 2003; Winzelberg and Humphreys 1999).

Court-Mandated Attendance Individuals who are court mandated to attend AA appear to have quite similar experiences in AA as do individuals who participate without a court mandate. In this vein, Humphreys et al. (1998) found that, compared with nonmandated patients, mandated patients attended more meetings and were more likely to report having had a spiritual awakening. By extension, patients who are court mandated to treatment should be as good candidates for referral to AA as patients who enter treatment without a court mandate. In fact, mandated and nonmandated patients may be equally likely to have prior experience with AA, to report an alcoholic identity, and to become involved in 12-step SHGs during and in the year after treatment.

Women Women with alcohol or drug use disorders are as or more likely than men to attend SHGs and to

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continue to participate in them. Participation in SHGs also is associated with as good or better outcomes for women as for men (Kaskutas et al. 2005). In a comparison of women and men with alcohol use disorders, women were more likely than men to attend AA and went to more AA meetings in the first year after initiating help seeking. More extended participation in AA was associated with a higher likelihood of 1-year remission for both women and men; however, the positive association between a longer duration of AA attendance and stable remission was stronger for women (Moos et al. 2006). Compared with men, women may be more in tune with 12-step philosophy, which involves acceptance of powerlessness over the abused substance and dependence on a higher power to attain sobriety. Women with SUDs often report low self-esteem, an external locus of control, stable attributions for failure, and frequent substance use when feeling powerless or inadequate. These personal characteristics are congruent with 12-step ideology, which expects individuals with substance use problems to admit past wrongdoing, acknowledge inability to control substance use, and trust a higher power to achieve recovery. Importantly, however, Women for Sobriety is a self-help program that provides an alternative for women who prefer an emphasis on improving self-esteem, independence, and personal responsibility rather than powerless, humility, and surrender (Kaskutas 1996).

Youth Many adolescents attend SHGs after treatment, and those who do tend to experience better substance use outcomes. SHG attendance in the 3 months after discharge is associated with better 3-month and 6-month outcomes among youth; the association between attendance and remission holds for youngsters who have severe substance use and personality problems (Kelly et al. 2000; Kennedy and Minami 1993). SHG attendance in the first 6 months after treatment also has been associated with better 12-month outcomes. According to Kelly et al. (2002), attendance at 12-step meetings in the first 3 months after treatment was associated with more motivation for abstinence and self-efficacy at 3-month follow-up, which predicted abstinence at 6-month follow-up. The strength of affiliation with SHGs explained part of the connection between 12-step attendance and motivation for abstinence, which explained some of the link between attendance and 6-month outcomes. Thus, youngsters' attendance appears to contribute to affiliation, which enhances motivation for abstinence; motivation then helps to explain why attendance is related to better substance use outcomes. Adolescents often attribute their relapses to social situations and the pressure to use substances. Therefore, they may benefit from contact with a sponsor who can be a role model, structure that helps them avoid high-risk situations, participation in substance-free social events, and the opportunity to try out a new lifestyle. However, there also are important barriers to SHG participation for adolescents, including less severe substance-related problems and less motivation for abstinence, discomfort with the emphasis on spirituality, and younger age relative to most members, who may be concerned with marital and employment problems that are less relevant to adolescents.

Older Adults Late-middle-aged and older adults participate in and benefit from 12-step SHGs. In two studies, groups of older patients (ages 55 years or more) with SUDs were matched with younger (ages 21–39 years) and middle-aged (ages 40–59 years) patients on the basis of demographic factors and dual diagnosis status. These three groups of patients attended a comparable number of SHG meetings during and in the 2 years after residential treatment and were equally likely to have a sponsor. Overall, patients who attended more group meetings and those who had a sponsor in the first year experienced better 1-year alcohol and psychological distress outcomes. Patients who attended more meetings and had a sponsor in the second year reported less alcohol consumption at a 5-year follow-up. The three age groups did not differ in the associations between 12-step SHG attendance and these outcomes (Lemke and Moos 2003a, 2003b).

SELF-HELP GROUPS FOR FAMILY MEMBERS

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Al-Anon and other mutual help groups, such as Nar-Anon, Alateen, and Adult Children of Alcoholics (ACA), were developed to support the family members and friends of individuals with substance use problems. These groups try to help individuals affected by another person's substance use increase their own well-being, independence, and self-esteem. The groups provide support and guidance, teach members new coping skills, and expose them to models of how to handle a family member's abuse. Although these groups have not been extensively evaluated, some evidence indicates that they improve their members' psychological well-being and functioning (Fernandez et al. 2006). In a study that compared family members of patients with SUDs who attended Al-Anon with those who did not, the Al-Anon group improved more in family functioning; moreover, the 3-month relapse rate for patients whose family members attended Al-Anon was lower than that for patients whose family members did not attend (Friedemann 1996). Another study showed that ACAs who had substance use problems and attended an ACA-specific mutual help group, which followed Al-Anon and 12-step principles, reported more benefits from being an ACA member than did comparable individuals who attended substance abuse education classes. The group participants also declined more in depression and substance use; individuals who participated more intensively in the group experienced less stigma and more self-esteem at a 6-month follow-up (Kingree and Thompson 2000).

INGREDIENTS OF SELF-HELP GROUP OUTCOMES The effectiveness of SHGs in curtailing substance use is based largely on four key ingredients: 1) support, goal direction, and structure that emphasizes abstinence and the importance of strong bonds with family, friends, work, and religion; 2) participation in substance-free social activities, 3) identification with abstinence-oriented role models and a consistent belief system that espouses a substance-free lifestyle, and 4) an emphasis on bolstering members' self-efficacy and coping skills and helping others overcome substance use problems. SHGs are an important source of abstinence-specific and general support and may be especially effective in counteracting the influence of substance users in a social network. These groups provide guidance, goal direction, and monitoring by offering modeling of substance use refusal skills, ideas about how to avoid relapse-inducing situations, and practical advice for staying sober. Individuals who continue to attend AA more regularly after treatment are more likely to have social network members who support cutting down or quitting substance use than are individuals who attend AA less regularly. In fact, the increase in friends' support associated with SHGs explains part of their positive influence on remission (Humphreys et al. 1999b). In addition to obtaining support, providing support to others may benefit recovering individuals because it increases a commitment to abstinence, satisfaction from helping other individuals in need, and the helper's own sense of independence and self-efficacy. In fact, recovering individuals who help their peers to maintain long-term sobriety are better able to maintain sobriety themselves (Pagano et al. 2004). Patients who engage in more helping during treatment tend to be more involved in SHGs after treatment and, in turn, are more likely to achieve abstinence (Zemore et al. 2004). Moreover, SHG members who become sponsors are more likely to maintain abstinence than those who do not; this effect appears to be independent of SHG attendance (Crape et al. 2002). Participation in SHGs also is related to increases in common change factors other than social support, especially motivation for recovery, self-efficacy to resist drinking, and approach coping (Morgenstern et al. 1997). In Project MATCH, participation in AA was related to more self-efficacy to avoid drinking, which predicted a higher likelihood of abstinence. Self-efficacy explained part of the association between participation in AA and abstinence. In addition, AA attendance at 6 months posttreatment predicted self-efficacy at 9 months, which predicted abstinence at 15 months. Self-efficacy to avoid drinking mediated part of the effect of AA attendance on abstinence for both less severe and more severe alcoholic individuals (Bogenschutz et al. 2006; Connors et al. 2001). A few other studies have also shown that improvements in common change factors explain some of the effects of SHGs. Individuals who attend 12-step groups tend to develop new friends who are more likely

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to abstain from substances and provide more support for recovery (Humphreys and Noke 1997); this is also associated with increases in approach coping. According to Humphreys et al. (1999b), almost half of the association between SHG involvement and 1-year substance use was explained by these support and coping indices. Friends' support for abstinence was a more powerful mediator of the relationship between SHG involvement and substance use than was general friendship quality. Affiliation with 12-step SHGs also tends to promote more reliance on behaviorally oriented substance use coping processes. In this respect, Snow et al. (1994) found that individuals who were more involved in AA were more likely to rely on specific coping responses aimed toward reducing substance use, such as spending time with nondrinking friends, talking to someone about their drinking problems, rewarding themselves for trying to stop drinking, and becoming more aware of social efforts to help people stop drinking. The effective ingredients of SHGs reflect the four critical factors that appear to aid long-term recovery from an SUD: 1) forming bonds and obtaining social support from new relationships, such as a new spouse or partner or a sponsor; 2) supervision or monitoring, such as by a sponsor or a spouse or partner, and the provision of positive consequences for continued remission; 3) involvement in rewarding activities that do not involve substance use, such as a program of exercise, spiritual or religious pursuits, or social and service activities and include helping other people; and 4) affiliation with a group that provides a sustained source of hope, inspiration, and self-esteem, such as AA or a religion.

KEY POINTS Sustained attendance at self-help groups (SHGs) is associated with a higher likelihood of abstinence and better substance use outcomes. Involvement in SHGs may accrue benefits over and above those of attendance itself. Delay in participation and dropout from SHGs foreshadows poorer substance use outcomes. Participation in SHGs can substitute for, bolster, and help to explain the benefits of treatment; it can also reduce health care utilization and costs. Less religious individuals appear to benefit from SHGs as much as do individuals who are more religious. Individuals who are court mandated to participate in SHGs benefit as much from them as do nonmandated patients. Women and older adults engage in and benefit from SHGs as much as or more than men and younger adults do. SHGs contribute to better substance use outcomes by providing support, goal direction, and structure; exposure to abstinent role models; reward for substance-free activities; and a focus for building self-confidence and coping skills.

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outpatient treatment. Drug Alcohol Depend 72:237–247, 2003 [PubMed] Ouimette PC, Moos R, Finney J: Influence of outpatient treatment and 12-step group involvement on one-year substance abuse treatment outcomes. J Stud Alcohol 59:513–522, 1998 [PubMed] Ouimette PC, Moos R, Finney J: Two-year mental health service use and course of remission in patients with substance use and posttraumatic stress disorders. J Stud Alcohol 61:247–253, 2000 [PubMed] Ouimette PC, Humphreys K, Moos R, et al: Self-help participation and functioning among substance use disorder patients with posttraumatic stress disorder. J Subst Abuse Treat 20:25–32, 2001 [PubMed] Pagano ME, Friend KB, Tonigan JS, et al: Helping other alcoholics in Alcoholics Anonymous and drinking outcomes: findings from Project MATCH. J Stud Alcohol 65:766–773, 2004 [PubMed] Ritsher JB, McKellar JD, Finney JW, et al: Psychiatric comorbidity, continuing care, and mutual-help as predictors of five-year remission from substance use disorders. J Stud Alcohol 63:709–715, 2002a Ritsher JB, Moos R, Finney J: Relationship of treatment orientation and continuing care to remission among substance abuse patients. Psychiatr Serv 53:595–601, 2002b Room R, Greenfield T: Alcoholics Anonymous, other 12-step movements, and psychotherapy in the U.S. population, 1990. Addiction 88:555–562, 1993 [PubMed] Snow MG, Prochaska JO, Rossi JS: Processes of change in Alcoholics Anonymous: maintenance factors in long-term sobriety. J Stud Alcohol 55:362–371, 1994 [PubMed] Timko C, Sempel JM: Intensity of acute services, self-help attendance, and one-year outcomes among dual diagnosis patients. J Stud Alcohol 65:274–282, 2004 [PubMed] Timko C, Billow R, DeBenedetti A: Determinants of 12-step group affiliation and moderators of the affiliation–abstinence relationship. Drug Alcohol Depend 83:111–121, 2006a Timko C, DeBenedetti A, Moos B, et al: Predictors of 16-year mortality among initially untreated individuals with alcohol use disorders. Alcohol Clin Exp Res 30:1711–1720, 2006b Tonigan JS, Connors GJ, Miller WR: Participation and Involvement in Alcoholics Anonymous, in Matching Alcoholism Treatments to Client Heterogeneity: The Results of Project MATCH. Edited by Babor TF, Del Boca FK. New York, Cambridge University Press, 2003, pp 184–204 Tonigan JS, Bogenschutz MP, Miller WR: Is alcoholism typology a predictor of both Alcoholics Anonymous affiliation and disaffiliation after treatment? J Subst Abuse Treat 30:323–330, 2006 [PubMed] Toumbourou JW, Hamilton M, U'Ren A, et al: Narcotics Anonymous participation and changes in substance use and social support. Drug Alcohol Depend 23:61–66, 2002 [PubMed] Weiss RD, Griffin ML, Gallop RJ, et al: Self-help group attendance and participation among cocaine dependent patients. Drug Alcohol Depend 60:169–177, 2000 [PubMed] Weiss RD, Griffin ML, Gallop RJ, et al: The effect of 12-step self-help group attendance and participation on drug use outcomes among cocaine-dependent patients. Drug Alcohol Depend 77:177–184, 2005 [PubMed] Winzelberg A, Humphreys K: Should patients' religiosity influence clinicians' referral to 12-step self-help groups: evidence from a study of 3,018 male substance abuse patients. J Consult Clin Psychol 67:790–794, 1999 [PubMed] Witbrodt J, Kaskutas LA: Does diagnosis matter? Differential effects of 12-step participation and social networks on abstinence. Am J Drug Alcohol Abuse 31:685–707, 2005 [PubMed] Zemore SE, Kaskutas LA, Ammon LN: In 12-step groups, helping helps the helper. Addiction 99:1015–1023, 2004 [PubMed]

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Humphreys K: Circles of Recovery. New York, University Press, 2004 Kelly JF: Self-help for substance use disorders: history, effectiveness, knowledge gaps, and research opportunities. Clin Psychol Rev 23:639–663, 2003 McCrady BS, Miller WR (eds): Research on Alcoholics Anonymous. New Brunswick, NJ, Rutgers Center of Alcohol Studies, 1993 Nowinski J: Facilitating 12-step recovery from substance abuse and addiction, in Treating Substance Abuse: Theory and Technique, 2nd Edition. Edited by Rotgers F, Morgenstern J, Walters ST. New York, Guilford, 2003, pp 31–66 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 37. Adolescent Substance Abuse

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Yifrah Kaminer: Chapter 37. Adolescent Substance Abuse, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.360150. Printed 1 0/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Adolescent Substance Abuse Yifrah Kaminer, M.D.

ADOLESCENT SUBSTANCE ABUSE: INTRODUCTION Childhood and adolescence are not only critical phases for normal development but also periods when various pathological behaviors or disorders including substance use disorders (SUDs) are first recognized. Substance use among American youth rose to alarming rates between 1992 and 1997. Since then it has decreased significantly for alcohol, tobacco, and all drug classes but prescription opiates, the use of which continues to increase (Johnston et al. 2006). There is a concern regarding the short- and long-term physical and mental health outcomes of adolescents who use psychoactive drugs. The use of alcohol and other drugs is a leading cause of morbidity and mortality among adolescents from motor vehicle accidents, suicidal behavior, violence, drowning, and unprotected sexual activity, including unplanned pregnancy and sexually transmitted diseases (Blum and Nelson-Mmari 2004). Lifetime diagnoses of alcohol and drug abuse among adolescents in different states in the United States range from 3% to 10% (Harrison et al. 1998; Lewinsohn et al. 1996). The National Survey on Drug Use and Health reported that 6% and 5.4% of youth ages 12–17 years were classified as needing treatment for alcohol use and illicit drug use, respectively (SAMHSA 2006). Due to lack of motivation among youth, limited resources, lack of a broad consensus on preferred treatment strategies, and inadequate age-appropriate programs, only a small segment of adolescents in need of treatment end up receiving services. In this chapter, I first review the literature on the normative and pathological development of adolescent substance use, including nosological aspects, while placing particular emphasis on the transition from substance use to substance abuse and dependence (i.e., SUDs). I then discuss the difference between substance use and SUDs and describe psychiatric comorbidity. The last sections of the chapter address the prevention, assessment, and treatment of SUDs in adolescents and aftercare of adolescent patients with SUDs.

NOSOLOGY Normative Behavior Although any nonmedical use of drugs (including tobacco and alcohol) by adolescents is illegal and can therefore be viewed as a form of abuse, this perspective ignores some key epidemiological findings. Specifically, the high prevalence of alcohol and tobacco use underscores the fact that use of alcohol and tobacco can be viewed as normative, or at least not exceptionally deviant. By age 18 years, approximately 80% of youth in the United States have consumed alcohol, two-thirds have smoked cigarettes, and half have used an illicit drug at least once. Four percent of adolescents drink alcohol daily and 13% smoke half a pack of cigarettes a day (Johnston et al. 2006). Most adolescents who engage in substance use do not develop SUDs as defined by DSM-IV-TR criteria (American Psychiatric Association 2000). It is thus imperative to understand adolescent substance use in the context of changeable patterns of normative behavior and to distinguish this behavior from an SUD. Adolescence has long been recognized as a phase of transition (Erikson 1968). During this period of life, biological and psychological maturation are completed. "Adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity, and addiction. Adolescent impulsivity and/or novelty seeking as a transitional trait behavior can be explained in part by maturational changes in frontal

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cortical and subcortical monoaminergic Greg/APPI Editor: I assume you meant "monoaminergic" (vs "monoamingergic"). systems. These developmental processes may advantageously promote learning drives for adaptation to adult roles and may also confer greater vulnerability to the addictive actions of drugs" (Chambers et al. 2003, p. 1041). The social roles of adulthood are increasingly assumed during the final stage of sexual, physical, and psychological maturation. Working, driving, engaging in sexual activity, and experimentation with psychoactive substances in social contexts, particularly alcohol and tobacco, are adultlike activities and behaviors that become increasingly common. Some substance use during adolescence may represent a social norm in an environment where drug availability is perceived as high and harmfulness is perceived as low.

Pathological Behavior Temperament deviations have been shown to be associated with psychopathology and substance abuse (Reich et al. 1993). Children having a "difficult temperament" commonly manifest externalizing and internalizing behavior problems by middle childhood (Earls and Jung 1987) and in adolescence (Maziade et al. 1990). High levels of behavioral activity have been noted in youth at high risk for substance abuse as well as in those with an SUD. High levels of behavioral activity also correlate with disorder severity (Tarter et al. 1990a, 1990b). Other temperamental trait deviations found in youth at high risk include reduced attention span (Schaffer et al. 1984); high impulsivity (Noll et al. 1992); negative affect states, such as irritability (Brook et al. 1990); and emotional reactivity (Blackson 1994). Tarter et al. (1994) used the Difficult-Temperament Index to classify adolescent alcoholic patients. The obtained clusters were similar to the adult subtypes as reported by Cloninger (1987) and Babor et al. (1992). The smaller subset of adolescents manifesting behavioral dyscontrol and hypophoria were included in Cluster 2, whereas those with primarily negative affect were included in Cluster 1. Compared with Cluster 1 subjects, Cluster 2 subjects were younger at the time of first substance use, first substance abuse diagnosis, and first psychiatric diagnosis. Moreover, adolescents with a difficult temperament had a high probability of developing psychiatric disorders, such as conduct disorder, attention-deficit/hyperactivity disorder (ADHD), anxiety disorder, and mood disorders (Tarter et al. 1994). Tarter et al. (1997) also reported that Cluster 1 and Cluster 2 were identified in both genders.

INITIATION, MAINTENANCE, AND TRANSITIONS OF SUBSTANCE USE A number of behavioral dispositions and environmental influences are predictive of age at initiation of drug use, drug use intensity, and the experience of negative consequences during adolescence (Hawkins et al. 1992; Petraitis et al. 1995). Behavioral characteristics most commonly include impulsivity, aggression, sensation seeking, low levels of harm avoidance, inability to delay gratification, low levels of striving to achieve, lack of religiosity, and psychopathology, especially conduct disorder. Contextual or environmental factors that are most common include stressful life events, lack of support from parents, absence of normative peers, perception of high availability of drugs, social norms that facilitate drug use, and relaxed laws and regulatory policies. Clearly, manifold risk factors, each having different salience, determine overall risk for each person. In aggregate, these risk factors determine the slope and momentum of the developmental trajectory into adulthood, culminating in substance use, abuse, or dependence (Bates and Labouvie 1995). Temperament precursors such as impulsivity and novelty and sensation seeking tend to peak in late adolescence or early adulthood (Zuckerman 1994). Kandel (1982), the initial proponent of the gateway theory, argued that there are at least four distinct developmental stages of drug use: 1) beer or wine consumption, 2) cigarette smoking or hard liquor consumption, 3) marijuana use, and 4) other illicit drug use. According to Kandel, 26% of adolescents who use marijuana progress to the next stage of further illicit drug use, compared with only 4% who have never used marijuana. Golub and Johnson (1994) indicated that alcohol is losing its importance as a prerequisite for progression to marijuana, but marijuana's role as a gateway drug appears to have increased, and marijuana use nearly always precedes use of substances that are associated with less-normative attitudes (e.g., heroin). The best-supported hypothesis for the common comorbidity between alcohol dependence and illicit drug dependence in adolescents is a model hypothesizing that

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comorbid disorders are alternate forms of a single underlying liability (Rhee et al. 2006). The next best-fitting models are correlated risk factors and reciprocal causation. Kandel et al. (1986) studied the 10-year outcome of adolescent substance use at ages 15–16 years and found that the strongest predictor of drug use is prior drug use. However, the consequences of drug use affect every aspect of life in early adulthood. Illicit drug use begun at an early age has also been found to increase the risk of drug problems during late adolescence. According to the results of a retrospective analysis of the Epidemiologic Catchment Area data (Anthony and Petronis 1995), prior drug use predicts future drug use. However, in a prospective study of adolescents (Bates and Labouvie 1997), age at first use of illicit drugs did not emerge as an independent risk factor for either persistence or severity of drug use in adulthood. Alcohol and substance use increases until the early 20s and then plateaus when young adults manifest moderation or even cessation of youthful activities (Labouvie 1996). The decrease is accompanied by an increase in cognitive structure. When substance use behaviors at age 18 years are controlled, there is no significant relationship between adolescent risk and adult substance use intensity and consequences (Teichman et al. 1989). In effect, the impact of child and adolescent risk factors on adult substance use may be mediated by the intensity of substance use in late adolescence (Bates and Labouvie 1997). The available results suggest that programs aimed at reducing risk factors during adolescence may have more beneficial, long-term effects if they can limit drug use during the peak lifetime period, ages 18–21 years. Programs that focus on postadolescence thus need to concentrate on the concurrent risk factors that are not necessarily the same as those during adolescence. In early adolescence, prevention efforts should be directed at delaying onset of and increases in drug use because drug use predicts future drug use, although not in an invariant fashion. Approximately 8% of the U.S. population will fulfill the criteria for a diagnosis of an SUD. The cutoff point for a diagnosis of an SUD or substance dependence is somewhat arbitrary, however, particularly in adolescents (Rohde et al. 1996). The importance of differentiating between substance abuse and dependence in treatment was supported by empirical evidence provided by Hasin et al. (1990). They concluded that most adults with a diagnosis of substance abuse had never progressed to dependence. Abuse and dependence are therefore distinct, and abuse is not always a prodrome and may be developmentally limited in many adolescents. The DSM-IV (American Psychiatric Association 1994) diagnostic criteria for substance abuse and dependence are the same for adolescents and adults. Empirical data generally support the validity of the DSM-IV criteria for adolescents (Lewinsohn et al. 1996; Martin et al. 1995). Pollock and Martin (1999) demonstrated the importance of a new nosological entity in youth, titled orphan diagnoses, that includes subthreshold symptomatology of alcohol dependence (i.e., one or two symptoms only). A 3-year follow-up study demonstrated that this entity has a unique trajectory dissimilar to the trajectory of abuse or dependence.

PSYCHIATRIC COMORBIDITY Psychiatric disorders in childhood, particularly the disruptive behavior disorders, confer an increased risk for the development of SUDs (Bukstein et al. 1989; Diamond et al. 2006). However, the etiological mechanisms have not been systematically researched. A number of possible relationships exist between SUDs and psychopathology. Psychopathology may precede SUDs, develop as a consequence of preexisting SUDs, moderate the severity of SUDs, or originate from a common vulnerability (Hovens et al. 1994). A number of psychiatric disorders are commonly associated with SUDs in youth. Conduct disorder is commonly associated with adolescent SUDs, and if it occurs it usually precedes the SUD (Loeber 1988; Milin et al. 1991). Rates of conduct disorder range from 50% to 80% in adolescent patients with SUDs. ADHD is frequently observed in substance-abusing youth; such an association is likely due to the high level of comorbidity between conduct disorder and ADHD as well as to a direct positive causation (Molina and Pelham 2003; Wilens 2004). In addition, mood disorders, especially depression, frequently precede substance use and SUDs in adolescents (Bukstein et al. 1992; Deykin et al. 1992). The

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prevalence of depressive disorders ranges from 24% occurrence among adolescents to more than 50%. The empirical literature also supports an association between SUDs and suicidal behavior in adolescents (Goldston 2004). Adolescents who commit suicide are frequently under the influence of alcohol or other drugs at the time of suicide (Brent et al. 1987). Possible mechanisms underlying this relationship include the direct acute pharmacological effects and chronic neurological effects of psychoactive substances. Acute intoxication may be experienced as a transient but intense dysphoric state, with behavioral disinhibition and impaired judgment. Substance use may also exacerbate preexisting psychopathology, especially impulse dyscontrol, depression, and anxiety. Several studies of clinical populations have found a high rate of anxiety disorder among youth with SUDs (Clark and Sayette 1993; Clark et al. 1995). In adolescent patients with SUDs, the prevalence of anxiety disorder ranged from 7% to more than 40% (Clark et al. 1995; Stowell 1991). The order of appearance of anxiety and SUDs is variable, depending on the specific anxiety disorder. Social phobia usually precedes substance abuse, whereas panic and generalized anxiety disorder more often follow the onset of SUDs (Kushner et al. 1990). Adolescents with SUDs often have a history of posttraumatic stress disorder from physical or sexual abuse (Clark et al. 1995; Van Hasselt et al. 1993). Bulimia nervosa (Bulik et al. 2004) and personality disorders, particularly those in Cluster B (Grilo et al. 1995), are also commonly found in adolescents with SUDs. Griffiths (1995) reported that pathological gambling in British youth preceded substance abuse. However, my colleagues and I did not find elevated rates of pathological gambling among adolescent substance abusers (Kaminer et al. 2002a). Treatment of dually diagnosed conditions should be addressed simultaneously and not sequentially. Integrative psychosocial interventions or a combination of psychopharmacological and psychosocial interventions are the rule rather than the exception (Riggs and Davies 2002). For more comprehensive information please refer to the only textbook on dual diagnosis in youth, by Kaminer and Bukstein (2008).

PREVENTION Efforts to curtail substance abuse have historically concentrated on modifying the supply to-demand ratio. However, reduction of supply cannot succeed as long as a demand exists. Hence, reducing demand is an integral component of prevention. Laws and regulations can reduce demand. For example, alcohol consumption decreased in youth when the cost of alcoholic beverages or the legal drinking age was increased. A reduction in car accidents was associated with the increase in the legal drinking age to 21 years. Finally, alcohol advertising has been found to contribute to increased drinking among youth (Snyder et al. 2006). An overarching goal of prevention is to delay initiation of use of gateway substances such as cigarettes, alcohol, and marijuana. Research findings over the past two decades have provided a foundation for the development of effective approaches to substance abuse prevention. The traditional prevention strategy involves an educational program designed to increase knowledge of the consequences of drug use. However, that increased knowledge alone prevents drug use is not supported by available evidence (Schinke et al. 1991). Alternative activities programs and affective education that is designed to increase self-esteem and responsible decision making have also been found to be ineffective in preventing drug use (Tobler 1986). More promising prevention strategies are aimed at enhancing social skills and drug-refusal skills. Botvin et al. (1995) developed a curriculum involving teaching of general life skills and of skills for resisting social influences to use drugs. This Life Skills Training (LST) program was initially developed as a smoking prevention program led effectively by older peers or classroom teachers. Botvin et al. (1995) implemented the LST curriculum in the seventh grade at 56 schools (N = 3,597) and in booster sessions during the 2 years after completion of the initial intervention. The investigators reported evidence of long-term effectiveness and lasting reduction in drug use 5 years later among the twelfth graders who received the LST curriculum compared with those who did not. The generalizability of the LST prevention approach for African American and Hispanic youth has been supported (Botvin and Griffin

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2001). The challenge confronting health care providers is to identify high-risk individuals before or shortly after initiation of substance use. One of the largest high-risk populations comprises children who have a biological parent with a diagnosis of substance dependence. A balanced view is needed regarding the development and outcomes of children of alcoholic individuals because most children raised by an alcoholic parent do not develop alcoholism (Wilson and Crowe 1991). The interaction between risk and protective factors may influence the development or arrest of substance abuse in the vulnerable child. The study of resilience among youth growing up in substance-abusing families is of great importance (Wolin and Wolin 1996). To optimize outcomes of prevention efforts, an understanding of the heterogeneity of the adolescent population is required. In addition, prevention efforts need to take into account the developmental staging of substance use behavior. In this regard, prevention of SUDs must address the needs of adolescents in multiple domains of life. Prevention programs that are sensitive to ethnic differences also need to be continually devised (Catalano et al. 1993). Finally, dissemination is important because primary prevention programs proven to be successful, such as LST, are unlikely to have any real public health impact unless they are used in a large number of schools. Masterman and Kelly (2003) noted that the empirical literature suggests that universal prevention programs may delay the onset of drinking among low-risk baseline abstainers; however, there is little evidence supporting their utility for at-risk adolescents. Furthermore, they argue that motivational interviewing within a harm-reduction framework is well suited for secondary prevention in adolescents (see Chapter 25 in this volume, "Motivational Enhancement," for more on this topic).

ASSESSMENT An excellent review of issues in the assessment of adolescent substance use by Winters et al. (2001) stresses the importance of a meaningful assessment of a wide range of variables. Two major sets of assessment variables are considered here. One set of measures has been traditionally included in standardized screening and comprehensive assessment tools and is viewed as essential to the identification, referral, and treatment of problems associated with adolescent drug involvement. These measures include the severity of the drug abuse problem (e.g., preferred drugs; past and present use; age at onset of abuse; frequency, quantity, consequences of use; and treatment experience and response), risk factors, and protective factors. The second set of variables is important because of their mediating and moderating effects on treatment outcome. These include reasons for drug use and drug preference, expectations, readiness to change behavior, and self-efficacy. Self-reporting of substance use among adolescents is generally valid and detects more use than do laboratory tests (Buchan et al. 2002) or collateral reports (Fisher et al. 2006). Parental/collateral reporting of internalizing disorders has been traditionally much lower than that of externalizing disorders. Collateral reports of alcohol and drug abuse have been low to moderate in frequency compared with self-reporting or drug urinalysis (Burleson and Kaminer 2006). The use of screening instruments is essential as a brief first step for assessment of drug use before moving, if necessary, to the assessment of problem severity. Examples of reliable and valid screening tests include the Personal Experience Screening Questionnaire (PESQ), CRAFFT (a brief test named for the first letter of key words in six questions), Substance Abuse Subtle Screening Inventory (SASSI), Drug Use Screening Inventory–Revised (DUSI-R), and Problem-Oriented Screening Instrument for Teenagers (POSIT). Measures for the assessment of severity should follow once a positive screen is elicited. These include the Teen Addiction Severity Index (T-ASI), Adolescent Drug Abuse Diagnosis (ADAD), and Personal Experience Inventory (PEI). (For an updated comprehensive list of domains of measurement and respective instruments please refer to Knight et al. 2003 and Winters et al. 2001.) Finally, advancement in technology has allowed the development of telephone interactive voice response systems, which contribute to daily measurement of using situations and drug use (Kaminer et al. 2006). Computerized assessment is also progressing; for example, the Teen Addiction Severity Index (Kaminer et al. 1991, 1993) can be administered as a self-report instrument by telephone or by

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accessing a Web site (Brodey et al. 2005).

TREATMENT AND AFTERCARE The volume of research on psychosocial treatment for adolescent alcohol and other substance use disorders (AOSUDs) has increased significantly since the mid-1990s (Dennis and Kaminer 2006). Contrary to reviews of studies from the 1980s (Catalano et al. 1990–1991), more recent studies of treatment efficacy reveal that treatment is better than no treatment; however, there is no substantial variability in posttreatment outcomes (Dennis et al. 2004; Waldron and Kaminer 2004). Most studies in which prediction of outcome was a goal have focused on patient characteristics measured at the time treatment was initiated. Factors such as age, race, socioeconomic status, severity of drug use, and mental health status have been postulated to be associated with prognosis. Although some studies provide evidence of a relationship between pretreatment patient characteristics and outcome, the findings are not consistent. Variables such as severity of alcohol problems, severity of other drug use, severity of internalizing symptoms, and level of self-esteem are prognostic of treatment completion in American, Canadian, and Irish adolescents (Blood and Cornwall 1994; Doyle et al. 1994; Kaminer et al. 1992). Psychopathology, particularly conduct disorder, is negatively correlated with treatment completion and posttreatment abstinence (Kaminer et al. 2002b; Myers et al. 1995). Self-efficacy has been shown to be directly correlated with outcomes (Burleson and Kaminer 2005). Studies of psychosocial treatment strategies that have shown promise in reducing SUDs among adolescents include the following: Family therapies such as multisystemic therapy (Henggeler et al. 1996) Functional family therapy (Waldron et al. 2001) Multidimensional family therapy (MDFT; Liddle et al. 2001) Behavioral therapy (Azrin et al. 1994) Cognitive-behavioral therapy (CBT; Kaminer et al. 1998, 2002b; Waldron and Kaminer 2004) Motivational interviewing or motivational enhancement therapy (MI/MET; Tevyaw and Monti 2004) The 12-step Minnesota Model (Winters et al. 2000) Contingency management reinforcement (Kaminer 2000; Kamon et al. 2005) Adolescent community reinforcement approach (Godley et al. 2007) Integrative models of treatment (Dennis et al. 2004; Waldron et al. 2001) Although group therapy is widely used and presumed effective in practice, some scholars (Dishion et al. 1999) have raised the concern that group therapy for adolescents with SUDs and with a range of antisocial behaviors has the potential for causing iatrogenic effects (e.g., increased substance use, behavioral and legal problems) not only for those with high behavior deviancy but also for those with low deviancy (a contagion effect). Using data from 400 youth in the Cannabis Youth Treatment (CYT) study, Burleson et al. (2006) have recently demonstrated that a heterogeneous group including adolescents with and without conduct disorder did not have inferior substance use, psychological, environmental, or legal outcomes. In fact, the results indicated that there was a slight advantage for youth high in conduct disorder symptoms to be included in the groups with fewer symptoms. These results are consistent with recent meta-analyses of delinquency studies that have found no evidence of iatrogenic effects. The results support the common clinical experience that group therapy for youth with SUDs is a safe and effective treatment modality. The CYT study (Dennis et al. 2004) has been the largest (N = 600), most methodologically rigorous, multisite, randomized clinical trial designed to address the differential efficacy of the treatments implemented and treatment dose contribution to outcome. A total of five interventions were evaluated across the four sites. Two group CBT interventions were offered. Both began with two individual motivational enhancement sessions, followed by either three CBT sessions (MET/CBT-5; Sampl and Kadden 2001) or 10 CBT sessions (MET/CBT-12; Webb et al. 2002). A third intervention represented a family-based, add-on intervention involving MET/CBT-12 plus a 6-week family psychoeducational

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intervention. In addition, a 12-session individual adolescent community reinforcement approach (ACRA) and a 12-week family therapy condition were included. The five treatment models were evaluated in two arms, in a community-based program and an academic medical center. Although all five models were not implemented within treatment sites, the replication of the MET/CBT-5 intervention across all four sites made it possible to study site differences and conduct quasi-experimental comparisons of the interventions across study arms. All five interventions produced significant reductions in cannabis use and negative consequences of use from pretreatment to the 3-month follow-up, and these reductions were sustained through the 12-month follow-up. In addition, changes in marijuana use were accompanied by reductions in behavioral problems, family problems, school problems, school absences, argumentativeness, violence, and illegal activity. Although not entirely expected, some initial differences were found across the interventions. For example, the 12-session MET/CBT produced initially poorer outcomes relative to the briefer CBT intervention, findings that are inconsistent with a simple dose-response relationship. Also, despite considerable support for family interventions in the literature, the individual (ACRA) and individual/group (MET/CBT-5) behavioral interventions produced better outcomes than the family approach (MDFT) in terms of days of substance use at 3 months. Nevertheless, these initial differences were not sustained, and the best predictor of long-term outcomes was initial level of change. In terms of cost-effectiveness, MDFT was almost three times more expensive than any of the MET/CBT variants (French et al. 2002). Recognition of the heterogeneity of individuals with an SUD led to increasing interest in the issue of patient–treatment matching, or the identification of variables that predict differential response to various interventions. The development of American Society of Addiction Medicine (ASAM) Patient Placement Criteria for adults and adolescents works toward establishing a matching effect. The purpose of these criteria is to enhance objective decisions for matching different severity levels to various settings of care (Fishman 2008). Nevertheless, this might be an elusive goal; a patient may not have the option of referring or switching to a more appropriate treatment program. Chances may be limited by geographical factors, slot availability, insurance, psychiatric comorbidity, legal status, or other considerations. Following a comprehensive, multidimensional, functional assessment of patients' needs, it has been suggested that efforts be redirected from matching patients with programs to matching patients' problems with targeted services that meet their needs within the program. This model could be tailored to be complementary to or an alternative to future revised and tested ASAM Patient Placement Criteria (McLellan and Meyers 2004). Most studies on treatment outcomes for adolescents with SUDs have focused on completion of treatment rather than follow-up status. Reports of follow-up studies indicate that relapse rates are high. Eighty percent of adolescents with AOSUDs are treated in outpatient settings (SAMHSA 2005). Most treatment programs advocate a goal of abstinence. Yet, rates of dropout from treatment as well as partial or no reduction in use may range between 20% and 50% (Winters 1999). Maintenance of treatment gains in the months after treatment ends is another focus of concern. Brown et al. (1989) reported 60% and 80% relapse rates at 3 months and at 1 year, respectively, after completing treatment. Williams and Chang's (2000) comprehensive and comparative review of adolescent treatment outcomes reported that the average rate of sustained abstinence is 38% (range, 30%–55%) at 6 months and 32% at 12 months (range, 14%–47%). The findings from more recent studies (Dennis et al. 2004; Kaminer et al. 2002b; Waldron et al. 2001) have not been different. Relative to research evaluating the efficacy of psychosocial interventions for adolescent substance use problems, research evaluating the efficacy of pharmacotherapeutic interventions for teen substance abuse has been neglected. Yet, the largest subgroup of adolescents with SUDs presenting in clinical settings consists of those with both substance use and other psychiatric disorders. This particular subgroup may stand to benefit most from effective pharmacotherapies. Reports of substance-of-abuse-

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specific pharmacotherapies or comorbid psychiatric disorder pharmacotherapies in youth have usually been in the form of single case reports or small open-label studies. Only recently have several controlled studies been initiated. Most findings indicate that treatment of the psychiatric comorbidity, such as ADHD (Riggs et al. 2004) or depression (Cornelius et al. 2005), does not affect the AOSUD. Continued studies are necessary. For a comprehensive review of specific pharmacotherapies the interested reader is referred to Waxmonsky and Wilens (2005). Hoffmann and Kaplan (1991) reported that many communities often are lacking in aftercare/continued care services for adolescents with SUDs. Even if referrals are being made, many adolescents do not link to or only participate minimally in aftercare interventions. Godley et al. (2007) found that only 36% of adolescents discharged from residential treatment attended one or more aftercare sessions at community clinics. Many of those who do link to aftercare attend only a few sessions. There have been only two published empirical studies examining the efficacy of aftercare interventions in adolescents with SUDs discharged from residential treatment programs using an assertive aftercare model (Godley et al. 2007; Kaminer et al. 2006). Adolescents referred to continuing care services were significantly more likely to initiate and receive more continuing care services, to be abstinent from marijuana at 3 months postdischarge, and to reduce their 3-month postdischarge days of alcohol use when assigned to an assertive continuing care protocol (Godley et al. 2007). Kaminer et al. (2006) conducted an aftercare study with adolescents diagnosed with AOSUD in an outpatient setting comparing a no-active-aftercare condition to brief phone intervention and in-person therapy, both utilizing an integrative approach of CBT and MET (Kaminer and Napolitano 2004). There was a significant reduction in number of drinking days, days of heavy drinking, and suicidal ideations, and an increase in readiness to change marijuana use as a function of combined active aftercare conditions versus the no-activeaftercare condition. Aftercare intervention for adolescents with AOSUD shows promise in enhancing short-term relapse prevention and should be routinely implemented in treatment discharge plans. Furthermore, active engagement of adolescents referred from treatment to aftercare needs to be implemented. Finally, adolescents who do not complete planned treatment are usually those most in need because of an increased risk for being nonresponders and for relapse. Special efforts should be made to engage them in aftercare.

CONCLUSION The recent controlled clinical trials evaluating treatments for adolescent SUDs have contributed substantial new empirical evidence supporting the efficacy of treatment for SUDs. Research focusing on improving short- and long-term outcomes, improving engagement techniques, especially for individuals with conduct disorder and other individuals at risk for poor outcomes, and identifying youth for whom different treatment modalities or integrative interventions are likely to be beneficial (e.g., placement criteria) is essential. Finally, the problems of relapse and lack of maintenance of treatment gains make research on continuity of care, including aftercare, a priority.

KEY POINTS Adolescents are not "miniature adults." Developmental perspectives need to be addressed in the design of any intervention. Treatment is clearly better than no treatment, yet no single treatment modality has been found to be superior. Dual diagnoses need to be assessed and the conditions need to be treated simultaneously. Active aftercare is necessary to prevent relapse.

REFERENCES American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Washington, DC, American Psychiatric Association, 1994

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SUGGESTED READING Galanter M (ed): Recent Developments in Alcoholism, Vol 17: Alcohol Problems in Adolescents and Young Adults. New York, Kluwer Academic, 2004 Kaminer Y, Bukstein OG (eds): Adolescent Substance Abuse: Psychiatric Comorbidity and High Risk

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Behaviors. Binghamton, NY, Francis & Taylor, 2008 Liddle HA, Rowe CL (eds): Adolescent Substance Abuse: Research and Clinical Advances, London, Cambridge University Press, 2006 Wagner EF, Waldron HB (eds): Innovations in Adolescent Substance Abuse Interventions. Amsterdam, Pergamon, 2001 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 38. The Mentally Ill Substance Abuser

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Stephen Ross: Chapter 38. The Mentally Ill Substance Abuser, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.355147. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

The Mentally Ill Substance Abuser Stephen Ross, M.D.

THE MENTALLY ILL SUBSTANCE ABUSER: INTRODUCTION Although substance use disorders (SUDs) occur commonly in the psychiatrically ill, they are often underrecognized and undertreated. This has dire consequences for both individual patients and society in general. The immense economic burden of alcohol- and drug-related disorders alone and their associated adverse consequences has been estimated to cost the United States $375 billion annually (Office of National Drug Control Policy 2001). Moreover, in comparison with patients with only a mental illness or an SUD, patients with co-occurring mental illness and an SUD across a broad spectrum of diagnostic types and combinations have greater severity of illness and a worse longitudinal course of illness in multiple domains, including increased risk for psychiatric and substance use relapses; higher rates of recidivism; higher levels of psychological distress; poorer psychosocial functioning; worse treatment retention; poor medication compliance; higher rates of violence, suicide, legal difficulties, medical problems, and family stress; and higher utilization of health care services such as emergency department and inpatient services (Hser et al. 2006; Mueser et al. 1998; Ziedonis 2004). This chapter on co-occurring disorders includes the following sections: "History and Definitions," "Epidemiology," "Diagnostic Assessment," "Treatment," and "Treatment Outcomes." Of the non-SUD Axis I disorders, schizophrenia, affective disorders (bipolar disorder and major depression), the anxiety spectrum disorders, attention-deficit/hyperactivity disorder (ADHD), eating disorders, and personality disorders are emphasized.

HISTORY AND DEFINITIONS The history of defining and characterizing co-occurring disorders has evolved over time. Beginning in the early 1960s and continuing into the 1970s, the process of deinstitutionalization began to shift the responsibility of treating patients with severe and persistent mental illness (SPMI) from state hospitals toward other, less restrictive settings. The reasons for this move were many, including economic and sociocultural considerations as well as the introduction of new medications that could treat SPMI (e.g., first-generation neuroleptics) and the advent of the community mental health movement. The ultimate goal was to shift the responsibility of treating people with SPMI to community mental health settings. For a variety of reasons, this transition was largely a failure, and the community setting did not adequately address the enormous needs of this patient population (Elpers 1995). Many individuals ended up homeless or in jail. Released from state hospitals with inadequate housing, support, and treatment, many began to use alcohol and drugs. By the late 1970s and early 1980s, clinicians first began to characterize and name the problem of patients with mental illness and SUDs (Drake et al. 2004). An initial term that became popular was dual diagnosis, a term used in the mental retardation field to characterize patients with mental retardation and a co-occurring mental illness. Other terms also began to be used to describe this population, including dually disordered, mentally ill chemical abusers, mentally ill substance abusers, and substance-abusing mentally ill. The publication in 1980 of DSM-III (American Psychiatric Association 1980) also helped to legitimize the use of multiple diagnoses to describe patients, given that previous versions of DSM did not provide the means to do so (Hendrickson 2006). For example, patients could now be diagnosed with schizophrenia in addition to an SUD. The problem with all of these terms, however, is that they failed to adequately address the enormous heterogeneity and complexity of

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patients with both mental illness and SUDs. Did dual diagnosis only connote the co-occurrence of an Axis I non-SUD with an Axis I SUD? What about patients with more than two Axis I non-SUDs co-occurring with an Axis I SUD? What about patients with SUDs who had co-occurring Axis II or III disorders? The term triply diagnosed evolved over time and has variably been used to describe dually diagnosed patients with personality psychopathology (Ross et al. 2003) or medical problems such as HIV/AIDS (Conover et al. 2006). To better address the complexity and heterogeneity of presentations, the term comorbidity was introduced and defined as the presence of any additional coexisting disorder in an individual with a given index disorder (Feinstein 1970). This term is used commonly within general psychiatry, and the terms co-occurring disorder and dual disorders have become adopted as the most common terms in the addiction research literature used to describe patients with SUDs and one or more additional disorders, including the full spectrum of non-SUD Axis I disorders, personality disorders, mental retardation, and medical problems. To further complicate the issue of nomenclature and categorical diagnostic classification, a vital factor to consider is severity of illness. This is especially salient to treatment and prognosis. An example is patients who have the same diagnoses (e.g., bipolar disorder and cocaine dependence) but have very different courses of illness due to the relative severity of either disorder. These relative differences dictate different biological and psychosocial interventions and require varying intensity of levels of care. One helpful model of subcategorization that addresses the continuum of severity as a factor in the heterogeneity of patients with both mental illness and SUDs divides patients into four subgroups (see Table 38–1; Ries 1993).

EPIDEMIOLOGY Singly Diagnosed In the United States, there have been five large, third-generation, epidemiological community studies conducted that help shed light on the epidemiology of singly diagnosed patients with SUDs (see Table 38–2) and the dually diagnosed: 1) the Epidemiologic Catchment Area (ECA) study (Regier et al. 1990), sponsored by the National Institute of Mental Health (NIMH) and conducted in five U.S. communities in households and institutional settings from 1980 to 1984; 2) the National Comorbidity Survey (NCS; Kessler et al. 1996), sponsored by NIMH and conducted with household and college residents throughout the country from 1990 to 1992; 3) the National Longitudinal Alcohol Epidemiologic Survey (NLAES; Grant and Pickering 1996), sponsored by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and conducted nationally with household residents from 1991 to 1992; 4) the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC; Stinson et al. 2005), sponsored by NIAAA and conducted from 2001 to 2002 nationally in the civilian noninstitutionalized population; and 5) the National Comorbidity Survey Replication (NCS-R; Kessler and Merinkangas 2004), sponsored by NIMH and the National Institute on Drug Abuse and conducted nationally with household residents. Based on these studies (see Table 38–2), the current prevalence of alcohol use disorders (AUDs) and drug use disorders (DUDs) ranges from 4.4% to 9.7% and from 1.5% to 3.6% of the population, respectively, and the lifetime prevalence of AUDs and DUDs ranges from 13.5% to 30.3% and from 6.1% to 13.8%, respectively.

Specific Drugs of Abuse The NESARC provides data on 12-month and lifetime prevalence of DUDs, excluding nicotine (see Table 38–3). It ranges from the most commonly abused illicit substance—cannabis—to inhalant use disorders, the least prevalent SUD. Nicotine use disorders are prevalent in the United States, occurring in approximately 23% of the general population (Centers for Disease Control and Prevention 2002), but they are approximately two- to fourfold higher in patients with mental illness and SUDs (Kalman et al. 2005).

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Regarding the dually diagnosed, SUDs co-occur with mental illness at higher rates than in the general population without a previously diagnosed mental illness. In the ECA study, the lifetime prevalence of any SUD in a community sample was 16.7%, whereas 29% of patients with a lifetime history of mental illness met criteria for a lifetime comorbid SUD. Furthermore, of those with a history of a DUD, more than half also had a lifetime history of mental disorder and had more than four times the risk (odds ratio [OR] = 4.5) of having a mental disorder compared with individuals with no history of a DUD (Regier et al. 1990). Similarly, the NCS study found an odds ratio of 2.4 for comorbidity between any lifetime mental illness and any lifetime SUD, with 50.9% of individuals with a lifetime mental illness having a history of an SUD and 51.4% of those with a lifetime SUD meeting criteria for a lifetime mental illness (Kessler et al. 1996). The prevalence of individuals with co-occurring disorders is dramatically elevated from a baseline of 3%–4% among people living in the community to 40%–60% among those in mental health treatment settings and 50%–60% among those in substance abuse treatment settings (Hendrickson 2006). Of patients with co-occurring disorders, those with SPMI have a particularly high co-occurrence of SUDs, estimated to be as many as 4 million adults in the United States (Substance Abuse and Mental Health Services Administration 2004).

Schizophrenia In the ECA study, 47% of patients with schizophrenia had a lifetime history of an SUD, with 34% having an AUD and 28% having a DUD (Regier et al. 1990). In mental health treatment settings, the rate of current SUDs in persons with schizophrenia ranges from 25% to 75% (Ziedonis et al. 2003). According to the recent NIMH Clinical Antipsychotic Trials of Intervention Effectiveness project, 60% of schizophrenic patients were actively using substances of abuse and 37% met criteria for a current SUD (Swartz et al. 2006). Furthermore, in that study, SUDs were strongly associated with male gender and a history of conduct disorder. The most common substances used by schizophrenic persons are nicotine (75%–90%), alcohol (25%–45%), cocaine (15%–50%), and cannabis (31%) (Buckley 2006; Centers for Disease Control and Prevention 2005).

Affective disorders Bipolar disorder According to the ECA study, bipolar spectrum disorders were the Axis I disorders most likely to co-occur with an SUD, with 56% of any bipolar diagnosis being associated with a lifetime SUD (Regier et al. 1990). The rate was the highest for bipolar I disorder at 61%, versus bipolar II disorder at 48%; among the patients with bipolar I disorder, 46% had a lifetime rate of an AUD and 41% had a lifetime history of a DUD. Furthermore, according to the NCS, the odds ratios of 12-month AUDs and DUDS in patients with bipolar disorder were 6.3 and 8.2, respectively, and the odds ratios of having a lifetime AUD and DUD were 9.7 and 8.4, respectively (Kessler et al. 1996). In treatment settings for bipolar disorder, the lifetime rates of DUDs range from 14% to 65%, compared with 6%–14% in the general population (Levin and Hennessy 2004). Similar to schizophrenia, nicotine use is particularly common in patients with bipolar disorder, with prevalence rates of 55%–70% (Cassidy et al. 2002; Corvin et al. 2001). In addition, the other most common substances used by bipolar patients include marijuana, alcohol, and cocaine (Brady and Lydiard 1992; Conway et al. 2006).

Depression In the ECA study, the prevalence of lifetime co-occurring AUDs and DUDs among patients with major depressive disorder (MDD) was 17% and 18%, respectively. The presence of drug abuse increased the risk for depression by a factor of 4.7 compared with individuals without a history of an SUD (Regier et al. 1990). Similarly, according to the NCS, individuals with MDD were 2.7 times more likely to have had an SUD in the previous 12 months and 3.6 times more likely than the general population to have a lifetime SUD (Kessler et al. 1996). In treatment settings for affective disorders, approximately half of patients with MDD have a lifetime

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history of an SUD (Brady et al. 2003), and similarly, in addiction treatment settings, about half of patients with SUDs have a lifetime history of MDD (Miller et al. 1996). Nicotine use in patients with MDD is common (40%–60%; Kalman et al. 2005). In treatment settings for SUDs, the lifetime prevalence of MDD in patients with alcohol dependence ranges from 20% to 67%, for patients with cocaine dependence the range is 30%–40%, and for patients with opiate dependence it has been reported as high as 54% (Brady et al. 2003). The abuse of other drugs by patients with MDD, including cannabis (Bovasso 2001) and sedative-hypnotics (Goodwin et al. 2002), is also common.

Anxiety spectrum disorders Data from the ECA and NCS reveal an approximate doubling to quadrupling of risk for an AUD or DUD for most anxiety disorders (Kessler et al. 1996; Kushner et al. 2000; Regier et al. 1990). From the ECA study, panic disorder (OR for AUD = 3.3; OR for DUD = 4.4) and obsessive-compulsive disorder (OR for AUD = 2.5, OR for DUD = 3.6) had particularly elevated rates of SUDs. From the NCS, generalized anxiety disorder was significantly associated with an elevated risk of alcohol dependence in both men and women (OR = 3.9 and 3.0, respectively) compared with the general population. Posttraumatic stress disorder (PTSD) is also particularly associated with an increased risk of SUDs. In some studies, as many as 75% of combat veterans with lifetime PTSD also met criteria for an SUD (Kulka et al. 1990). Women with SUDs in the civilian population are particularly at risk, with 30%–60% also meeting lifetime criteria for PTSD. These rates are highest among pregnant women in residential substance abuse treatment settings (Najavits et al. 1997; Thompson and Kingree 1998).

Attention-deficit/hyperactivity disorder There is evidence that ADHD plays a role in developing an SUD. Regarding individuals with ADHD, the transition from childhood to adolescence is associated with conduct disorders and the earlier onset of an SUD, and the transition from adolescence to adulthood is associated with antisocial personality disorder, SUDs, and greater treatment episodes for substance abuse (Wilson and Levin 2005). Although ADHD by itself is a risk factor for developing an SUD in adolescents, conduct disorder appears to predominantly mediate the relationship between ADHD and SUDs (Biederman et al. 1998; Wilens 2002). In adults, approximately 20%–40% of individuals with ADHD have a lifetime history of an SUD, and similarly, in patients presenting for treatment for an SUD, 20%–30% have co-occurring ADHD (Schubiner 2005).

Eating disorders Eating disorders co-occur with SUDs at elevated rates, with bulimic patients at higher risk compared with those with anorexia nervosa (Levin et al. 2003). Lifetime prevalence of AUD ranges from 17% in patients with anorexia nervosa, restricting subtype, to 46% in those with bulimia nervosa (Bulik et al. 2004). In treatment settings for SUDs, high rates of eating disorders have been found in patients with alcohol, cocaine, and stimulant use disorders (Levin et al. 2003).

Personality disorders Numerous studies have demonstrated that Axis II psychopathology is highly prevalent among individuals with SUDs. According to Verheul (2001), the median prevalence of personality disorders among a population of treated SUD patients was 56.5% (range of 35%–73%) when studies were chosen based on samples selected consecutively or randomly, with sample sizes of 100 subjects or more, and when semistructured interviews were used for classification. In this cohort of studies, the two most common personality disorders represented among treated patients with SUDs were antisocial personality disorder (median prevalence, 23%) and borderline personality disorder (median prevalence, 18%), with the next most common diagnoses being paranoid (median prevalence, 10%) and avoidant (median prevalence, 6%) personality, and the least common being schizotypal personality (median

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prevalence, 0.6%). Antisocial personality disorder is particularly strongly associated with AUD. In the ECA study, the lifetime prevalence of AUD was 74% among individuals with antisocial personality, compared with a lifetime prevalence of 14% in the general population (Regier et al. 1990). In this study, antisocial personality had the strongest association with alcohol dependence of any Axis I or II disorder, with an odds ratio of 21 (Helzer and Pryzbeck 1998).

DIAGNOSTIC ASSESSMENT Theoretical Basis Before discussing the practical aspects of clinical diagnostic assessments for patients with co-occurring disorders, a discussion of the etiological theories of these disorders, as well as any evidence that supports a particular model, is in order. Four general models have been used: common factor models, two etiological diagnostic models (secondary SUD and secondary psychopathology models), and bidirectional models (Mueser et al. 1998). Although some of the models have more data supporting them than others, no single model has clear explanatory power by itself. Common factor models propose that the co-occurrence of mental illness and substance abuse is caused by shared vulnerabilities or risk factors, ranging from genetic to sociocultural, of both disorders. From a genetic perspective, it is salient to know if genetic susceptibility to one disorder increases the risk for another. If shared genetic risk factors for both mental illness and addiction were to account for the increased comorbidity, an elevated incidence of one disorder (e.g., SUD) would be expected in relatives of individuals with the other disorder (e.g., mental illness). However, there is little evidence to support this model, particularly in patients with SPMI, and no common gene has been identified. However, there is more evidence to suggest that the presence of antisocial personality disorder serves as a common risk factor that accounts for some of the elevated rates of mental illness and SUDs (Mueser et al. 1998). Its low prevalence, however, can only account for a minority of the comorbidity. In secondary SUD models, the presence of mental illness is a risk factor to develop addictive spectrum disorders. Of these models, the self-medication hypothesis has been extensively studied and posits that addicted patients do not choose substances randomly but do so specifically for specific psychopharmacological properties to treat symptoms of mental disorders (Khantzian 1985, 1997). According to Mueser et al. (1998), three types of evidence would be needed to support the self-medication hypothesis: 1) patient self-report of specific substances relieving specific symptoms of a particular mental illness, 2) epidemiological studies demonstrating such specificity of substance choice with a particular mental illness, and 3) evidence that patients with severe symptomatology have an elevated likelihood of abusing substances compared with patients with milder symptoms. Unfortunately, the evidence does not definitively support any of these conditions. Despite some studies from treatment samples suggesting specificity between a particular substance being used for a particular mental illness (Carrigan and Randall 2003; Ogborne et al. 2000; Tournier et al. 2003), the majority of the data across a broad spectrum of mental illnesses do not reveal a strong relationship between type of mental illness and type of substance used (Kessler 2004). However, there is evidence that patients may use substances of abuse to medicate unpleasant affective (e.g., dysphoric affect) states across a variety of diagnoses, in a less specific way, to alleviate the dysphoria (Mueser et al. 1998). This construct makes more sense when considering substance abuse (rather than dependence), in which the use of substances over shorter periods of time can alleviate psychic distress, but continued use has less and less psychological utility and ultimately worsens psychiatric symptoms. Also, there is evidence that treating dually diagnosed patients, such as those with mood disorders (Khantzian et al. 2005) and ADHD (Wilens et al. 2003), with medication for their mental illness is associated with a trend toward a decreased use of substances of abuse. This indirectly suggests that the mental illness may cause the substance abuse problem. Another secondary SUD model, the supersensitivity model, has moderate data supporting it, especially in patients with schizophrenia. This model posits that patients with mental illness are sensitive to the

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effects of substances and that at lower dosages, compared with the general population, they will experience greater negative medical and psychosocial consequences related to their substance use, such as greater rates of relapse of recidivism (Mueser et al. 1998). In secondary psychopathology models, primary substance abuse is a risk factor to develop psychiatric illness. The types of research used to evaluate this theory—longitudinal follow-up studies of individuals with SUDs and studies that compare patients who develop mental illness after substance abuse with those without any SUD—have failed to provide convincing, consistent evidence (Mueser et al. 1998). Finally, bidirectional models posit ongoing negative effects between mental illness and substance abuse that account for the elevated rates of comorbidity. Although there is evidence that failure to treat one disorder (either mental illness or the SUD) negatively affects the severity of illness and longitudinal course of the other (Hser et al. 2006), the bidirectional model remains mostly untested and in need of further research. It is imperative in any setting to make accurate diagnoses that will lead to appropriate treatment. The following sections review obstacles and pitfalls that lead to incorrect diagnoses of patients with co-occurring disorders and detail practical aspects of diagnostic assessment.

Obstacles to Diagnosis Although SUDs occur commonly in both mental health and medical settings, they are not routinely screened for and diagnosed by most physicians (Carey and Correia 1998; Ewing et al. 1999; Fleming and Barry 1991). A large part of the problem is lack of training, beginning in medical school and continuing into residency training (Ross et al. 2006). Many physicians believe they do not have the adequate core competency skills to treat patients with SUDs, and many mistakenly believe that it is not important to identify addictive disorders because they believe that treatment is ineffective (Ewan and Whaite 1982). Moreover, clinicians in primary mental health settings often receive little or no training in how to assess for substance abuse and often miss an SUD diagnosis (Bennett et al. 2006). This lack of substance abuse assessment in mental health settings is problematic in that it adversely affects optimal treatment planning, leading to poor treatment outcomes such as recidivism, relapse, and added financial costs (Carey and Correia 1998). Diagnostic confusion is another common problem in multiply diagnosed patients for whom it is difficult to discern whether impairment is due to substance abuse alone; to some complex interaction between substance abuse, mental illness, and medical illness; or to other factors. An important factor that adds to this confusion is cognitive impairment seen in multiply diagnosed patients with SPMI as a result of a variety of factors, including chronic substance abuse, SPMI, and medical problems (Bellack et al. 1999). This cognitive impairment can make it very difficult to get the accurate longitudinal history from the patient that is necessary to make a diagnostic formulation.

Diagnostic Dilemmas/Pitfalls: Under- and Overdiagnosis It is important to differentiate between etiological and multiple diagnoses, especially as it relates to treatment. One potential pitfall occurs when there is the incorrect assumption of an etiological diagnosis when, in fact, multiple diagnoses are present. This can be an appealing construct because it implies that the presenting problem will disappear if the etiological problem is treated. For example, for patients in whom mental distress appears related to substance abuse (e.g., cocaine-induced panic symptoms), it is appealing to assume that once the patient is abstinent from the substance, the psychological symptoms will disappear. Underdiagnosis leads to undertreatment, which is problematic because, as mentioned earlier, failure to treat one disorder (either mental illness or the SUD) negatively affects the severity of illness and longitudinal course of the other (Hser et al. 2006). Another diagnostic pitfall relates to incorrectly assuming that multiple diagnoses are present when it really is the case of an etiological diagnosis. An example of this is phencyclidine (PCP)-induced psychosis. PCP, like heavy methamphetamine and chronic alcohol use, can induce psychosis that can

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last from several weeks to several months in the absence of any underlying psychotic spectrum illness (Ziedonis et al. 2003). A failure to know the time course by which a particular substance of abuse can induce mental phenomena can lead to the problem of overdiagnosis and overtreatment. In the case of PCP-induced psychosis in an individual without co-occurring schizophrenia, the optimal course is to treat the psychosis acutely but then taper off the antipsychotic once the psychosis has resolved. If schizophrenia is erroneously diagnosed in addition to a PCP use disorder, there is a potential for iatrogenic harm—sometimes irreversible—due to medication side effects (e.g., tardive dyskinesia from typical neuroleptics). To avoid overdiagnosis and overtreatment, it is important to know the optimal time of abstinence necessary before making a formal mental illness diagnosis. It is prudent to wait until an individual is no longer in active withdrawal before attempting to make a psychiatric diagnosis. Besides PCP-induced psychosis, methamphetamine- and chronic alcohol-induced psychoses necessitate waiting up to several months before making a formal diagnosis of a psychotic spectrum illness. For most other substances of abuse, a general rule of thumb is to wait 2–4 weeks after acute withdrawal before diagnosing a mental illness.

Assessment The main features of assessment in patients with co-occurring disorders include screening, diagnostic formulation, treatment planning and outcome assessment, and prognosis.

Screening Screening for SUDs in mentally or medically ill patients is a vital first step in the treatment process. There are various techniques and some formal instruments available to clinicians. The objective of screening is both to identify at-risk substance users and to serve as an initial step in the process of identifying patients with an existing disease process (Conigliaro 2003). Screening can be broken down into several components, including direct clinician observation, laboratory testing, gathering of collateral history, and self-report measures (Carey and Correia 1998). Optimal screening is best performed using all available techniques rather than relying on any single approach. This increases the validity of the screening assessment (Sobell and Sobell 1980). Initially, the evaluating clinician should ask about quantity, frequency, and patterns of alcohol or drug use. This approach best identifies at-risk users who are misusing substances, because these patients tend to display less denial and minimization regarding drug- and alcohol-related problems than do patients with dependence syndromes, making them more reliable historians (Williams et al. 1985). Specifically, clinicians ask how many days a week the individual uses drugs or alcohol, followed by the number and type of substances used in a typical day and the maximum number of substances consumed on any given occasion in the previous month. A thorough physical examination along with laboratory testing can be helpful in making the diagnosis of an SUD, but these are less sensitive at picking up at-risk patients who have yet to develop the overt physical stigmata usually seen in patients with dependence syndromes (Bohn et al. 1995). Laboratory tests can help provide confirmatory evidence of an SUD but are inadequate if used alone as screening tools. Toxicology testing is an important part of any evaluation in which an SUD is suspected. Urine testing is the most commonly used route, given its relative ease of collection and limited invasiveness. Given the ambivalence and denial inherent in addiction, it is imperative to use collateral information as an alternative source of history taking. Collateral sources commonly include spouses, other family members, friends, the criminal justice system (e.g., parole officers, drug court judges), other treatment providers, hospital and/or clinic records, and case managers. There is significant evidence that obtaining information from collateral sources is necessary and useful in patients with co-occurring disorders (Carey and Correia 1998). Self-report is another important source of screening but one that is less accurate in patients with SPMI. It tends to be a more accurate source of information when gathered in a stable outpatient setting as opposed to acute care settings, such as the emergency department or inpatient dual diagnosis units

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(Carey and Correia 1998). An important aspect of screening is having reliable and valid assessment tools that measure both psychiatric and SUD domains and that are tailored toward the level of severity of illness. For patients who are higher functioning with less severe mental illness in primary mental health settings, several measures have been found to be adequately reliable screening instruments, including the Addiction Severity Index (Appleby et al. 1997), the CAGE Questionnaire (Friedmann et al. 2001; Mayfield et al. 1974), the Drug Abuse Screening Test (Cocco and Carey 1998), and the Alcohol Use Disorders Identification Test (Dawe et al. 2000; Volk et al. 1997). However, many of these measures have been found to be unreliable when applied to dually diagnosed patients with SPMI; their focus on substancerelated dysfunction is more pertinent to higher-functioning patients, and they lack sensitivity to the cognitive impairment common in patients with SPMI (Bennett et al. 2006). In an attempt to address the lack of screening tools for dually diagnosed patients with SPMI, two tools for this population have been developed. The first, the Dartmouth Assessment of Lifestyle Instrument, consists of 18 interviewer-administered items that assess DUDs or AUDs. It has been shown to be a reliable tool that may be more sensitive and specific than the Michigan Alcohol Screening Test (Selzer 1971), CAGE Questionnaire, TWEAK (Tolerance, Worried, Eye-opener, Amnesia, Cutdown; Russell et al. 1991), or Drug Abuse Screening Test (Rosenberg et al. 1998). Another tool recently developed for SPMI patients with co-occurring disorders is the Substance Use Event Survey for Severe Mental Illness (Bennett et al. 2006). Its format is based on the Addiction Severity Index in that it assesses medical, alcohol/drug use and treatment, family, and psychiatric domains. In addition, it specifically was designed to address issues pertinent to SPMI, such as cognitive impairment, psychotropic medications and their side effects, and trauma. Preliminarily, it appears to be both reliable and valid (Bennett et al. 2006).

Diagnoses After the initial screening and history taking, the goal of assessment is to identify patients with substance abuse or dependence. Although the task of making a definitive diagnosis or diagnoses is most complex when substance abuse, psychiatric illness, and medical illness all coexist, there are certain elements of assessment that are helpful in the diagnostic formulation (see Table 38–4). Two significant factors that contribute to misdiagnoses are the use of single, cross-sectional assessments, especially in the acute setting, and the use of single sources of information. An optimal approach at making definitive diagnoses relies on using serial longitudinal assessments as well as multiple sources to gather data, such as clinician-administered structured or semistructured interviews, self-report, collateral information, physical examination, and laboratory tests (Carey and Correia 1998). An important aspect of longitudinal assessments is the ability to control for a particular variable. For instance, being able to observe patients during extended periods of abstinence or stable mental health can have enormous diagnostic value.

TREATMENT For any particular treatment setting, the types of treatment approaches include biological/pharmacological interventions, psychosocial interventions, and disposition/placement planning. This section highlights the concept of integrated treatment from several perspectives and outlines the general goals of treatment for patients with co-occurring disorders with a stage-specific approach related to safety and engagement, motivation, active treatment, and maintenance (Osher and Kofoed 1989). Such an approach emphasizes the need to tailor interventions to a patient's particular stage of illness or recovery for both substance abuse and mental illness, and for integrated care to proceed with parallel phases of treatment and recovery. In addition, specific medication and psychosocial interventions that have been developed for particular dual disorders (e.g., schizophrenia and SUDs) are discussed. Regarding medication, those used to treat primary addictive spectrum disorders are briefly discussed as well as those used to treat mental illness comorbid with SUDs. Given the breadth of the topic of medication and psychosocial interventions used to

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treat mental illness in patients with co-occurring disorders, those that have evidence in being effective for treating both the psychiatric and substance abuse symptoms are emphasized.

Integrated Models of Care The term integrated treatment, when used regarding patients with co-occurring disorders, can have several different meanings. Traditionally, it has been used to describe systems of care in which mental health and substance abuse clinical services are provided simultaneously in the same treatment setting, in contrast to serial models wherein patients are treated in one setting (e.g., substance abuse clinic) for a period of time and then another setting subsequently (e.g., mental hygiene clinic), or parallel models wherein patients with dual disorders simultaneously receive treatment for both mental illness and substance abuse, but in separate treatment settings. The most reliable finding from research in the past decade is that integrated treatment from a systems perspective, and across a wide spectrum of psychiatric and SUD diagnoses, is the optimal model, especially when comprehensive services are provided that increase the intensity of treatment (Drake et al. 2004). Integrated treatment has also been used in reference to integrating medications and psychosocial interventions for either substance abuse and/or mental illness; integrating individual, group, couples, and family treatments; addressing tobacco misuse in co-occurring treatment settings; integrating complementary techniques with traditional evidence-based ones; integrating recovery, medical, and rehabilitation models of care; integrating secondary disorder prevention into treatment; and integrating prevention and management of medical illnesses into the treatment (Ziedonis 2004).

General Goals of Treatment Safety, acute stabilization, and engagement Safety is the most obvious and urgent initial treatment consideration in treating acute intoxication and withdrawal syndromes, especially those that are life threatening (i.e., opiate intoxication and alcohol withdrawal), and managing acute medical and psychiatric emergencies, such as active suicidality and homicidality, that would require psychiatric hospitalization. Another vital, initial goal is to engage the patient by forming a positive alliance, which is often a predictor of positive treatment outcome (Ziedonis 2004). Starting with a nonconfrontational, open-ended, neutral approach is often helpful given that many patients with co-occurring disorders have had negative experiences with medical personnel and may be distrustful of doctors. This is especially true of those with SPMI, who may be better engaged with a more supportive initial approach. Strategies such as assertive outreach (e.g., into the community) and motivational counseling have been associated with higher rates of treatment engagement (Drake et al. 2004). As part of forming a positive alliance, managing countertransference on the part of the clinician is vital because countertransferential anger, denial, enmeshment, and burnout are common in treating patients with co-occurring disorders, especially those toward the more severe end of the illness spectrum. Furthermore, the initial drug use history should focus on the positive aspects of use rather than the traditional model of inquiring about and lecturing patients on the adverse consequences of their use. Forming an effective alliance is a key factor in being able to engage, motivate, and retain patients, and doing so provides greater leverage for making confrontational, coercive interventions, which are often needed in this population in which denial and ambivalence are the norm.

Motivational techniques Some of the psychosocial treatment approaches that have targeted enhancing motivation for change in addictive behavior include motivational interviewing, contingency management, and coercion (Ross et al. 2006). There continues to be a great need, however, to further improve treatment outcomes and better engage and retain individuals (especially those with SPMI) in treatment by enhancing their motivation and self-efficacy. One approach includes integrating complementary therapies such as acupuncture, hypnosis, art, dance, music therapy (Ross et al. 2006), herbal therapy, and other

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alternative approaches into traditional co-occurring disorder treatments (Ziedonis 2004). Clinical programs are increasing the use of these complementary treatments within treatment programs, and there is a need to better understand the potential enhancement of outcomes with these approaches.

Active treatment Active interventions span a wide range, from informal treatments that lack a hierarchical structure separating patient from treatment provider (e.g., 12-step mutual help programs such as Alcoholics Anonymous) to treatments in formal settings that range from brief interventions in primary psychiatric or medical settings to comprehensive treatment in integrated dual diagnosis treatment settings. An initial objective is to promote a change in substance use, with the goal either of use reduction or abstinence, depending on the severity of illness (mental illness, SUD, medical) and the motivational stage of the patient. Use reduction is an example of harm reduction, which aims to diminish the harm caused by substance use in nonabstinent patients. For patients not motivated for abstinence (e.g., those in the pre-contemplation and contemplation phases), motivational techniques become vital in engaging patients in treatment and moving them along the motivational continuum. It is also important to treat psychiatric and medical comorbidities, because if they are left untreated, or partially treated, they can serve as risk factors for substance use or relapse. Formal programs include outpatient, intensive outpatient, and residential or inpatient settings. Model programs provide a variety of comprehensive services and match patients carefully regarding the level and intensity of services necessary. They use multidisciplinary teams (e.g., including psychiatrists, psychologists, social workers, nurses, activity therapists) and provide integrated pharmacological and psychosocial treatments for both substance abuse and mental illness. The counseling services available should include all possible modalities, including individual, couples, group, family, and peer-oriented psychotherapies. Comprehensive substance abuse assessment and monitoring includes both self-report and objective measures of substance use (e.g., urine toxicology or breath alcohol testing). Other services for optimal treatment, particularly for individuals with SPMI, include social skills training, involvement in alternative pleasurable activities, intensive case management services to manage vulnerable transition points in treatment and to maximize treatment adherence/retention, assertive community outreach, liaison with the criminal justice system, money management, trauma interventions, and psychosocial rehabilitation (Brunette and Mueser 2006; Drake et al. 2004). The use of medication in patients with dual disorders is an important aspect of treatment. Table 38–5 lists general principles of psychotropic interventions in patients with co-occurring disorders. Medications can be used for treatment of the SUD (see Table 38–6) and to treat the mental illness.

Maintenance Once patients achieve sobriety or symptom control, it is important to maintain these gains. Relapse prevention is a cognitive-behavioral therapy based on social learning theory wherein addictive patterns are learned and maladaptive behaviors can be modified through a variety of techniques, including identifying triggers for relapse and high-risk situations; managing cues, craving, frustration, and social pressures; coping with cognitive distortions that predispose to a return to substance use; and managing a lapse or relapse (Marlatt and Gordon 1985). Attendance at 12-step mutual help programs can be another important means to form healthy, supportive relationships with others in recovery and a way to foster a new identity through spiritual and group cohesive factors that promote the maintenance of abstinence.

Schizophrenia Medication In treating patients with schizophrenia and co-occurring SUDs, the second-generation antipsychotics are preferable to the first-generation typical agents, given that typical neuroleptics appear not to decrease substance use in patients with schizophrenia, and there is some evidence that these agents may actually

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increase substance use in this population (Green 2006). Of the second-generation antipsychotics, clozapine is the most promising medication in patients with schizophrenia and co-occurring SUDs and has been associated with decreased psychosis, increased abstinence, and decreased substance use, including decreased cocaine and nicotine intake; however, there are also data to support the efficacy of risperidone, olanzapine, quetiapine, and aripiprazole for both treating psychotic symptoms and diminishing substance use in this patient population (Green 2006).

Psychosocial Several manualized psychotherapeutic treatments have been developed for patients with schizophrenia and comorbid SUDs. The four most commonly used in clinical settings include dual recovery therapy, modified cognitive-behavioral therapy, modified motivational enhancement therapy, and the Substance Abuse Management Module (Ziedonis et al. 2005). All of these approaches are similar in that they include components of motivational interviewing, relapse prevention, and social skills training as well as encourage participation in 12-step mutual help programs. All were developed to take into account the special needs of patients with psychotic disorders, such as low motivation, poor self-efficacy, and cognitive impairment.

Bipolar Disorder Medication Unfortunately, there are few published data to guide the optimal pharmacological management of patients with bipolar spectrum disorders comorbid with SUDs, with few placebo-controlled, randomized, double-blind studies and no head-to-head trials of one agent versus another. However, there is indirect evidence to suggest picking anticonvulsants (valproic acid or carbamazepine) over lithium as first-line agents. First, substance abuse is a predictor of poor response to lithium. Second, mixed/rapid-cycling variants are more prevalent in bipolar patients with co-occurring SUDs, and these variants are more likely to respond to anticonvulsants than to lithium (Brady et al. 2003). Third, there is some evidence that valproic acid decreases heavy drinking in patients with bipolar I disorder comorbid with alcohol dependence (Salloum et al. 2005). However, lithium is still a viable option given it is the only mood stabilizer with known antisuicide properties, and it has greater antidepressant and depression prophylactic properties than the anticonvulsants (Baldessarini et al. 2006). Also, one randomized, double-blind, placebo-controlled study by Geller et al. (1998) suggested that lithium treatment of bipolar disorder with secondary SUD in adolescents was effective in reducing both affective symptoms and substance use. There is also emerging evidence that lamotrigine may be useful in this patient population by reducing both mood symptoms and substance use (Brown et al. 2006). There are also some data, although limited, to suggest the efficacy of second-generation antipsychotics in the treatment of patients with co-occurring bipolar disorder and SUDs, in which both affective symptoms and substance use were diminished by both quetiapine (Brown et al. 2002) and aripiprazole (Brown et al. 2005).

Psychosocial Two cognitive-behavioral approaches have been used specifically for patients with co-occurring bipolar disorder and SUDs. One approach, integrated group therapy, is a manualized, integrated treatment approach developed by Weiss et al. (2000) that has shown promising results in terms of greater abstinence compared with patients with co-occurring bipolar and SUDs who did not receive the treatment. Another cognitive-behavioral approach, developed by Schmitz et al. (2002), was tested in a 12-week randomized trial in which cognitive-behavioral therapy plus "medication monitoring" was compared with medication monitoring alone in patients with bipolar disorder comorbid with an SUD. Although substance use was not significantly reduced in the combination group more than the monitoring-only group, there was some evidence for enhanced medication adherence and mood improvement for the combined treatment group.

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Depression Medication The literature on medication to treat depression co-occurring with an SUD has focused primarily on alcohol, cocaine, opioids, and nicotine. Although there is no solid evidence for the use of any particular agent, the evidence does support the use of antidepressants in patients with cocaine use disorders and depression, with some evidence that stimulating antidepressants (especially tricyclics and bupropion) are preferable to ones that are less stimulating (Rounsaville 2004). The literature on the use of antidepressants in patients with depression comorbid with an AUD generally suggests that antidepressants (alone or with psychosocial treatments), while diminishing symptoms of depression, do not appreciably reduce alcohol consumption (Pettinati 2004). There are two studies, however, wherein both depressive symptoms and alcohol use diminished with desipramine (Mason et al. 1996) and fluoxetine (Cornelius et al. 1997). The data on the use of antidepressants with depression and comorbid opioid use disorders come mostly from samples of patients receiving methadone maintenance treatment. Although antidepressants can safely be used in this population, the data on the drugs' abilities to reduce both depressive symptoms and substance abuse are mixed, with the majority of studies showing no improvement in symptoms of both illnesses (Nunes et al. 2004).

Psychosocial Several standard psychotherapeutic techniques used to treat singly diagnosed patients have been applied to patients with co-occurring depression and SUDs. The data suggest three effective approaches: 1) motivational interviewing can help with treatment engagement and retention; 2) cognitive-behavioral techniques appear somewhat effective at reducing substance abuse and, to a lesser degree, depressive symptoms; and 3) contingency management significantly reduces substance abuse (Carroll 2004).

Anxiety Disorders Medication Of all the anxiety disorders, only generalized anxiety disorder has appreciable data supporting the efficacy of an agent that is able to positively affect both anxiety symptoms and substance use. In generalized anxiety comorbid with an AUD, buspirone has been shown to reduce both anxiety symptoms and alcohol consumption (Nitenson and Gastfriend 2003). As a general rule for all of the other anxiety spectrum disorders, serotonin reuptake inhibitors should be considered first-line agents, and benzodiazepines should be avoided as much as possible unless absolutely necessary (e.g., in the case of severe panic disorder). If a benzodiazepine has to be used, slower-onset and longer-acting agents should be used (e.g., clonazepam).

Psychosocial Of the anxiety disorders, PTSD has been the most extensively studied with regard to the use of psychotherapy to treat PTSD comorbid with SUDs. One integrated approach, Seeking Safety, is a manualized cognitive-behavioral therapy that has been shown to significantly decrease both PTSD core symptoms and substance abuse in patients with co-occurring PTSD and SUDs (Hien et al. 2004; Najavits et al. 1996).

Attention-Deficit/Hyperactivity Disorder Medication Effective agents for ADHD include psychostimulants, catecholaminergic antidepressants (e.g., bupropion, desipramine, venlafaxine), and noradrenergic agents (e.g., atomoxetine, clonidine). Other potentially effective agents include

adrenergic blockers and modafinil. However, there are not enough

data to definitely guide the optimal treatment for adolescents or adults with ADHD and comorbid SUDs.

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Despite fears that treating such patients with stimulants (especially those with a history of stimulant use disorders) will exacerbate their SUDs, the evidence suggests that these drugs are safe and effective in reducing core ADHD symptoms as well as possibly decreasing substance abuse (Levin et al. 1998; Wilson and Levin 2005). Furthermore, the agents may serve as a protective factor to decrease the longitudinal risk of developing an SUD in patients with ADHD (Wilens et al. 2003). One approach for treating patients with co-occurring ADHD and SUDs is to start with nonreinforcing agents such as bupropion or atomoxetine. If this approach fails to effectively manage core ADHD symptoms, then stimulants should be considered, particularly ones with lower abuse potential, such as the extended-release preparations of either methylphenidate (e.g., Concerta) or amphetamine/dextroamphetamine preparations (e.g., Adderall XR). Care should be taken to monitor for abuse of the stimulant. Some helpful approaches include having the patient sign a contract that outlines the parameters of use and consequences of breaking certain agreed-upon rules; monitoring of prescriptions; use of urine toxicology screenings to monitor for substance use; and involvement of family members to aid in monitoring compliance and reinforcing abstinence.

Psychosocial Although no formal, manual-based psychotherapeutic treatments have been established as optimal treatment for patients with ADHD comorbid with SUDs, there are behavioral and cognitive approaches effective for either ADHD (e.g., coping skills, cognitive restructuring, use of organizers/calendars, goal setting/planning) or SUDs (e.g., relapse prevention) that can be applied in this patient population (Wilson and Levin 2005).

Eating Disorders Medication In patients with co-occurring eating disorders and SUDs, no data definitively support the use of agents that can alleviate symptoms related both to eating disorders and substance abuse, especially in anorexia, where there is little to no evidence that pharmacotherapeutic agents are effective. However, in patients with bulimia nervosa and alcohol dependence, naltrexone or fluoxetine should be considered because they each have some demonstrated efficacy for reducing both binge eating and alcohol consumption (Levin et al. 2003).

Psychosocial Although no integrated manualized treatments have been formally tested to treat patients with eating disorders comorbid with SUDs, cognitive-behavioral techniques have demonstrated efficacy for both disorders individually (Levin et al. 2003).

Personality Disorders Medication There is no established pharmacotherapeutic algorithm to treat patients with personality disorders comorbid with SUDs. However, particularly for borderline personality disorder, a variety of agents are commonly used in an attempt to manage the large spectrum of psychological distress inherent with the disorder, including antidepressants, anxiolytics, mood stabilizers, and antipsychotics.

Psychosocial For personality disorders, two specific integrated, manual-based psychotherapeutic treatments have been developed—dialectical behavioral therapy, for patients with co-occurring borderline personality disorder and SUDs (Dimeff et al. 2003), and dual focus schema therapy (Ball 1998)—that specifically address both symptoms of personality psychopathology and substance abuse. Dialectical behavior therapy has demonstrated efficacy for improving symptoms related to both borderline personality

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disorder and substance abuse in patients with both disorders (Dimeff et al. 2003).

TREATMENT OUTCOMES As mentioned earlier, integrated treatment for patients with co-occurring disorders, from a systems perspective, has generally been associated with better outcomes than treatment in either serial or parallel treatment paradigms, especially integrated treatments with an increased duration/intensity of treatment and added ancillary services (Drake et al. 2004). Moreover, it has been well established that addiction treatment is effective across the spectrum of SUDs in multiple types of treatment settings, as well as being cost-effective and providing savings to individuals, their employers, and society in general (McLellan and McKay 2003). Several variables predict better response to treatment: in pretreatment, increased motivation beyond the precontemplative stage, active employment, low severity of psychiatric symptoms or addictive disorder, and having a supportive social network; during treatment, longer length of time spent in treatment, having an individual therapist as part of treatment, receiving proper psychotropic interventions for both psychiatric and addictive disorders, participation in voucherincentivized behavioral reinforcement programs, and having added ancillary services to treat ongoing psychiatric, medical, and/or family problems; and posttreatment, participation in self-help programs such as Alcoholics Anonymous and Narcotics Anonymous, which has been associated with improved treatment outcomes such as increased abstinence rates (McLellan and McKay 2003). Despite the success of integrated systems of care for patients with co-occurring disorders and the known variables that predict successful outcomes in patients with SUDs, the system of care in the United States to address these problems, on both state and national levels, is inadequate. Integrated systems of care are the exception rather than the rule, and patients with co-occurring disorders often receive suboptimal, fragmented care, or worse, they fall between the cracks and receive no treatment at all. The few programs that do exist often present barriers for admission, such as long waiting lists or long distances to travel given the particular geographical area. Finally, according to McLellan and Meyers (2004), "the organizational, administrative, and personnel infrastructures of many treatment programs are fragile and unstable, making them unable to implement evidence-based care serious in the adult system and even worse in the adolescent system" (p. 764).

KEY POINTS In comparison with individuals who have a mental illness or a substance use disorder (SUD) alone, those with a co-occurring mental illness and SUD have a greater severity of illness and a worse longitudinal course of illness. SUDs co-occur with mental illness at higher rates than they occur in the general population in individuals without mental illness and they occur at higher rates than would be expected by chance. Of all non-SUD Axis I disorders, schizophrenia has the highest rate of comorbidity with any SUD when considering its co-occurrence with nicotine dependence. Excluding nicotine, bipolar disorder has the highest co-occurrence of any non-SUD Axis I disorder with an SUD. The clinician treating a patient with co-occurring mental illness and SUDs should use multiple sources of information as well as serial longitudinal assessments to increase the reliability and validity of diagnoses rather than relying on single sources or assessments, especially those done in acute settings. Substance-induced psychosis with phencyclidine, methamphetamine, and chronic, heavy alcohol use can last as long as several weeks to months, even in patients without an underlying psychotic spectrum illness. From a systems perspective, integrated treatment is the optimal model as compared with serial or parallel treatment paradigms, especially when comprehensive services are provided. Of the antipsychotics, clozapine has the most evidence supporting its ability to decrease both psychotic symptoms and substance abuse in patients with co-occurring schizophrenia and an SUD.

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There is indirect evidence to support using anticonvulsants (i.e., valproic acid) as first-line agents in treating patients with bipolar disorder comorbid with SUDs. However, lithium and lamotrigine should also be considered because there are some data indicating their effectiveness in reducing both affective symptoms and substance abuse in this patient population. As a general rule of thumb in treating patients with co-occurring disorders with psychotropic medication, it is prudent to start with a medication that has the least addictive liability as well as having a broad spectrum of activity in terms of treating symptoms of both mental illness and substance abuse.

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SUGGESTED READING Graham AW, Schultz TK, Mayo-Smith MF, et al (eds): Principles of Addiction Medicine, 3rd Edition. Chevy Chase, MD, American Society of Addiction Medicine, 2003 Kranzler HR, Rounsaville BJ (eds): Dual Diagnosis and Treatment: Substance Abuse and Comorbid Medical and Psychiatric Disorders. New York, Marcel Dekker, 1998 New Freedom Commission on Mental Health: Achieving the Promise: Transforming Mental Health Care in America, Final Report (DHHS Publ No SMA-03-3832). Rockville, MD, U.S. Department of Health and Human Services, 2003 Substance Abuse and Mental Health Services Administration: Report to Congress on the Prevention and Treatment of Co-occurring Substance Abuse Disorders and Mental Disorders. Rockville, MD, U.S. Department of Health and Human Services, 2002 Substance Abuse and Mental Health Services Administration: Strategies for Developing Treatment Programs for People With Co-occurring Substance Abuse and Mental Disorders (SAMHSA Publ No 3782). Rockville, MD, U.S. Department of Health and Human Services, 2003 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 39. Women and Addiction

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Kathleen T. Brady, Sudie E. Back: Chapter 39. Women and Addiction, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.355951. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Women and Addiction Kathleen T. Brady, M.D., Ph.D. Sudie E. Back, Ph.D.

WOMEN AND ADDICTION: INTRODUCTION Until the early 1990s, much of the research in substance abuse was focused on males or mixed-gender samples without significant attention to gender differences. In 1994, the National Institutes of Health published guidelines concerning the inclusion of women and minorities as subjects in clinical research (National Institutes of Health 1994). Since that time, the number of published research reports examining various aspects of substance use disorders in women and gender differences in substance use disorders has increased tremendously. There is now greater recognition that important biological and psychosocial differences between men and women influence the prevalence, presentation, comorbidity, and treatment of substance use disorders. This increase in awareness of gender-specific issues is also seen in the clinical sector, with approximately 40% of substance abuse treatment facilities now providing special programs or groups for women (Substance Abuse and Mental Health Services Administration 2006a). This chapter provides an overview of the current knowledge base concerning substance use disorders in women. Specifically, the epidemiology, neurobiology, psychiatric comorbidity, course of illness, and treatment of substance use disorders in women is reviewed.

EPIDEMIOLOGY As shown in Table 39–1, epidemiological studies consistently demonstrate that the prevalence rates of drug and alcohol use disorders are higher among men than among women (Conway et al. 2006; Kessler et al. 1994; Regier et al. 1990). In the most recent of these studies, the National Institute on Alcohol Abuse and Alcoholism's National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), more than 40,000 adults were surveyed. Data from the NESARC indicates that men are twice as likely as women to meet lifetime DSM-IV-TR (American Psychiatric Association 2000) criteria for any drug use disorder (13.8% men vs. 7.1% women; Conway et al. 2006). Twelve-month prevalence rates of alcohol abuse in the NESARC were almost three times as high in men as compared with women (6.9% men vs. 2.6% women; Grant et al. 2004a). These ratios are consistent with past epidemiological surveys in finding that the gender differential for alcohol use disorders is higher than that for drug use disorders (Grant and Harford 1995; Kessler et al. 1994). In contrast, the rates of prescription drug abuse in women closely approach that of men. The National Survey on Drug Use and Health reported 12-month prevalence rates of abuse or dependence for nonmedical use of pain relievers to be 1.4% for males and 1.1% for females ages 18–25 years and 0.5% for males and 0.4% for females ages 26 years and older (Substance Abuse and Mental Health Services Administration 2006b). Also of interest, the gender differential for tobacco use and dependence is substantially less than for other substances of abuse, with only slightly more men than women meeting criteria for nicotine dependence in the past 12 months (14.1% men vs. 11.5% women) (Grant et al. 2004b). The gender gap in prevalence of substance use disorders narrows in adolescents, and there are equal rates of illicit drug and alcohol use in boys and girls and greater use of cigarettes and nonmedical use of prescription drugs in girls (Substance Abuse and Mental Health Services Administration 2006b).

GENDER DIFFERENCES IN COURSE OF ILLNESS

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Telescoping One of the most consistent findings in studies focused on gender differences in substance use disorders is the increased vulnerability of women to the adverse medical and psychosocial consequences of substance use (Chatham et al. 1999; Gentilello et al. 2000; Henskens et al. 2005; Hernandez-Avila et al. 2004; Mann et al. 2005). Women appear to advance more rapidly than men from initial to regular use and to first treatment episode (Hernandez-Avila et al. 2004; Johnson et al. 2005; Piazza et al. 1989; Randall et al. 1999). Despite fewer years of use and smaller quantities of substances consumed, when women enter treatment their substance use severity is generally equivalent to men, and women average significantly more medical, psychiatric, and adverse social consequences from substance use than do men (Hernandez-Avila et al. 2004; Mann et al. 2005; Piazza et al. 1989; Randall et al. 1999). This has been coined the "telescoping" of substance use disorders in women, and it is likely that differences in biological as well as psychosocial factors contribute to this gender-specific phenomenon.

Biological Influences on Gender Differences A number of biological factors are likely to contribute to the telescoping of substance use disorders in women. First, important gender differences exist in the physiological effects of alcohol. Women become intoxicated after drinking smaller amounts of alcohol and achieve higher blood alcohol concentrations after drinking equivalent amounts of alcohol as compared with men. This is primarily because women have less total body water than men of comparable size (Marshall et al. 1983) and a lower concentration of gastric alcohol dehydrogenase, an enzyme responsible for the metabolism of a substantial amount of alcohol before it enters systemic circulation (Frezza et al. 1990). These gender differences contribute to higher blood-alcohol concentrations in women and provide a biological basis for the heightened vulnerability to psychological and medical consequences of alcohol consumption. Women develop liver disease after comparatively shorter and less-intense drinking as compared with men, and heavy alcohol consumption is also associated with an increased risk for breast cancer in women (Fuchs et al. 1995). Neuroimaging studies also suggest increased sensitivity to alcohol-induced brain atrophy in women as compared with men (Hommer et al. 1996; Mann et al. 2005). There are fewer data available concerning gender differences in the physiological effects and medical consequences of other drugs of abuse. Women generally metabolize nicotine more slowly than men (Benowitz 1997). Some studies suggest that men are more sensitive to the rewarding effects of nicotine than are women (Perkins et al. 2000). In addition, negative affect regulation may be a stronger motivation for nicotine use in women (Hogle and Curtin 2006; McGee and Williams 2006). Both animal studies and human laboratory data indicate that females are more sensitive to the subjective effects of stimulants (Kosten et al. 1996; Roth et al. 2004). Of interest, cocaine-dependent women experience fewer cerebral perfusion defects (Levin et al. 1994) and less frontal cortical neuronal loss (Chang et al. 1999) than do men with comparable cocaine use histories, a finding that could be related to gender differences in cocaine-induced cerebral vasoconstriction (Kaufman et al. 2001). There have been many gender differences observed in the pharmacological properties of opiates, including analgesic effects, but gender differences in abuse potential have not been systematically studied in humans. However, several animal studies suggest that

agonists may be reinforcing to females over a broader dose range, and

females self-administer more opiates as than do males (Cicero et al. 2000, 2003). Accumulating evidence from preclinical and clinical studies indicate that hormonal fluctuation during the menstrual cycle may impact response to and craving for drugs. For example, estrogen augments behavioral responses to cocaine in female rats by modulating the mesocorticolimbic dopamine system (Lynch et al. 2002; Perrotti et al. 2001; Russo et al. 2003). In humans, this may help explain the reported increased responsiveness to cocaine cues and greater consequences of use in women presenting for treatment (Kosten et al. 1993; Robbins et al. 1999). In a study by Sofuoglu et al. (1999), women reported lower ratings of "feeling high" on cocaine during the luteal phase compared with women in the follicular phase and with men. As such, ovulating women may be more vulnerable to relapse during the follicular phase, when the progesterone levels are lower, compared with the luteal

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phase (Wilcox and Brizendine 2006). In another study (Evans and Foltin 2006), administration of progesterone in women during the follicular phase was found to attenuate the positive subjective effects of cocaine, indicating that progesterone may reduce the response to cocaine in women (Sofuoglu et al. 2004). This is an area of active investigation that could have important implications for treatment. Neuroimaging studies have also provided important information about the neural processes underlying sex differences in substance use disorders. During a stress imaging task, female cocaine users showed greater left frontolimbic brain activation than did male cocaine users (Li et al. 2005). Using positron emission tomography to compare men and women during cue-induced cocaine craving, Kilts et al. (2004) found greater activation in women than men in the dorsal striatum and anterior cingulate cortices and lower activity in the amygdala, which assesses the pleasure of an experience and connects it with its consequences. The gender differential in brain activation by stress and drug cues provides important information about gender differences in reasons for drug use that could also have preventative and treatment implications (Li et al. 2005). Gender differences in the physiological and subjective effects and medical consequences of opiates, marijuana, and other drugs of abuse are vastly underexplored. Considering the important gender differences that have surfaced with careful investigation in the areas of alcohol, nicotine, and cocaine dependence to date, this is clearly an area that warrants attention in future studies.

PSYCHIATRIC COMORBIDITY A substantial proportion of individuals with a substance use disorder meet criteria for co-occurring psychiatric conditions. Data from the National Comorbidity Study found that 51.4% of individuals meeting lifetime criteria and 42.7% meeting 12-month criteria for an alcohol or drug use disorder had at least one co-occurring psychiatric disorder (Kessler et al. 1996). Patterns of comorbid psychiatric disorders found in men and women with addiction parallel those found in the general population. Epidemiological and treatment studies show that, regardless of substance use disorder status, women evidence higher rates of anxiety, depression, eating disorders, and borderline personality disorder, whereas men evidence higher rates of antisocial personality disorder (Brady et al. 1993; Sinha and Rounsaville 2002). Among substance users, gender differences in the temporal onset of comorbid psychiatric conditions have been observed. Specifically, a number of studies indicate that women have a primary mental health disorder that antedates the onset of their substance use disorder more often than do men. This suggests differences in the etiological relationship of substance use and comorbid psychiatric conditions among men and women (Kessler 2004). Using the Epidemiologic Catchment Area data set, one study explored gender differences in the onset of a major depressive episode and alcohol dependence and found that women with depression were more than seven times as likely as women without depression to have alcohol dependence at a 2-year follow-up point (Gilman and Abraham 2001). In contrast, men with major depressive episodes were no more likely than men without depression to develop alcohol dependence over the 2-year follow-up period. Similarly, a recent study demonstrated that women with a history of major depressive episodes were twice as likely to relapse to smoking at 1-year follow-up compared with women without depression (Oncken et al. 2007). Converging lines of evidence suggest that the relationship between trauma, posttraumatic stress disorder, and addiction is also particularly important for women. Early life stress, particularly childhood sexual abuse, is more common in girls than boys and is associated with increased risk of developing substance use disorders (Kendler et al. 2000). Women exposed to violence in adulthood also demonstrate an increased risk for subsequent drug and alcohol dependence. Moreover, alcohol and drug abuse place women at risk for repeated victimization, thus perpetuating the cycle of victimization and substance use (Kilpatrick et al. 1998). Animal studies have demonstrated that uncontrollable stress increases drug self-administration, and neurobiological correlates of stress appear to mediate this response (Stewart 2000). Gender differences in the neurobiological response to stress may be especially important in understanding the relationship between trauma and substance use disorders for women.

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TREATMENT Overview A number of studies indicate that women are less likely than men to enter substance abuse treatment (Greenfield et al. 2007). Reasons for lower rates of treatment entry are complex (Brady and Randall 1999; Canterbury 2002; Greenfield et al. 2007) and may include Sociocultural factors (e.g., stigma, lack of partner/family support to enter treatment) Socioeconomic factors (e.g., child care, financial resources) Pregnancy and fears concerning incarceration or child custody issues Complexities associated with increased rates of co-occurring psychiatric disorders and the availability of appropriate dual-diagnosis treatments Furthermore, many women seek treatment at settings or clinics other than substance abuse clinics, such as primary care or mental health clinics (Weisner and Schmidt 1992). Although fewer women enter substance abuse treatment, treatment outcomes for women appear comparable with those for men. Few consistent gender differences have been observed in outcomes, retention rates, or relapse rates across various types of substances, treatment settings, and types of treatment (Greenfield et al. 2007; Hser et al. 2001; Mangrum et al. 2006). In studies that have found gender differences, women typically demonstrate better outcomes than do men. For example, women have been found to have shorter relapse episodes and higher rates of abstinence at follow-up visits of 6 months (79.3% women vs. 54% men) and 5 years (odd ratio 1.9) (Dawson et al. 2005; Henskens et al. 2005). In a recent study (Moos et al. 2006), women were more likely to have ongoing commitment and benefit from Alcoholics Anonymous participation as compared with men. In comparison with men, women have also been shown to have greater improvement in other areas of functioning such as medical problems and to be more likely to seek assistance after a relapse (Hser et al. 2005; McKay et al. 1996; Project MATCH Research Group 1997).

Gender-Specific Treatment Programs It is still unclear whether women-focused or gender-specific treatments are more effective than standard substance abuse treatments (Ashley et al. 2003; Copeland et al. 1993; Greenfield et al. 2007; Niv and Hser 2007). Some data suggest that women-focused outpatient or residential treatments produce higher rates of treatment completion and continuity of care than do traditional programs (Brady and Ashley 2005; Claus et al. 2007; Dahlgren and Willander 1989). Data also suggest that residential programs that allow women to be accompanied by their children result in higher rates of retention, which is an important factor in predicting treatment outcome (Hughes et al. 1995; Szuster et al. 1996). However, common sense dictates that programs, whether made up of both men and women or women only, that pay special attention to psychiatric comorbidity, family and parenting issues, victimization, and gender-specific barriers to treatment are likely to be more successful for women.

Pharmacotherapy The findings concerning gender differences in the neurobiology of substance use disorders and the potential impact of hormones on the subjective effects of substances of abuse and relapse suggest that there may be gender differences in the most efficacious approach to pharmacotherapeutic treatment. Findings from animal studies also indicate important gender differences in response to the medications that can be used to treat addictions. Campbell et al. (2002) reported that baclofen-treated female rats were less likely to acquire cocaine self-administration as compared with baclofen-treated male rats. In another study (Carroll et al. 2001), ketoconazole was found to decrease opiate self-administration more in female than in male rats. However, there has been little clinical research exploring gender differences in response to agents currently used in the treatment of substance use disorders. Based on animal research demonstrating that progesterone decreases response to stimulants, Evans and Foltin (2006) explored the impact of exogenous progesterone on smoked cocaine and found an attenuation of the positive subjective effects of cocaine in women but not in men. This is clearly an area that warrants

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further gender-specific investigation. As detailed earlier, substance-dependent women are more likely to have mood and anxiety disorders and to be victims of physical and sexual abuse than are men. As such, medication treatment of comorbid conditions is likely to be particularly important in the treatment of substance-dependent women. In this regard, one study comparing a serotonin reuptake inhibitor (sertraline) with a tricyclic antidepressant (imipramine) in the treatment of depression found that premenopausal women had a preferential response to sertraline (Kornstein et al. 2000). However, in a study of sertraline treatment of nondepressed, alcohol-dependent individuals, sertraline treatment reduced drinking in early-onset, alcohol-dependent males but not in any of the female groups (Pettinati et al. 2004). Cornelius et al. (2000, 2001, 2005) explored the use of fluoxetine in depressed alcohol-dependent individuals and found significant improvement in both mood and alcohol outcomes. As such, although the evidence does not support the use of antidepressant medications in the absence of depression in substance-dependent individuals, careful evaluation of depression and psychiatric disorders and appropriate treatment will likely improve treatment outcomes. Other studies have provided preliminary evidence that bupropion, a pharmacological agent with U.S. Food and Drug Administration approval for both the treatment of depression and smoking cessation, may be more efficacious in women than in men (Perkins et al. 1999).

Special Issue: Pregnancy Maternal substance use during pregnancy remains a significant problem. A study of 863 pregnant women in the United States and Canada found that 32% used alcohol occasionally, 16% regularly, and 11% heavily (Edwards and Werler 2006). Among 1,632 mothers, 25% reported using tobacco, 23% alcohol, 6% marijuana, and 1% barbiturates during pregnancy (Arria et al. 2006). As indicated by these investigations, one of the most commonly abused substances during pregnancy is alcohol. In utero exposure to alcohol is associated with a spectrum of effects, the most severe of which is fetal alcohol syndrome, characterized by irreversible neurological damage, mental retardation, facial malformations, and behavioral disturbances (Manning and Hoyme 2007). Self-report measures, such as the Alcohol Use Disorders Identification Test (AUDIT) or the CAGE Questionnaire, are useful for screening in primary health care and obstetric clinics (Caprara et al. 2007). Reliance on self-report, however, is problematic because pregnant substance-using women face social stigma and litigious fears that might prevent admission of use. Biomarkers to detect substance use during pregnancy are strongly needed to overcome the reliance on self-report. Supplementing self-report with mean corpuscular volume, -glutamyl transferase, and carbohydrate deficient transferrin, for example, may be useful. However, no single marker has been found to be sensitive and specific enough to be used as a diagnostic tool in pregnant women (Mancinelli et al. 2007). The chance of an individual biomarker correctly identifying a heavy alcohol consumer ranges from 39% to 72% (Wurst et al. 2004), and studies evaluating the efficacy of using biomarkers to identify problematic use in pregnant women is very limited (Caprara et al. 2007). More sensitive measures to monitor alcohol and drug use during pregnancy are needed. Screening for substance use in pregnant women must be approached with sensitivity to concerns about legal issues that have been raised about the use of drugs and alcohol during pregnancy. Screening for substance use should be conducted for the purpose of encouraging substance abuse treatment for the mother rather than the threat of prosecution and jail. Substance abuse treatment in pregnant women is complicated by social, political, and legal factors. Many pregnant substance-abusing women refrain from seeking treatment, in large part because they fear potential incarceration or losing their children. In a number of U.S. states, pregnant substanceabusing women have been prosecuted, with charges ranging from misdemeanors to criminal homicide, and such prosecution has resulted in life sentences for some women (Harris 2003; Minkoff and Paltrow 2005). This approach may deter pregnant substance-abusing women from seeking drug abuse treatment and from obtaining critical prenatal care. Recent studies indicate that psychosocial and pharmacological interventions may be helpful in reducing substance use and associated issues (e.g.,

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depression and posttraumatic stress disorder symptoms, criminal behavior) among pregnant and postpartum substance-dependent women (Chang et al. 2006; Conners et al. 2006; Jones 2006; Ondersma et al. 2005) and that environmental risk factors (e.g., poor nutrition, toxins, poverty, inadequate health care) must also be adequately accounted for and addressed (Jones 2006). Approaching the issue of substance use among pregnant women as a public health concern, rather than a criminal justice issue to be enforced by physicians and health care providers (Annas 2001), will be more effective in combating addiction. Lifetime rates of physical (71.3%) and sexual abuse (44.5%) and posttraumatic stress disorder (19%) are often high among drug-dependent pregnant women, and studies also show that rates of abuse remain high for many women during their pregnancies (Moylan et al. 2001; Velez et al. 2006). Maternal depression is common and may increase the risk of substance use or relapse to use during pregnancy (Fitzsimons et al. 2007). A recent investigation showed that pregnant women who discontinued the use of antidepressants during pregnancy were significantly more likely to relapse to depression (68%) as compared with those who were maintained on their medication regimen (26%) (Cohen et al. 2006). Questions remain concerning the most optimal and safe treatments for depression among pregnant women. Routine screening for trauma, victimization, and depression for this at-risk population is warranted (Tuten et al. 2004; Velez et al. 2006).

CONCLUSION In conclusion, there are important gender differences in substance use disorders that are meaningful for screening, diagnosis, course of illness, and treatment. Fortunately, gender differences have been a focus of increased attention in recent studies. This line of investigation will be important in informing prevention and treatment efforts for both men and women.

KEY POINTS The overall prevalence rates of drug and alcohol use disorders are higher among men than among women. However, for prescription drugs and nicotine, prevalence rates of women closely approach those of men. One of the most consistent findings in studies focused on gender differences in substance use disorders is the increased vulnerability of women to the adverse medical and psychosocial consequences of substance use. This has been coined the "telescoping" of substance use disorders in women. Women become intoxicated after drinking smaller amounts of alcohol and achieve higher bloodalcohol concentration after drinking equivalent amounts of alcohol as compared with men. This is primarily because women have less total body water than do men of comparable size and a lower concentration of gastric alcohol dehydrogenase, which metabolizes alcohol. Patterns of comorbid psychiatric disorders found in men and women with addiction parallel those found in the general population. Epidemiological and treatment studies show that, regardless of substance use disorder status, women evidence higher rates of anxiety, depression, eating disorders, and borderline personality disorder, whereas men evidence higher rates of antisocial personality disorder. Among substance users, gender differences in the temporal onset of comorbid psychiatric conditions have been observed. Women more often than men have a primary mental health disorder (e.g., depression) that precedes the onset of their substance use disorder. This suggests differences in the etiological relationship of substance use and comorbid psychiatric conditions among men and women. Women are less likely than men are to enter substance abuse treatment. Possible reasons for lower rates include sociocultural factors (e.g., stigma, lack of partner/family support to enter treatment), socioeconomic factors (e.g., child care), pregnancy, and fears concerning incarceration and child custody issues.

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Although fewer women enter substance abuse treatment, treatment outcomes for women appear comparable with those for men. Few consistent gender differences have been observed in outcomes, retention rates, or relapse rates. It is unclear whether women-focused or gender-specific treatments are more effective than standard substance abuse treatments. Programs that allow women to be accompanied by their children may result in higher rates of retention, which is important in predicting treatment outcome. Programs that pay special attention to psychiatric comorbidity, family and parenting issues, victimization, and genderspecific barriers to treatment are likely to be more successful. Maternal substance use during pregnancy remains a significant problem. Self-report measures, such as the Alcohol Use Disorders Identification Test or the CAGE Questionnaire, are useful for screening in primary health care and obstetric clinics. Psychosocial and pharmacological interventions may be helpful in reducing substance use and associated issues (e.g., depression, posttraumatic stress disorder, criminal behavior) among pregnant and postpartum substance-dependent women.

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Substance Abuse and Mental Health Services Administration: National Survey on Drug Use and Health. Rockville, MD, Substance Abuse and Mental Health Services Administration, 2006b. Available at http://www.oas.samhsa.gov/nsduh.htm. Accessed March 7, 2007. Szuster RR, Rich LL, Chung A, et al: Treatment retention in women's residential chemical dependency treatment: the effect of admission with children. Subst Use Misuse 31:1001–1013, 1996 [PubMed] Tuten M, Jones HE, Tran G, et al: Partner violence impacts the psychosocial and psychiatric status of pregnant, drug-dependent women. Addict Behav 29:1029–1034, 2004 [PubMed] Velez ML, Montoya ID, Jansson LM, et al: Exposure to violence among substance-dependent pregnant women and their children. J Subst Abuse Treat 30:31–38, 2006 [PubMed] Weisner C, Schmidt L: Gender disparities in treatment for alcohol problems. JAMA 268:1872–1876, 1992 [PubMed] Wilcox C, Brizendine L: For women only: hormones may prevent addiction relapse. Curr Psychiatry 5:39–45, 2006 Wurst FM, Wiesbeck GA, Metzger JW, et al: On sensitivity, specificity, and the influence of various parameters on ethyl glucuronide levels in urine: results from the WHO/ISBRA study. Alcohol Clin Exp Res 28:1220–1228, 2004 [PubMed]

SUGGESTED READING Conners NA, Grant A, Crone CC, et al: Substance abuse treatment for mothers: treatment outcomes and the impact of length of stay. J Subst Abuse Treat 31:447–456, 2006 Evans SM, Foltin RW: Exogenous progesterone attenuates the subjective effects of smoked cocaine in women, but not in men. Neuropsychopharmacology 31:659–674, 2006 Greenfield SF, Brooks AJ, Gordon SM, et al: Substance abuse treatment entry, retention, and outcome in women: a review of the literature. Drug Alcohol Depend 86:1–21, 2007 Kendler KS, Bulik CM, Silberg J, et al: Childhood sexual abuse and adult psychiatric and substance use disorders in women: an epidemiological and cotwin control analysis. Arch Gen Psychiatry 57:953–959, 2000 Sinha R, Rounsaville BJ: Sex differences in depressed substance abusers. J Clin Psychiatry 63:616–627, 2002 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 40. Perinatal Substance Abuse: Drug Dependence, M...

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Loretta P. Finnegan, Stephen R. Kandall: Chapter 40. Perinatal Substance Abuse: Drug Dependence, Motherhood, and the Newborn, in The American Psychiatric Publishing Tex tbook of Subs Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psyc hiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440 356218. Printed 10/7/ 2011 from www.psychiatryonline com Textbook of Substance Abuse Treatment >

Perinatal Substance Abuse Drug Dependence, Motherhood, and the Newborn Loretta P. Finnegan, M.D. Stephen R. Kandall, M.D.

PERINATAL SUBSTANCE ABUSE: INTRODUCTION The perinatal period should be regarded as a continuum that extends from the beginning of a woman's pregnancy through delivery and the first month of a child's life. Although in th discuss discrete drugs, clinicians must be aware that the use of any psychoactive drug during pregnancy may mean that other psychoactive agents are being used concomitantly. Pe therefore reflect pharmacological effects of individual agents or the combined effects of multiple drugs. In all cases, substance use during pregnancy must be considered to be high r medical, obstetric, neonatal, pediatric, and psychosocial standpoints. It is extremely important, however, to recognize that providing comprehensive, supportive, nonjudgmental ca woman and her family in a well-integrated, multidisciplinary setting offers a unique opportunity to restructure the woman's life in a positive direction.

THE SUBSTANCE-USING MOTHER Epidemiology Determining the epidemiology of drug use during pregnancy has always been an inexact science (American Academy of Pediatrics 1998; National Institute on Drug Abuse 1996). Thi resulted from factors such as changes in drug use patterns over time, variations in sample populations in individual hospitals and larger geographic areas, differing applications of his techniques and drug-detection technologies, and the varying attention that society has paid over time to this specific subset of female drug users (Kandall 1996). In its 1992–1993 National Pregnancy and Health Survey, the National Institute on Drug Abuse (1996) used cross-sectional analysis to estimate the incidence of maternal drug use du Information was obtained from 2,613 women delivering at 52 participating hospitals in the United States, and data were extrapolated to estimate drug exposure in the 4,023,307 liv The National Institute on Drug Abuse estimated that approximately 220,000 women (5.5% of pregnant women) used an illicit drug during pregnancy. Marijuana was used most frequ women; 3%), followed by amphetamines, sedatives, tranquilizers, and analgesics in a nonmedical context (61,000 women; 1.5%); cocaine (benzoylmethylecgonine) (45,000 wome methamphetamine, heroin, methadone, inhalants, and hallucinogens (smaller percentages). These numbers are all considerably lower, however, than those for alcohol use (757,00 and cigarette smoking (820,000 women; 20.4%) during pregnancy. Because a decade and a half has transpired since this survey, current national figures would be important to dete treatment needed by pregnant substance-abusing women. Although national epidemiological studies are of interest, each community should determine its own incidence of materna best assess the effect on its obstetric, medical, social services, and addiction treatment needs (Chasnoff et al. 1990; Gomby and Shiono 1991; Lester et al. 2001; Vega et al. 1993).

Medical Issues Given the chronic, relapsing nature of addiction, the chaotic lives of substance-abusing women, and the frequent lack of consistent prenatal care, it is not surprising that many medic arise during pregnancy. Substance-abusing women are at increased risk for anemia, bacteremia and septicemia, bacterial endocarditis, cellulitis, dental caries, endocrinopathies, he deficiencies, phlebitis, pneumonia, tetanus, tuberculosis, and urinary tract infections (Finnegan and Kandall 2005). The pregnant woman who is addicted to opiates and is not enrolle methadone maintenance program may have periods of physical well-being but also may feel the extremes of being "high" or "sick" within a relatively brief time. The cocaine user ha of hypertensive crises, cardiac and cerebrovascular complications, seizures, and a range of psychiatric disorders such as dysphoric agitation. Excessive alcohol intake has been linked of hypertension, cardiovascular mortality, and breast cancer, as well as to fatty liver and cirrhosis, gastrointestinal hemorrhage, and peptic ulcer (Blume and Zilberman 2005). Sexually transmitted diseases, particularly human immunodeficiency virus (HIV), have become inextricably linked to illicit drug use because of direct sex-for-drugs activity, prostitu drugs, and the sharing of infected needles and drug paraphernalia. An estimated 120,000–160,000 women in the United States are living with HIV; many of the women are unaware HIV-positive. Each year, about 6,000–7,000 of these women give birth. Of the approximately 15,000 children in the United States who have contracted HIV, resulting in about 3,000 contracted the virus from their mothers during pregnancy or birth (P. Dole 2003; Public Health Service Task Force 2006). Studies also found that some HIV transmission rates can be reduced by opting for a cesarean delivery before the onset of labor and rupture of membranes occur. A 1999 study by th of Child Health and Human Development found maternal-to-infant transmission rates of only 2% in women who were given antiretroviral drugs during pregnancy and who had a ces compared with 7.3% in women who took those medications but did not have a cesarean delivery (P. Dole 2003; Public Health Service Task Force 2006). The American College of Ob Gynecologists recommends that HIV-infected women be offered a cesarean delivery at 38 weeks to further reduce the risk to their babies, unless they have very low or undetectabl virus in their blood. It is not yet certain that a cesarean delivery reduces the risks when a woman has very low or undetectable amounts of the virus in her blood (as a result of drug Committee Opinion 1999). The U. S. government has put together guidelines to help HIV-positive women make treatment decisions. The standard three-part zidovudine (AZT, ZDV) treatment is recommende a viral load of more than 1,000 copies/mL or whose disease status otherwise requires HIV treatment should be given the standard three-part zidovudine treatment plus additional H to treatment guidelines for nonpregnant women. Women who are in the first trimester of pregnancy may consider delaying therapy until after the first 10–12 weeks of the pregnanc benefits of this should be discussed with the physician responsible for the patient's care. Specific guidelines exist for women who are already taking HIV drugs who learn that they ar Health Service Task Force 2006; U.S. Department of Health and Human Services 2006). The standard three-part zidovudine treatment for prevention of transmission of HIV from pr child is 1) zidovudine throughout the pregnancy; 2) zidovudine intravenously to mother during labor and delivery; 3) zidovudine syrup given to newborn beginning at 6–12 hours afte first 6 weeks. The use of zidovudine alone is recommended for women with a viral load below 1,000 copies/mL. Advances in HIV treatment initially reduced the perinatal HIV transmission rate from 25% to 5%–8%; highly active combination antiretroviral therapy has further reduced the trans than 2%. Because infants can be infected with HIV through breast milk, they should not be breast-fed if other options are available. Illicit substance use during pregnancy also places the fetus and newborn at increased obstetric risk. Abruptio placentae, amnionitis, early pregnancy loss, intrauterine growth retarda intrauterine death, placental insufficiency, postpartum hemorrhage, preeclampsia and eclampsia, premature labor, premature rupture of membranes, and septic thrombophlebitis a potential complications (Finnegan and Kandall 2005). This means that all such pregnancies should be considered high risk, and medical-obstetric addiction management should be ca knowledgeable, supportive health care providers in a program that has relevant experience. Potential barriers to entry into a treatment program, such as a woman's fear of the loss of her children to protective agencies, insufficient financial means, unsafe living conditions, d obtaining suitable transportation, lack of support from family and social contacts, and inaccessibility of gender-specific programs, must be addressed (Murphy and Rosenbaum 1999) Substance Abuse Prevention and Treatment Block Grant (P.L. 102-321 1992), states are required to grant pregnant women priority for treatment and to provide them with access to child care and assistance with transportation. A source for referral of individuals to relevant state and local services is the Health Resources and Services Administration's National M Health Clearinghouse (1-888-275-4772). Treatment for heroin dependency during pregnancy should be tailored to the woman's individual needs. Highly motivated women or those facing barriers to obtaining methadone m treatment may be considered for medical withdrawal during pregnancy if the process can be undertaken under careful medical supervision (Center for Substance Abuse Treatment 1 pharmacological treatment of choice for heroin-dependent women is methadone maintenance, which offers a unique opportunity for careful supervision of a woman's addiction, preg medical and psychosocial health (Kandall et al. 1999). Methadone maintenance treatment has been shown for three decades to reduce both maternal mortality rate and rates of feta morbidity, and pregnancy-associated complications (Berghella et al. 2003; Blinick et al. 1973; Finnegan et al. 1991). Although suggested regimens of methadone maintenance vary, adequate dosage of methadone (60–150 mg/day) is associated with a lower incidence of illicit drug use and higher rates of treatment retention (Ward et al. 1998). Single daily dosin represents the standard of care, but split daily dosing also may be considered to maintain a steady-state level of medication (Wittmann and Segal 1991). Although buprenorphine ha be useful in many case series and limited randomized clinical trials, no studies with large numbers of patients exist. A randomized clinical trial (The MOTHER Study, Lester 2006) is in the potential use of buprenorphine in the treatment of opiate-dependent pregnant women and its safety in exposed neonates.

Psychosocial Issues The complexity of medical management of the pregnant substance abuser is mirrored in the attendant psychosocial problems seen in this population. Drug-dependent and alcohol-u manifest anxiety, depression, and low self-esteem (Hagan et al. 1994; Murphy and Rosenbaum 1999). Degrading descriptive terms reflect the disrespect with which women are reg drug culture and should never be used in the treatment setting (Murphy and Rosenbaum 1999).

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Many addicted women share a history of past and current physical abuse and sexual assault. A Philadelphia, Pennsylvania, study reported that 83% of the women entering drug trea households in which parents used drugs, 67% had experienced sexual assault, and 60% had been physically assaulted (Finnegan et al. 1991). Similarly, in a New York study involvin women, homelessness, sexual abuse, and drug use by family members were prominent historical facts about their pasts and current environments (Chavkin et al. 1993). A study by Triangle Institute compared the characteristics of out-of-treatment, homeless, crack-using African American women with those of women who were not homeless to determine the r factors that differentiated the two groups. Their findings suggested not only that these women overall reported psychologically painful histories and currently stressful lives but also t women were more likely than women who were not homeless to have experienced childhood abuse and to be more involved with drug use (Wechsberg et al. 2003). In a report by F (1993), women in recovery from drug addiction were likely to have a history of violent trauma and were at high risk for posttraumatic stress disorder (PTSD). The investigators sug screening for PTSD among women with an addictive disorder should become part of the diagnostic and treatment routine. A stressful psychosocial setting, often aggravated by reduced socioeconomic circumstances, makes it more likely that a woman will enter the drug subculture. Society's decision to p who use drugs during pregnancy (Kandall 1996, pp. 273–279) and draconian sentences for drug-related offenses have resulted in a large increase in the number of women incarcera 20 years (National Institute on Justice 1990; Snell 1994). Drug-using pregnant women have been prosecuted despite opposition by a wide spectrum of medical, public health, and ad addition, fear of criminal prosecution has been shown to deter women from seeking prenatal care (Chavkin 1991). Once incarcerated, both addiction treatment and gynecological-ob penal system are often substandard, which jeopardizes pregnancy outcome (Wellisch et al. 1993). Lynn Paltrow (1999, pp. 15–16) of the National Advocates for Pregnant Women ends her article on the subject of pregnant women and prosecution as follows: The truth is that we do not have to pit the woman against the fetus to promote healthy pregnancies or to value life. In fact, creating fetal personhood hurts both women and the p healthier pregnancies. We could treat addiction for what it is, a health problem. We could fund programs designed to meet women's needs not only during pregnancy, but through because we value women as whole persons. We could respect people's different values regarding fetuses without creating the legal fiction that fetuses are separate persons. We c ending poverty, the greatest threat to children's health. We could attempt to develop a sane drug policy and ensure that health care and reproductive freedom are realities for al Most people think these goals are too unrealistic to fight for. But it is exactly because we have given up these goals that there is now so much room for arguments for punishmen protection not of life or health in general but only of fetal life alone. The complex matrix of intertwining medical and psychosocial risk factors that usually characterize substance use during pregnancy dictates that a successful outcome can best be ob comprehensive, supportive, nonjudgmental environment that focuses on the multidimensional needs of the woman (Center for Substance Abuse Treatment 1993b, 1994; Finnegan e approach encompasses a wide range of services (residential, outpatient, home-based, and prison-based); multiple counseling modalities (individual, group, and family); counseling domestic violence; services for children (day care, play therapy, parental training); concrete services (transportation, housing, food); comprehensive family-based health care (obst general medical); educational training (job training, high school equivalency training); appropriate staffing (including female members and being supportive and culturally and racial advocacy services (legal, child protection, welfare); and aftercare. Provision of these services at a single location will enhance compliance and will make accessing the multiple aspe easier for the pregnant woman. Three decades ago, we began such a multidimensional program in Philadelphia; Figure 40–1 describes this schema that was successful in our setting many other treatment programs nationally (Finnegan et al. 1990). FIGURE 40–1. Family center schema for treatment of drug dependency in the perinatal period and aftercare.

Note. DHHS = Department of Health and Human Services; DPW = Department of Public Welfare; WIC = Special Supplemental Nutrition Program for Women, Infants, and Children Source. Adapted from Finnegan et al. 1991.

THE SUBSTANCE-EXPOSED INFANT Neonates born to substance-using mothers should be admitted to units that provide observation, assessment, and treatment by trained personnel. In cases in which a suspicion of m under consideration, confirmation of fetal exposure may be accomplished by testing of urine. Analysis of meconium (Ostrea et al. 1992) and/or hair (Callahan et al. 1991; Lester et longer window of fetal drug exposure, but these testing methodologies are generally restricted to research laboratories. Under all circumstances, however, testing should not be car purpose of punitive referral but to identify both mothers who are in need of medical and addiction-treatment services and infants who require special observation for medical compli neonatal abstinence syndrome.

Opiates Many pharmacological agents have been reported to produce signs resembling neonatal abstinence syndrome. The most notable agents are opiates, including opium, meperidine, m morphine, and controlled-release oxycodone hydrochloride. Other substances reported in case reports or small series to produce signs of neonatal abstinence include alcohol, barbitu clomipramine, chlordiazepoxide, desipramine, diazepam, diphenhydramine hydrochloride, ethchlorvynol, glutethimide, hydroxyzine hydrochloride, meprobamate, propoxyphene hy

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selective serotonin reuptake inhibitors (SSRIs) (Finnegan and Kandall 2005; Zeskind and Stephens 2004). Because signs of abstinence syndrome may overlap among these categorie documentation of maternal drug-taking patterns is critical. This can be accomplished prenatally with sensitive history taking and at birth by urine testing. In the newborn period, signs of drug abstinence may mimic other serious conditions such as sepsis or meningitis, hypoglycemia, adrenal insufficiency, and cardiorespiratory disease these serious conditions should proceed while the neonatal abstinence is being evaluated (Weiner and Finnegan 2006). Because most opiates are short acting, signs of abstinence wi after delivery (generally within 1–3 days), when the cord is clamped and the infant is acutely deprived of the drug circulating in the maternal bloodstream. The onset of methadoneabstinence symptoms, although usually early, is somewhat more unpredictable (Kandall and Gartner 1974) because methadone establishes a reservoir in fetal tissue (V. P. Dole and et al. 1985) and undergoes more variable metabolism and excretion (Finnegan and Kaltenbach 1992). Variations in amounts of maternal drug use (Connaughton et al. 1977; Dashe Kaltenbach et al. 1996; Madden et al. 1977; Ostrea et al. 1976; Rajegowda et al. 1972; M. E. Strauss et al. 1976), placental drug transfer, neonatal metabolism and excretion (Blini Doberczak et al. 1993; Harper et al. 1977; T. S. Rosen and Pippenger 1976), and gestational age (Doberczak et al. 1991) may all potentially affect the time to onset of abstinence s Signs of neonatal abstinence syndrome are usually divided into four groups (American Academy of Pediatrics 1998; Center for Substance Abuse Treatment 1993a; Finnegan and Kalt Kandall 1999; Weiner and Finnegan 2006): 1. Central nervous system signs include irritability; high-pitched crying; high-frequency, low-amplitude tremors; hypertonia; and hyperreflexia. Despite a voracious appetite, dy and swallowing often complicate feeding (Kron et al. 1976). Seizures may occur in approximately 5% of opiate-exposed infants (Finnegan 1986; Herzlinger et al. 1977; Zelson 1971). These seizures are often unpredictable as to occurrence, are most frequently myoclonic in nature, and tend to occur at about age 10 days, with a range of 3–34 days (H 1977; Kandall et al. 1983). Sleep disturbances are prominent. A study by O'Brien and Jeffery (2002) determined the exact nature and degree of sleep disturbances and sugges changes in sleep are a result of opiate withdrawal, but others may reflect opiate dependency in utero. 2. Gastrointestinal signs include vomiting and diarrhea, which, when combined with poor intake of nutrients and increased insensible water loss, often results in excessive weigh suboptimal weight gain in the first few weeks of life (Weinberger et al. 1986). 3. Respiratory signs include excessive secretions and nasal stuffiness (Finnegan 1980); tachypnea and hyperpnea, which may produce respiratory alkalosis (Glass et al. 1972), c if untreated. 4. Autonomic nervous system signs include sweating, sneezing, tearing, and hyperthermia. Infants exposed to drugs prenatally are considered to be at high risk and should be cared for in a structured setting by skilled personnel. Because an uncoordinated suck-swallow ref infants at risk for aspiration, the liberal amounts of fluids and calories needed to offset the infant's hypermetabolic state should be provided carefully. The recommendation to provid feedings (American Academy of Pediatrics 1998) should be balanced against the advantages of reduced sensory stimulation. Positioning techniques, use of a soothing waterbed, and darkened room often pacify the infant (Maichuk et al. 1999; Oro and Dixon 1988) but also increase the need for close surveillance, including observation for abstinence-associated se Because only 60%–80% of drug-exposed neonates experience abstinence symptoms, routine prophylactic treatment is not recommended. Close observation of clinical symptoms is a semi-objective abstinence symptom severity scoring system allows accurate evaluation of signs and symptoms, avoids unnecessary treatment of mildly affected infants, and provi for effective tapering of medications (Finnegan et al. 1975; Green and Suffet 1981; Lipsitz 1975; Zahorodny et al. 1998). A comprehensive abstinence assessment tool, the Finnegan Abstinence Score, is administered by nursing staff to monitor the in utero opiate-exposed neonate (Finnegan and Kaltenbach 1992). The score includes the vast array of symptoms t reported in infants with neonatal abstinence. If individuals are properly trained and interrater reliability is achieved, the score becomes a valuable objective measure to assess the o and diminution of symptoms of abstinence. Specific pharmacological treatment is tailored to the severity of the score. The score monitors the infant's clinical response to the pharma intervention necessary to control the symptoms and achieve medical detoxification. This scoring system rates 21 individual signs, assigning each a relative weight based on a postula outcomes of perinatal morbidity. Infants are evaluated 2 hours after birth and every 4 hours thereafter, or more frequently if the abstinence symptoms are severe. The Neonatal Ab Sheet is shown in Figure 40–2. Symptoms are listed on the left, with their respective scores listed on the right. The time of each evaluation is given at the top of the sheet, and the t for each interval. A comments column has been provided so that nursing and medical staff can record important clinical observations in addition to the symptoms noted. FIGURE 40–2. Neonatal abstinence scoring sheet used for the assessment of infants undergoing neonatal abstinence.

Note. Evaluator should check sign or symptom observed at various time intervals. Scores should be added to determine total at each evaluation. Source. From Finnegan et al. 1975. Although diazepam (Nathenson et al. 1971; M. Rosen 1972; Schiff et al. 1972), chlorpromazine (Kahn et al. 1969), and clonidine (Hoder et al. 1984) have been used to treat opiate a symptoms in the past, no large studies have confirmed their efficacy. Rather, short-acting opiate preparations have become the treatment of choice for neonatal opiate abstinence s Academy of Pediatrics 1998; Center for Substance Abuse Treatment 1993a). This treatment is based on the assumption that opiate exposure is best treated with another opiate and performed on neonates (Jackson et al. 2004). Paregoric (camphorated tincture of opium) is easily administered orally, has little toxicity, restores sucking reflexes to normal more rapidly than do nonspecific therapies such as ph al. 1976), and offers some protection against abstinence-associated seizures (Kandall et al. 1983). In the past, paregoric was most commonly used. One regimen suggested beginnin dosage of 0.2 mL every 3 hours; the dosage was raised by 0.05 mL on the basis of severity scoring to a maximum of 0.4 mL. The final stabilizing dosage was maintained for 3–5 day slow tapering regimen of 0.05 mL per dose every other day (Kandall 1999). A slightly different regimen recommended the administration of paregoric every 4 hours at a dosage bas severity of abstinence (Finnegan and Kaltenbach 1992). Initial total daily doses of paregoric ranged from 0.8 mL/kg/day to 2 mL/kg/day. Once the infant had been clinically stabilize abstinence scores, the total daily dosage was lowered by 10% every day. Pharmacokinetic studies indicate that duration of treatment, although variable, will be longer following me than following heroin exposure. Both regimens advised observation of the infant in a hospital setting for 48 hours after cessation of treatment.

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Recent concerns, however, have been raised about the safety of other ingredients found in paregoric, despite its record of efficacy and safety (American Academy of Pediatrics 1998 on Drugs of the American Academy of Pediatrics cautioned that paregoric contains isoquinoline derivatives (noscapine and papaverine), which are antispasmodics. Paregoric also con potentially dangerous central nervous system stimulant that is lipid-soluble and requires glucuronidation for excretion. In addition, paregoric contains alcohol, anise oil, and glycerin of Pediatrics 1994). Paregoric also contains 4 mg/mL of benzoic acid, which may compete for bilirubin binding sites. Benzyl alcohol (paregoric's oxidative product) has been reported syndrome of severe acidosis, central nervous system depression, hypotension, renal failure, seizures, and death in small premature infants who receive large doses (Gershanik et a As a result of these concerns, the American Academy of Pediatrics Committee on Drugs has recommended tincture of opium as the treatment of choice for neonatal opiate abstinenc Academy of Pediatrics 1998). The committee's recommendation is for the use of a 25-fold dilution of tincture of opium, which results in a concentration of morphine equivalent to tha mg/mL). The recommended initial dosage of the diluted tincture of opium is 0.1 mL/kg (2 drops/kg) with feedings every 4 hours. Dosage increases and decreases can be managed i with paregoric, by using the regimen and the severity scoring system discussed earlier in this section. Two other narcotic preparations, morphine and methadone, have been used on a limited basis to treat neonatal opiate abstinence (American Academy of Pediatrics 1998). The pare morphine contains sodium bisulfite and phenol. Langenfeld et al. (2005) compared the efficacy of the oral pure

agonist morphine with the alcoholic mixture of tincture of opium to

infants. The investigators found that morphine could be used to treat neonatal abstinence, to avoid unwanted effects of the alcoholic extracts, and to allow better weight gain in the are available regarding the efficacy and safety of treating neonatal opiate abstinence with methadone. Phenobarbital is a nonspecific central nervous system depressant that also can be used to treat neonatal abstinence syndrome. Phenobarbital offers the advantage of a broad spectr cases of maternal polydrug abuse. Its usefulness is limited, however, because it does not control non–central nervous system signs, it depresses sucking, and it may depress respira Recommendations include a loading dosage of 16 mg/kg intramuscularly over 24 hours followed by a maintenance dosage of 2–8 mg/kg/24 hours orally to control signs of abstinenc stabilization, the dosage usually can be reduced by 10%–20% per day when a severity scoring system is used as a guide to treatment. After cessation of either treatment, the infant monitored in the hospital for at least 2 days to observe for rebound withdrawal (Finnegan and Kaltenbach 1992; Kandall 1999). Abstinence-associated seizures should be treated acutely with a loading dose of 10–20 mg/kg of phenobarbital intramuscularly or intravenously (dependent on the severity) supplem of opium. The phenobarbital dose may be lowered sequentially once the seizures are controlled and a diagnostic workup has ruled out other causes of neonatal seizures. Most of the discharged without anticonvulsant medication, and the prognosis of infants with uncomplicated seizures is excellent (Finnegan and Kaltenbach 1992; Herzlinger et al. 1977; Kandall 1 If the mother is HIV negative, breast-feeding should be encouraged for its attendant medical and psychosocial benefits. Opiates pass to the nursing infant through the breast milk bu affect the severity of the neonatal abstinence syndrome or to achieve sufficient concentrations to serve as treatment for neonatal symptoms (McCarthy and Posey 2000).

Stimulants Maternal cocaine use is associated with specific obstetric complications, including early pregnancy loss, abruptio placentae, premature onset of labor, chronic fetal hypoxia, intrauter retardation, and an increased incidence of stillbirths (Plessinger and Woods 1991). Cocaine has a low molecular weight, is highly soluble in water and lipid, and passes easily transpla mother to fetus. Although the risk of cocaine-associated teratogenicity has been difficult to establish (Koren et al. 1993), cocaine has been reported to be responsible for a series of c in a pattern of "fetal vascular disruption" (Hoyme et al. 1990). After birth, cocaine-associated vasoconstriction has been reported to be the precipitating factor in necrotizing enteroco perforation, arterial thrombosis, hypertension, and myocardial ischemia (Finnegan and Kandall 2005). Cocaine-exposed newborns show neurological signs that are quite different from those seen in opiate-exposed neonates. Rather than showing signs of abstinence, cocaine-exposed i reported to show evidence of a neurotoxicity syndrome manifested initially by transient hypertonia, hyperreflexia, irritability, and tremors (Chasnoff et al. 1985; Doberczak et al. 19 al. 1996). This phase is followed by a period of depressed interactive behavior, lability of state, and poor organizational response to environmental stimuli (Chasnoff et al. 1985; May and Dixon 1987). Less commonly, these infants may show abnormal electroencephalogram results (Dixon and Bejar 1989; Doberczak et al. 1988; Scher et al. 2000) and more dram neuropathological signs, such as seizures (Chasnoff et al. 1989; Kramer et al. 1990) and cerebrovascular accidents (Chasnoff et al. 1989; Heier et al. 1991). Although the mechanism abnormalities is not clear, cocaine-associated derangements in dopaminergic and serotonergic systems have been postulated (Mayes 1994; Mirochnik et al. 1991; Scafidi et al. 1996 The literature on neurobehavioral adaptation is vast and includes the reports of many who used the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). Eisen et al. (1991) fo with control subjects, cocaine-exposed infants needed more trials to habituate to a presented stimulus on the BNBAS within the first week of life. Coles et al. (1992) compared infant cocaine-using mothers (although alcohol, marijuana, and cigarettes were also used) with control infants at 48–72 hours, 14 days, and 28 days. Although scores were generally norm infants appeared to show minimal and transient autonomic depression. Mayes et al. (1993) also found that cocaine-exposed infants showed impaired habituation on the BNBAS score found persistence of abnormalities in habituation at a 3-month assessment (Mayes et al. 1995). Delaney-Black et al. (1996) found that neurobehavioral abnormalities in the motor p state-regulation subareas of testing could be correlated with the amount of intrauterine cocaine exposure as determined by meconium testing. Napiorkowski et al. (1996) reported t infants tested at age 1–2 days showed increased tone, jerky movements and startles, and poorer auditory and visual following compared with control infants; the authors further su may act synergistically with alcohol and marijuana in producing these neonatal abnormalities. Tronick et al. (1996) found that cocaine-associated abnormalities in neurobehavioral p not be detected with the BNBAS when confounders were controlled. Abnormalities, particularly in arousal, could be identified, however, on the 3-week repeat examinations, raising learning capability of cocaine-exposed infants. In the literature, effects of prenatal cocaine exposure are described in many different ways, which makes their etiology difficult to determine. Are the immediate postpartum effects exposure a withdrawal effect as cocaine is metabolized or a transient effect and related to acute toxicity of the drug? A prospective, longitudinal study (Eyler et al. 2001) was design hypothesis that newborns whose urine was positive for cocaine metabolites, compared with those exposed to cocaine but urine-negative and with nonexposed control subjects, woul neurobehavioral scores (toxicity effect) and 2) worsen or show less improvement over the first week of life (withdrawal effect). Neurobehavioral testing was performed with the BNB and 5–7 postpartum. The data supported those of other controlled studies that did not find early effects of prenatal cocaine exposure but added to the understanding that effects obs to be related to acute toxicity or cocaine withdrawal. The investigators cautioned that the uncertainty of persistent effects of cocaine exposure warranted long-term follow-up. Although most cocaine-exposed infants do not require treatment, if excessive irritability occurs, treatment with short courses of phenobarbital may be warranted. Because these infa reported to be hyporeactive once the initial irritability subsides, they should be provided with an individualized program of structured physical contact, including gentle handling with social talking, and eye contact without overstimulation (Center for Substance Abuse Treatment 1993a). Intervention programs provided by trained personnel should include the pare possible. Breast-feeding by a cocaine-using mother poses risks of acute neonatal intoxication (Chaney et al. 1988; Chasnoff et al. 1987) (in contrast to opiate use) and is therefore c Similar to the action of cocaine, amphetamine and methamphetamine block the reuptake of neurotransmitters. Use of these drugs during pregnancy has been associated with a high rate; reductions in birth weight, length, and head circumference; associated congenital malformations; and abnormal neurological signs, muscle tone problems, abnormal cry patter feeding, and seizures (Eriksson et al. 1978, 1981; Oro and Dixon 1987; Smith et al. 2003).

Barbiturates Maternal use of phenobarbital at a dosage of at least 90 mg/day for 12 weeks before delivery has been reported to produce a neonatal abstinence syndrome marked by hyperactivit excessive crying, tremulousness, hyperreflexia, vomiting, and diarrhea (Blumenthal and Lindsay 1977; Desmond et al. 1972; Hill et al. 1977). This complex of signs is similar to opi syndrome (American Academy of Pediatrics 1998). The abstinence syndrome usually develops by age 4–8 days and should be treated with phenobarbital when symptoms cannot be conservative measures. A more prolonged abstinence syndrome, similar to the subacute withdrawal described occasionally with heroin exposure, may persist for 2–6 months. Barbi breast milk, but breast-feeding need not be discouraged.

Hallucinogens The effects of marijuana ( 9 -tetrahydrocannabinol) on the human fetus and neonate have been studied by Fried and colleagues (Fried 1995; Fried et al. 1983, 1998) for several deca linked maternal marijuana use with reduced fetal growth, preterm birth, and an increase in neonatal tremors and startle responses. Marijuana has been shown to affect the infant's visual stimulation and may cause developmental problems (Fried et al. 1998). Lysergic acid diethylamide (LSD) has been reported to cause chromosomal breakage, spontaneous ab prematurity. Phencyclidine, or 1-(1-phenylcyclohexyl)piperidine, also known as PCP and "angel dust," has been noted in limited studies to cause hypertonia, hyperreflexia, and trem 1980; A. A. Strauss et al. 1981).

Alcohol Despite ongoing educational campaigns, alcohol use during pregnancy continues to be a major health problem. Data from the 2002 Centers for Disease Control and Prevention's Beh Surveillance System (BRFSS) indicated that approximately 10% of pregnant women used alcohol and approximately 2% engaged in binge drinking or frequent use of alcohol. Alcoho itself or as part of a larger pattern of polysubstance use. Comprehensive management of the pregnant alcohol user should begin with preconception counseling and extend througho Biological variability makes it impossible to define a safe level of alcohol consumption during pregnancy; thus, total abstinence should be recommended. Alcohol abuse is generally d consumption of seven or more alcoholic drinks per week or consumption of three or more alcoholic drinks on multiple occasions (Finnegan and Kandall 2005; Hanson et al. 1978; So 1989; Streissguth and Finnegan 1996). The recently adopted terminology of fetal alcohol spectrum disorders denotes that alcohol-related effects may range from severe, devastating, and lifelong to less apparent and sub

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Centers for Disease Control and Prevention codified diagnostic criteria for the most severe manifestations, called fetal alcohol syndrome, which is thought to occur in 0.2–1.5 per 1,0 alcohol syndrome, which may escape detection despite its catastrophic nature, should include Dysmorphology. All three dysmorphic features (small philtrum, thin vermillion border, small palpebral fissures) should be present. Other facial dysmorphisms seen in fetal alc include hypoplastic maxilla, short upturned nose, micrognathia or retrognathia, and, less commonly, ptosis, strabismus, epicanthal folds, microphthalmia, posterior rotation o lip or palate. Other reported malformations involve the cardiac system, genitourinary and gastrointestinal tracts, skin, and joints. Growth. Prenatal or postnatal growth deficits in height or weight occur. Central nervous system. Abnormalities are seen, which may be structural (small head size, neuroimaging abnormalities), neurological (including seizures), or functional (test substantially below that expected for age, schooling, or circumstances). Less devastating effects of fetal alcohol exposure have been reclassified as partial fetal alcohol syndrome, alcohol-related birth defects, and alcohol-related neurodevelopmental diso Intrauterine exposure to alcohol also has been reported to produce neonatal signs consistent with withdrawal (Coles et al. 1984; Nichols 1967; Pierog et al. 1977). Alcohol-exposed n hyperactivity, irritability and excessive crying, tremors, poor sucking, and even seizures. Administration of phenobarbital in dosages of 5–10 mg/kg/day, dependent on the severity, regimen of slow tapering of the medication appears to control acute symptoms in the newborn.

Nicotine Long-term maternal smoking has been linked to increased rates of placenta previa, abruptio placentae, placental infarcts, and placental changes caused by vasoconstriction. Elevate monoxide in smokers also may adversely affect the delivery of oxygen to the fetus transplacentally. Many studies have shown a reduction in birth weight by approximately 150–200 cigarettes smoked. Hypertonia has been reported in neonates born to smoking mothers. Children born to mothers who smoke have increased rates of sudden infant death syndrom and death up to age 5 years, primarily from respiratory disorders such as bronchiolitis and pneumonia. Neonatal withdrawal also can occur in infants exposed to heavy maternal sm pregnancy (Godding et al. 2004).

Selective Serotonin Reuptake Inhibitors The increasing use of SSRIs to treat maternal depression during pregnancy has recently raised concerns about their effects on the fetus and newborn. Commonly used SSRIs include fluoxetine, paroxetine, sertraline, and venlafaxine. Fetal exposure to SSRIs has not been reported to be associated with major congenital malformations. Both anecdotal reports and series of patients tie maternal SSRI use during pregnancy to a neonatal syndrome that may be the result of a direct toxic effect or abstinence (Wisner et and Stephens 2004). Nordeng et al. (2001) reported a series of cases of neonatal abstinence syndrome in infants exposed to SSRIs (citalopram, fluoxetine, paroxetine) in the third t Withdrawal symptoms occurred within a few days after birth and lasted up to 1 month. Most of the infants required treatment. Symptoms included irritability, constant crying, shive tonus, eating and sleeping difficulties, and convulsions. In a prospective study (Zeskind and Stephens 2004), SSRI-exposed infants had a shorter mean gestational age, were more m and tremulous, and showed fewer rhythms in heart rate variability. In addition, the infants showed fewer changes in behavioral state, fewer different behavioral states, a lower pea and significantly more rapid eye movement sleep, which was characterized by longer continuous startles or arousals. The Food and Drug Administration is also assessing reports of r cyanosis, apnea, seizures, temperature instability, feeding difficulty, and vomiting in SSRI-exposed neonates. In a recent Israeli study, Levinson-Castiel et al. (2006) noted that 30% infants had withdrawal symptoms—most commonly, tremor, gastrointestinal problems, hypertonicity, sleep disturbances, and high-pitched cry. Although none of the infants require highest Finnegan withdrawal score did not occur until 48 hours after birth, suggesting the need for observation of such infants. The long-term effects of prolonged exposure to SSRIs neonates who develop severe symptoms, have yet to be determined.

Buprenorphine Several studies have been reported regarding the use of buprenorphine in opiate-dependent pregnant women. Buprenorphine does not interfere with fertility and appears to be safe regard to reproductive, teratogenic, and toxicity profiles. In a 1998 report in nine patients, Fischer et al. (1998) found that buprenorphine administration in opiate-dependent pregna efficacious and well tolerated. Babies born exposed in utero to buprenorphine had birth weights and Apgar scores within the normal range and no evidence of neonatal abstinence. In study with more patients, Fischer et al. (2000) reported similar findings, except that 50% of the neonates had mild to moderate abstinence symptoms of very short duration. In con report (Kayemba-Kay's and Laclyde 2003) found that 85% of their infants had abstinence symptoms, and all but one infant had to be treated. In follow-up of the infants, the investig transient lower limb hypertonia, jerky movements, and jitteriness that lasted 3–9 months. Overall milestones were within normal limits. Although current data are limited, pregnant women taking buprenorphine have not had adverse effects, and infants born to these women have been delivered at term with birth we range. Observations have varied concerning frequency, intensity, and duration of abstinence in newborns exposed in utero to buprenorphine (Loustauneau et al. 2002). Illicit drug u in 40% of the cases, confounding the data with regard to the role buprenorphine plays in the occurrence of abstinence symptoms. Neonatal symptoms following buprenorphine expo appear within 12–24 hours, peak at approximately 72–96 hours, and last 15–21 days. Nicotine exposure appears to exacerbate the severity of neonatal abstinence. Buprenorphine i milk, and the plasma-to-breast milk ratio is 1:1. Because of its poor bioavailability, the infant is exposed to one-fifth to one-tenth of the total amount available; therefore, the infant buprenorphine compared with other opiates (Johnson et al. 2001; Nanovskaya et al. 2002). With current studies in progress on buprenorphine exposure in the perinatal period (The funded by the National Institute on Drug Abuse, Lester 2006), we should soon have data to clarify further the use of this medication in pregnant women and its effect on neonatal ab

CONCLUSION Perinatal substance abuse is a problem of major public health importance for women and children. Societal moral attitudes that have stigmatized and dehumanized women who use pregnancy (Kandall 1996) have placed barriers in the way of obtaining optimal medical and obstetrical care. These considerations apply to women of all races and socioeconomic sta health result can be obtained once these barriers have been removed and women are able to find appropriate services in a supportive, multidimensional treatment facility. Although learned over the past several decades from research in the field of perinatal substance abuse, continued evidence-based studies are essential to determine the intricacies of neonata syndrome and the overall immediate and long-term effects of in utero substance exposure. To delineate the multifactorial aspects of perinatal substance abuse will require many mo researchers and a large funding commitment by government agencies.

KEY POINTS Because polysubstance use is common, proper evaluation and treatment of the substance-exposed infants rest with accurate assessment of maternal drug-taking patterns. Neonatal opiate abstinence, consisting of central nervous system, respiratory, gastrointestinal, and autonomic signs, is best treated with an opiate such as tincture of opium, with scale used as a guide to management. Neurotoxicity secondary to stimulant (cocaine, amphetamines) exposure consists of mainly neurological and neurobehavioral findings; the use of a supportive and comforting indiv usually makes specific pharmacotherapy unnecessary. Recent reports linking selective serotonin reuptake inhibitors to fetal and neonatal problems underscore the need for vigilance whenever new drugs are prescribed during pregnan Because more women consume alcohol during pregnancy than they do all illicit drugs combined, it is important to remember that fetal alcohol spectrum disorders range from subt are permanently disabling.

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J Pediatr 90:630–633, 1977 [PubMed] Plessinger MA, Woods JR: The cardiovascular effects of cocaine use in pregnancy. Reprod Toxicol 5:99–113, 1991 [PubMed] Pond SM, Kreek MJ, Tong TG, et al: Altered methadone pharmacokinetics in methadone-maintained pregnant women. J Pharmacol Exp Ther 233:1–6, 1985 [PubMed] Public Health Service Task Force: Recommendations for use of antiretroviral drugs in pregnant HIV-1 infected women for maternal health and interventions to reduce perinatal HIVthe United States. Available at http://www.aidsinfo.nih.gov.ezproxy2.library.usyd.edu.au/ContentFiles/PerinatalGL.pdf. Accessed July 2006 Rajegowda BK, Glass L, Evans HE: Methadone withdrawal in newborn infants. J Pediatr 81:532–534, 1972 [PubMed] Rosen M: Use of diazepam in neonatal narcotic withdrawal syndrome. Pediatrics 49:314, 1972 [PubMed] Rosen TS, Pippenger CE: Pharmacologic observations on the neonatal withdrawal syndrome. J Pediatr 88:1044–1048, 1976 [PubMed] Scafidi FA, Field TM, Wheeden A, et al: Cocaine-exposed preterm infants show behavioral and hormonal differences. Pediatrics 97:851–855, 1996 [PubMed] Scher MS, Richardson GA, Day NL: Effects of prenatal cocaine/crack and other drug exposure on electroencephalographic sleep studies at birth and one year. Pediatrics 105:39–48, 2 Schiff D, Chan G, Stern L, et al: Diazepam (Valium) for neonatal narcotic withdrawal: a question of safety. Pediatrics 49:928–930, 1972 [PubMed] Smith L, Yonekura ML, Wallace T, et al: Effects of prenatal methamphetamine exposure on fetal growth and drug withdrawal symptoms in infants born at term. J Dev Behav Pediatr [PubMed] Snell TJ: Women in Prison: Survey of State Prison Inmates. Bureau of Justice Statistics Special Report (Publ No NCJ-145321). Washington, DC, U.S. Department of Justice, 1994 Sokol RJ, Clarren SK: Guidelines for use of terminology describing the impact of prenatal alcohol on the offspring. 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Strauss AA, Modaniou HD, Bosu SK: Neonatal manifestations of maternal phencyclidine (PCP) abuse. Pediatrics 68:550–552, 1981 [PubMed] Strauss ME, Andresko M, Stryker JC, et al: Relationship of neonatal withdrawal to maternal methadone dose. Am J Drug Alcohol Abuse 3:339–345, 1976 [PubMed] Streissguth AP, Finnegan LP: Effects of prenatal alcohol and drugs, in Clinical Manual of Substance Abuse, 2nd Edition. Edited by Kinney J. St. Louis, MO, Mosby, 1996, pp 254–271 Substance Abuse Prevention and Treatment Block Grant 1992, Pub. L. No. 102-321, sec. 1931–1935, 1941–1954 Tronick EZ, Frank DA, Cabral H, et al: Late dose-response effects of prenatal cocaine exposure on newborn neurobehavioral performance. Pediatrics 98:76–83, 1996 [PubMed] U.S. Department of Health and Human Services: HIV during pregnancy, labor and delivery, and after birth. AIDS Info Fact Sheet. Available at http://aidsinfo.nih.gov.ezproxy2.libra /ContentFiles/Perinatal_FS_en.pdf. Accessed July 2006 Vega WA, Kolody B, Hwang J, et al: Prevalence and magnitude of perinatal substance exposure in California. N Engl J Med 329:850–854, 1993 [PubMed] Ward J, Mattick RP, Hall W: The use of methadone during maintenance treatment: pharmacology, dosage, and treatment outcome, in Methadone Maintenance Treatment and Other Replacement Therapies. Edited by Ward J, Mattick RP, Hall W. Amsterdam, Netherlands, Harwood Academic Publishers, 1998, pp 205–238 Wechsberg WM, Lam WK, Zule W, et al: Violence, homelessness, and HIV risk among crack-using African-American women. Subst Use Misuse 38:669–700, 2003 [PubMed] Weinberger SM, Kandall SR, Doberczak TM, et al: Early weight-change patterns in neonatal abstinence. Am J Dis Child 140:829–832, 1986 [PubMed] Weiner SM, Finnegan LP: Drug withdrawal in the neonate, in Handbook of Neonatal Intensive Care, 5th Edition. Edited by Merenstein G, Gardner S. St. Louis, MO, Mosby-Year Book Wellisch J, Anglin MD, Prendergast ML: Numbers and characteristics of drug-using women in the criminal justice system: implications for treatment. J Drug Issues 23:7–30, 1993 Wisner KL, Gelenberg AJ, Leonard H, et al: Pharmacologic treatment of depression during pregnancy. JAMA 282:1264–1269, 1999 [PubMed] Wittmann BK, Segal S: A comparison of the effects of single- and split-dose methadone administration on the fetus: ultrasound evaluation. Int J Addict 26:213–218, 1991 [PubMed] Zahorodny W, Rom C, Whitney W, et al: The Neonatal Withdrawal Inventory: a simplified score of newborn withdrawal. J Dev Behav Pediatr 19:89–93, 1998 [PubMed] Zelson C: Infant of the addicted mother. N Engl J Med 288:1393–1395, 1973 [PubMed] Zelson C, Rubio E, Wasserman E: Neonatal narcotic addiction; 10-year observation. Pediatrics 48:178–189, 1971 [PubMed] Zeskind PS, Stephens LE: Maternal selective serotonin reuptake inhibitor use during pregnancy and newborn neurobehavior. Pediatrics 113:368–375, 2004 [PubMed] Copyright © 2011 Amer can Psychiatr c Association. All Rights Reserved.

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Loretta P. Finnegan, Stephen R. Kandall: Chapter 40. Perinatal Substance Abuse: Drug Dependence, Motherhood, and the Newborn, in The American Psychiatric Publishing Tex tbook of Subs Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psyc hiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440 356218. Printed 10/7/ 2011 from www.psychiatryonline com Textbook of Substance Abuse Treatment >

Perinatal Substance Abuse Drug Dependence, Motherhood, and the Newborn Loretta P. Finnegan, M.D. Stephen R. Kandall, M.D.

PERINATAL SUBSTANCE ABUSE: INTRODUCTION The perinatal period should be regarded as a continuum that extends from the beginning of a woman's pregnancy through delivery and the first month of a child's life. Although in th discuss discrete drugs, clinicians must be aware that the use of any psychoactive drug during pregnancy may mean that other psychoactive agents are being used concomitantly. Pe therefore reflect pharmacological effects of individual agents or the combined effects of multiple drugs. In all cases, substance use during pregnancy must be considered to be high r medical, obstetric, neonatal, pediatric, and psychosocial standpoints. It is extremely important, however, to recognize that providing comprehensive, supportive, nonjudgmental ca woman and her family in a well-integrated, multidisciplinary setting offers a unique opportunity to restructure the woman's life in a positive direction.

THE SUBSTANCE-USING MOTHER Epidemiology Determining the epidemiology of drug use during pregnancy has always been an inexact science (American Academy of Pediatrics 1998; National Institute on Drug Abuse 1996). Thi resulted from factors such as changes in drug use patterns over time, variations in sample populations in individual hospitals and larger geographic areas, differing applications of his techniques and drug-detection technologies, and the varying attention that society has paid over time to this specific subset of female drug users (Kandall 1996). In its 1992–1993 National Pregnancy and Health Survey, the National Institute on Drug Abuse (1996) used cross-sectional analysis to estimate the incidence of maternal drug use du Information was obtained from 2,613 women delivering at 52 participating hospitals in the United States, and data were extrapolated to estimate drug exposure in the 4,023,307 liv The National Institute on Drug Abuse estimated that approximately 220,000 women (5.5% of pregnant women) used an illicit drug during pregnancy. Marijuana was used most frequ women; 3%), followed by amphetamines, sedatives, tranquilizers, and analgesics in a nonmedical context (61,000 women; 1.5%); cocaine (benzoylmethylecgonine) (45,000 wome methamphetamine, heroin, methadone, inhalants, and hallucinogens (smaller percentages). These numbers are all considerably lower, however, than those for alcohol use (757,00 and cigarette smoking (820,000 women; 20.4%) during pregnancy. Because a decade and a half has transpired since this survey, current national figures would be important to dete treatment needed by pregnant substance-abusing women. Although national epidemiological studies are of interest, each community should determine its own incidence of materna best assess the effect on its obstetric, medical, social services, and addiction treatment needs (Chasnoff et al. 1990; Gomby and Shiono 1991; Lester et al. 2001; Vega et al. 1993).

Medical Issues Given the chronic, relapsing nature of addiction, the chaotic lives of substance-abusing women, and the frequent lack of consistent prenatal care, it is not surprising that many medic arise during pregnancy. Substance-abusing women are at increased risk for anemia, bacteremia and septicemia, bacterial endocarditis, cellulitis, dental caries, endocrinopathies, he deficiencies, phlebitis, pneumonia, tetanus, tuberculosis, and urinary tract infections (Finnegan and Kandall 2005). The pregnant woman who is addicted to opiates and is not enrolle methadone maintenance program may have periods of physical well-being but also may feel the extremes of being "high" or "sick" within a relatively brief time. The cocaine user ha of hypertensive crises, cardiac and cerebrovascular complications, seizures, and a range of psychiatric disorders such as dysphoric agitation. Excessive alcohol intake has been linked of hypertension, cardiovascular mortality, and breast cancer, as well as to fatty liver and cirrhosis, gastrointestinal hemorrhage, and peptic ulcer (Blume and Zilberman 2005). Sexually transmitted diseases, particularly human immunodeficiency virus (HIV), have become inextricably linked to illicit drug use because of direct sex-for-drugs activity, prostitu drugs, and the sharing of infected needles and drug paraphernalia. An estimated 120,000–160,000 women in the United States are living with HIV; many of the women are unaware HIV-positive. Each year, about 6,000–7,000 of these women give birth. Of the approximately 15,000 children in the United States who have contracted HIV, resulting in about 3,000 contracted the virus from their mothers during pregnancy or birth (P. Dole 2003; Public Health Service Task Force 2006). Studies also found that some HIV transmission rates can be reduced by opting for a cesarean delivery before the onset of labor and rupture of membranes occur. A 1999 study by th of Child Health and Human Development found maternal-to-infant transmission rates of only 2% in women who were given antiretroviral drugs during pregnancy and who had a ces compared with 7.3% in women who took those medications but did not have a cesarean delivery (P. Dole 2003; Public Health Service Task Force 2006). The American College of Ob Gynecologists recommends that HIV-infected women be offered a cesarean delivery at 38 weeks to further reduce the risk to their babies, unless they have very low or undetectabl virus in their blood. It is not yet certain that a cesarean delivery reduces the risks when a woman has very low or undetectable amounts of the virus in her blood (as a result of drug Committee Opinion 1999). The U. S. government has put together guidelines to help HIV-positive women make treatment decisions. The standard three-part zidovudine (AZT, ZDV) treatment is recommende a viral load of more than 1,000 copies/mL or whose disease status otherwise requires HIV treatment should be given the standard three-part zidovudine treatment plus additional H to treatment guidelines for nonpregnant women. Women who are in the first trimester of pregnancy may consider delaying therapy until after the first 10–12 weeks of the pregnanc benefits of this should be discussed with the physician responsible for the patient's care. Specific guidelines exist for women who are already taking HIV drugs who learn that they ar Health Service Task Force 2006; U.S. Department of Health and Human Services 2006). The standard three-part zidovudine treatment for prevention of transmission of HIV from pr child is 1) zidovudine throughout the pregnancy; 2) zidovudine intravenously to mother during labor and delivery; 3) zidovudine syrup given to newborn beginning at 6–12 hours afte first 6 weeks. The use of zidovudine alone is recommended for women with a viral load below 1,000 copies/mL. Advances in HIV treatment initially reduced the perinatal HIV transmission rate from 25% to 5%–8%; highly active combination antiretroviral therapy has further reduced the trans than 2%. Because infants can be infected with HIV through breast milk, they should not be breast-fed if other options are available. Illicit substance use during pregnancy also places the fetus and newborn at increased obstetric risk. Abruptio placentae, amnionitis, early pregnancy loss, intrauterine growth retarda intrauterine death, placental insufficiency, postpartum hemorrhage, preeclampsia and eclampsia, premature labor, premature rupture of membranes, and septic thrombophlebitis a potential complications (Finnegan and Kandall 2005). This means that all such pregnancies should be considered high risk, and medical-obstetric addiction management should be ca knowledgeable, supportive health care providers in a program that has relevant experience. Potential barriers to entry into a treatment program, such as a woman's fear of the loss of her children to protective agencies, insufficient financial means, unsafe living conditions, d obtaining suitable transportation, lack of support from family and social contacts, and inaccessibility of gender-specific programs, must be addressed (Murphy and Rosenbaum 1999) Substance Abuse Prevention and Treatment Block Grant (P.L. 102-321 1992), states are required to grant pregnant women priority for treatment and to provide them with access to child care and assistance with transportation. A source for referral of individuals to relevant state and local services is the Health Resources and Services Administration's National M Health Clearinghouse (1-888-275-4772). Treatment for heroin dependency during pregnancy should be tailored to the woman's individual needs. Highly motivated women or those facing barriers to obtaining methadone m treatment may be considered for medical withdrawal during pregnancy if the process can be undertaken under careful medical supervision (Center for Substance Abuse Treatment 1 pharmacological treatment of choice for heroin-dependent women is methadone maintenance, which offers a unique opportunity for careful supervision of a woman's addiction, preg medical and psychosocial health (Kandall et al. 1999). Methadone maintenance treatment has been shown for three decades to reduce both maternal mortality rate and rates of feta morbidity, and pregnancy-associated complications (Berghella et al. 2003; Blinick et al. 1973; Finnegan et al. 1991). Although suggested regimens of methadone maintenance vary, adequate dosage of methadone (60–150 mg/day) is associated with a lower incidence of illicit drug use and higher rates of treatment retention (Ward et al. 1998). Single daily dosin represents the standard of care, but split daily dosing also may be considered to maintain a steady-state level of medication (Wittmann and Segal 1991). Although buprenorphine ha be useful in many case series and limited randomized clinical trials, no studies with large numbers of patients exist. A randomized clinical trial (The MOTHER Study, Lester 2006) is in the potential use of buprenorphine in the treatment of opiate-dependent pregnant women and its safety in exposed neonates.

Psychosocial Issues The complexity of medical management of the pregnant substance abuser is mirrored in the attendant psychosocial problems seen in this population. Drug-dependent and alcohol-u manifest anxiety, depression, and low self-esteem (Hagan et al. 1994; Murphy and Rosenbaum 1999). Degrading descriptive terms reflect the disrespect with which women are reg drug culture and should never be used in the treatment setting (Murphy and Rosenbaum 1999).

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Many addicted women share a history of past and current physical abuse and sexual assault. A Philadelphia, Pennsylvania, study reported that 83% of the women entering drug trea households in which parents used drugs, 67% had experienced sexual assault, and 60% had been physically assaulted (Finnegan et al. 1991). Similarly, in a New York study involvin women, homelessness, sexual abuse, and drug use by family members were prominent historical facts about their pasts and current environments (Chavkin et al. 1993). A study by Triangle Institute compared the characteristics of out-of-treatment, homeless, crack-using African American women with those of women who were not homeless to determine the r factors that differentiated the two groups. Their findings suggested not only that these women overall reported psychologically painful histories and currently stressful lives but also t women were more likely than women who were not homeless to have experienced childhood abuse and to be more involved with drug use (Wechsberg et al. 2003). In a report by F (1993), women in recovery from drug addiction were likely to have a history of violent trauma and were at high risk for posttraumatic stress disorder (PTSD). The investigators sug screening for PTSD among women with an addictive disorder should become part of the diagnostic and treatment routine. A stressful psychosocial setting, often aggravated by reduced socioeconomic circumstances, makes it more likely that a woman will enter the drug subculture. Society's decision to p who use drugs during pregnancy (Kandall 1996, pp. 273–279) and draconian sentences for drug-related offenses have resulted in a large increase in the number of women incarcera 20 years (National Institute on Justice 1990; Snell 1994). Drug-using pregnant women have been prosecuted despite opposition by a wide spectrum of medical, public health, and ad addition, fear of criminal prosecution has been shown to deter women from seeking prenatal care (Chavkin 1991). Once incarcerated, both addiction treatment and gynecological-ob penal system are often substandard, which jeopardizes pregnancy outcome (Wellisch et al. 1993). Lynn Paltrow (1999, pp. 15–16) of the National Advocates for Pregnant Women ends her article on the subject of pregnant women and prosecution as follows: The truth is that we do not have to pit the woman against the fetus to promote healthy pregnancies or to value life. In fact, creating fetal personhood hurts both women and the p healthier pregnancies. We could treat addiction for what it is, a health problem. We could fund programs designed to meet women's needs not only during pregnancy, but through because we value women as whole persons. We could respect people's different values regarding fetuses without creating the legal fiction that fetuses are separate persons. We c ending poverty, the greatest threat to children's health. We could attempt to develop a sane drug policy and ensure that health care and reproductive freedom are realities for al Most people think these goals are too unrealistic to fight for. But it is exactly because we have given up these goals that there is now so much room for arguments for punishmen protection not of life or health in general but only of fetal life alone. The complex matrix of intertwining medical and psychosocial risk factors that usually characterize substance use during pregnancy dictates that a successful outcome can best be ob comprehensive, supportive, nonjudgmental environment that focuses on the multidimensional needs of the woman (Center for Substance Abuse Treatment 1993b, 1994; Finnegan e approach encompasses a wide range of services (residential, outpatient, home-based, and prison-based); multiple counseling modalities (individual, group, and family); counseling domestic violence; services for children (day care, play therapy, parental training); concrete services (transportation, housing, food); comprehensive family-based health care (obst general medical); educational training (job training, high school equivalency training); appropriate staffing (including female members and being supportive and culturally and racial advocacy services (legal, child protection, welfare); and aftercare. Provision of these services at a single location will enhance compliance and will make accessing the multiple aspe easier for the pregnant woman. Three decades ago, we began such a multidimensional program in Philadelphia; Figure 40–1 describes this schema that was successful in our setting many other treatment programs nationally (Finnegan et al. 1990). FIGURE 40–1. Family center schema for treatment of drug dependency in the perinatal period and aftercare.

Note. DHHS = Department of Health and Human Services; DPW = Department of Public Welfare; WIC = Special Supplemental Nutrition Program for Women, Infants, and Children Source. Adapted from Finnegan et al. 1991.

THE SUBSTANCE-EXPOSED INFANT Neonates born to substance-using mothers should be admitted to units that provide observation, assessment, and treatment by trained personnel. In cases in which a suspicion of m under consideration, confirmation of fetal exposure may be accomplished by testing of urine. Analysis of meconium (Ostrea et al. 1992) and/or hair (Callahan et al. 1991; Lester et longer window of fetal drug exposure, but these testing methodologies are generally restricted to research laboratories. Under all circumstances, however, testing should not be car purpose of punitive referral but to identify both mothers who are in need of medical and addiction-treatment services and infants who require special observation for medical compli neonatal abstinence syndrome.

Opiates Many pharmacological agents have been reported to produce signs resembling neonatal abstinence syndrome. The most notable agents are opiates, including opium, meperidine, m morphine, and controlled-release oxycodone hydrochloride. Other substances reported in case reports or small series to produce signs of neonatal abstinence include alcohol, barbitu clomipramine, chlordiazepoxide, desipramine, diazepam, diphenhydramine hydrochloride, ethchlorvynol, glutethimide, hydroxyzine hydrochloride, meprobamate, propoxyphene hy

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selective serotonin reuptake inhibitors (SSRIs) (Finnegan and Kandall 2005; Zeskind and Stephens 2004). Because signs of abstinence syndrome may overlap among these categorie documentation of maternal drug-taking patterns is critical. This can be accomplished prenatally with sensitive history taking and at birth by urine testing. In the newborn period, signs of drug abstinence may mimic other serious conditions such as sepsis or meningitis, hypoglycemia, adrenal insufficiency, and cardiorespiratory disease these serious conditions should proceed while the neonatal abstinence is being evaluated (Weiner and Finnegan 2006). Because most opiates are short acting, signs of abstinence wi after delivery (generally within 1–3 days), when the cord is clamped and the infant is acutely deprived of the drug circulating in the maternal bloodstream. The onset of methadoneabstinence symptoms, although usually early, is somewhat more unpredictable (Kandall and Gartner 1974) because methadone establishes a reservoir in fetal tissue (V. P. Dole and et al. 1985) and undergoes more variable metabolism and excretion (Finnegan and Kaltenbach 1992). Variations in amounts of maternal drug use (Connaughton et al. 1977; Dashe Kaltenbach et al. 1996; Madden et al. 1977; Ostrea et al. 1976; Rajegowda et al. 1972; M. E. Strauss et al. 1976), placental drug transfer, neonatal metabolism and excretion (Blini Doberczak et al. 1993; Harper et al. 1977; T. S. Rosen and Pippenger 1976), and gestational age (Doberczak et al. 1991) may all potentially affect the time to onset of abstinence s Signs of neonatal abstinence syndrome are usually divided into four groups (American Academy of Pediatrics 1998; Center for Substance Abuse Treatment 1993a; Finnegan and Kalt Kandall 1999; Weiner and Finnegan 2006): 1. Central nervous system signs include irritability; high-pitched crying; high-frequency, low-amplitude tremors; hypertonia; and hyperreflexia. Despite a voracious appetite, dy and swallowing often complicate feeding (Kron et al. 1976). Seizures may occur in approximately 5% of opiate-exposed infants (Finnegan 1986; Herzlinger et al. 1977; Zelson 1971). These seizures are often unpredictable as to occurrence, are most frequently myoclonic in nature, and tend to occur at about age 10 days, with a range of 3–34 days (H 1977; Kandall et al. 1983). Sleep disturbances are prominent. A study by O'Brien and Jeffery (2002) determined the exact nature and degree of sleep disturbances and sugges changes in sleep are a result of opiate withdrawal, but others may reflect opiate dependency in utero. 2. Gastrointestinal signs include vomiting and diarrhea, which, when combined with poor intake of nutrients and increased insensible water loss, often results in excessive weigh suboptimal weight gain in the first few weeks of life (Weinberger et al. 1986). 3. Respiratory signs include excessive secretions and nasal stuffiness (Finnegan 1980); tachypnea and hyperpnea, which may produce respiratory alkalosis (Glass et al. 1972), c if untreated. 4. Autonomic nervous system signs include sweating, sneezing, tearing, and hyperthermia. Infants exposed to drugs prenatally are considered to be at high risk and should be cared for in a structured setting by skilled personnel. Because an uncoordinated suck-swallow ref infants at risk for aspiration, the liberal amounts of fluids and calories needed to offset the infant's hypermetabolic state should be provided carefully. The recommendation to provid feedings (American Academy of Pediatrics 1998) should be balanced against the advantages of reduced sensory stimulation. Positioning techniques, use of a soothing waterbed, and darkened room often pacify the infant (Maichuk et al. 1999; Oro and Dixon 1988) but also increase the need for close surveillance, including observation for abstinence-associated se Because only 60%–80% of drug-exposed neonates experience abstinence symptoms, routine prophylactic treatment is not recommended. Close observation of clinical symptoms is a semi-objective abstinence symptom severity scoring system allows accurate evaluation of signs and symptoms, avoids unnecessary treatment of mildly affected infants, and provi for effective tapering of medications (Finnegan et al. 1975; Green and Suffet 1981; Lipsitz 1975; Zahorodny et al. 1998). A comprehensive abstinence assessment tool, the Finnegan Abstinence Score, is administered by nursing staff to monitor the in utero opiate-exposed neonate (Finnegan and Kaltenbach 1992). The score includes the vast array of symptoms t reported in infants with neonatal abstinence. If individuals are properly trained and interrater reliability is achieved, the score becomes a valuable objective measure to assess the o and diminution of symptoms of abstinence. Specific pharmacological treatment is tailored to the severity of the score. The score monitors the infant's clinical response to the pharma intervention necessary to control the symptoms and achieve medical detoxification. This scoring system rates 21 individual signs, assigning each a relative weight based on a postula outcomes of perinatal morbidity. Infants are evaluated 2 hours after birth and every 4 hours thereafter, or more frequently if the abstinence symptoms are severe. The Neonatal Ab Sheet is shown in Figure 40–2. Symptoms are listed on the left, with their respective scores listed on the right. The time of each evaluation is given at the top of the sheet, and the t for each interval. A comments column has been provided so that nursing and medical staff can record important clinical observations in addition to the symptoms noted. FIGURE 40–2. Neonatal abstinence scoring sheet used for the assessment of infants undergoing neonatal abstinence.

Note. Evaluator should check sign or symptom observed at various time intervals. Scores should be added to determine total at each evaluation. Source. From Finnegan et al. 1975. Although diazepam (Nathenson et al. 1971; M. Rosen 1972; Schiff et al. 1972), chlorpromazine (Kahn et al. 1969), and clonidine (Hoder et al. 1984) have been used to treat opiate a symptoms in the past, no large studies have confirmed their efficacy. Rather, short-acting opiate preparations have become the treatment of choice for neonatal opiate abstinence s Academy of Pediatrics 1998; Center for Substance Abuse Treatment 1993a). This treatment is based on the assumption that opiate exposure is best treated with another opiate and performed on neonates (Jackson et al. 2004). Paregoric (camphorated tincture of opium) is easily administered orally, has little toxicity, restores sucking reflexes to normal more rapidly than do nonspecific therapies such as ph al. 1976), and offers some protection against abstinence-associated seizures (Kandall et al. 1983). In the past, paregoric was most commonly used. One regimen suggested beginnin dosage of 0.2 mL every 3 hours; the dosage was raised by 0.05 mL on the basis of severity scoring to a maximum of 0.4 mL. The final stabilizing dosage was maintained for 3–5 day slow tapering regimen of 0.05 mL per dose every other day (Kandall 1999). A slightly different regimen recommended the administration of paregoric every 4 hours at a dosage bas severity of abstinence (Finnegan and Kaltenbach 1992). Initial total daily doses of paregoric ranged from 0.8 mL/kg/day to 2 mL/kg/day. Once the infant had been clinically stabilize abstinence scores, the total daily dosage was lowered by 10% every day. Pharmacokinetic studies indicate that duration of treatment, although variable, will be longer following me than following heroin exposure. Both regimens advised observation of the infant in a hospital setting for 48 hours after cessation of treatment.

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Recent concerns, however, have been raised about the safety of other ingredients found in paregoric, despite its record of efficacy and safety (American Academy of Pediatrics 1998 on Drugs of the American Academy of Pediatrics cautioned that paregoric contains isoquinoline derivatives (noscapine and papaverine), which are antispasmodics. Paregoric also con potentially dangerous central nervous system stimulant that is lipid-soluble and requires glucuronidation for excretion. In addition, paregoric contains alcohol, anise oil, and glycerin of Pediatrics 1994). Paregoric also contains 4 mg/mL of benzoic acid, which may compete for bilirubin binding sites. Benzyl alcohol (paregoric's oxidative product) has been reported syndrome of severe acidosis, central nervous system depression, hypotension, renal failure, seizures, and death in small premature infants who receive large doses (Gershanik et a As a result of these concerns, the American Academy of Pediatrics Committee on Drugs has recommended tincture of opium as the treatment of choice for neonatal opiate abstinenc Academy of Pediatrics 1998). The committee's recommendation is for the use of a 25-fold dilution of tincture of opium, which results in a concentration of morphine equivalent to tha mg/mL). The recommended initial dosage of the diluted tincture of opium is 0.1 mL/kg (2 drops/kg) with feedings every 4 hours. Dosage increases and decreases can be managed i with paregoric, by using the regimen and the severity scoring system discussed earlier in this section. Two other narcotic preparations, morphine and methadone, have been used on a limited basis to treat neonatal opiate abstinence (American Academy of Pediatrics 1998). The pare morphine contains sodium bisulfite and phenol. Langenfeld et al. (2005) compared the efficacy of the oral pure

agonist morphine with the alcoholic mixture of tincture of opium to

infants. The investigators found that morphine could be used to treat neonatal abstinence, to avoid unwanted effects of the alcoholic extracts, and to allow better weight gain in the are available regarding the efficacy and safety of treating neonatal opiate abstinence with methadone. Phenobarbital is a nonspecific central nervous system depressant that also can be used to treat neonatal abstinence syndrome. Phenobarbital offers the advantage of a broad spectr cases of maternal polydrug abuse. Its usefulness is limited, however, because it does not control non–central nervous system signs, it depresses sucking, and it may depress respira Recommendations include a loading dosage of 16 mg/kg intramuscularly over 24 hours followed by a maintenance dosage of 2–8 mg/kg/24 hours orally to control signs of abstinenc stabilization, the dosage usually can be reduced by 10%–20% per day when a severity scoring system is used as a guide to treatment. After cessation of either treatment, the infant monitored in the hospital for at least 2 days to observe for rebound withdrawal (Finnegan and Kaltenbach 1992; Kandall 1999). Abstinence-associated seizures should be treated acutely with a loading dose of 10–20 mg/kg of phenobarbital intramuscularly or intravenously (dependent on the severity) supplem of opium. The phenobarbital dose may be lowered sequentially once the seizures are controlled and a diagnostic workup has ruled out other causes of neonatal seizures. Most of the discharged without anticonvulsant medication, and the prognosis of infants with uncomplicated seizures is excellent (Finnegan and Kaltenbach 1992; Herzlinger et al. 1977; Kandall 1 If the mother is HIV negative, breast-feeding should be encouraged for its attendant medical and psychosocial benefits. Opiates pass to the nursing infant through the breast milk bu affect the severity of the neonatal abstinence syndrome or to achieve sufficient concentrations to serve as treatment for neonatal symptoms (McCarthy and Posey 2000).

Stimulants Maternal cocaine use is associated with specific obstetric complications, including early pregnancy loss, abruptio placentae, premature onset of labor, chronic fetal hypoxia, intrauter retardation, and an increased incidence of stillbirths (Plessinger and Woods 1991). Cocaine has a low molecular weight, is highly soluble in water and lipid, and passes easily transpla mother to fetus. Although the risk of cocaine-associated teratogenicity has been difficult to establish (Koren et al. 1993), cocaine has been reported to be responsible for a series of c in a pattern of "fetal vascular disruption" (Hoyme et al. 1990). After birth, cocaine-associated vasoconstriction has been reported to be the precipitating factor in necrotizing enteroco perforation, arterial thrombosis, hypertension, and myocardial ischemia (Finnegan and Kandall 2005). Cocaine-exposed newborns show neurological signs that are quite different from those seen in opiate-exposed neonates. Rather than showing signs of abstinence, cocaine-exposed i reported to show evidence of a neurotoxicity syndrome manifested initially by transient hypertonia, hyperreflexia, irritability, and tremors (Chasnoff et al. 1985; Doberczak et al. 19 al. 1996). This phase is followed by a period of depressed interactive behavior, lability of state, and poor organizational response to environmental stimuli (Chasnoff et al. 1985; May and Dixon 1987). Less commonly, these infants may show abnormal electroencephalogram results (Dixon and Bejar 1989; Doberczak et al. 1988; Scher et al. 2000) and more dram neuropathological signs, such as seizures (Chasnoff et al. 1989; Kramer et al. 1990) and cerebrovascular accidents (Chasnoff et al. 1989; Heier et al. 1991). Although the mechanism abnormalities is not clear, cocaine-associated derangements in dopaminergic and serotonergic systems have been postulated (Mayes 1994; Mirochnik et al. 1991; Scafidi et al. 1996 The literature on neurobehavioral adaptation is vast and includes the reports of many who used the Brazelton Neonatal Behavioral Assessment Scale (BNBAS). Eisen et al. (1991) fo with control subjects, cocaine-exposed infants needed more trials to habituate to a presented stimulus on the BNBAS within the first week of life. Coles et al. (1992) compared infant cocaine-using mothers (although alcohol, marijuana, and cigarettes were also used) with control infants at 48–72 hours, 14 days, and 28 days. Although scores were generally norm infants appeared to show minimal and transient autonomic depression. Mayes et al. (1993) also found that cocaine-exposed infants showed impaired habituation on the BNBAS score found persistence of abnormalities in habituation at a 3-month assessment (Mayes et al. 1995). Delaney-Black et al. (1996) found that neurobehavioral abnormalities in the motor p state-regulation subareas of testing could be correlated with the amount of intrauterine cocaine exposure as determined by meconium testing. Napiorkowski et al. (1996) reported t infants tested at age 1–2 days showed increased tone, jerky movements and startles, and poorer auditory and visual following compared with control infants; the authors further su may act synergistically with alcohol and marijuana in producing these neonatal abnormalities. Tronick et al. (1996) found that cocaine-associated abnormalities in neurobehavioral p not be detected with the BNBAS when confounders were controlled. Abnormalities, particularly in arousal, could be identified, however, on the 3-week repeat examinations, raising learning capability of cocaine-exposed infants. In the literature, effects of prenatal cocaine exposure are described in many different ways, which makes their etiology difficult to determine. Are the immediate postpartum effects exposure a withdrawal effect as cocaine is metabolized or a transient effect and related to acute toxicity of the drug? A prospective, longitudinal study (Eyler et al. 2001) was design hypothesis that newborns whose urine was positive for cocaine metabolites, compared with those exposed to cocaine but urine-negative and with nonexposed control subjects, woul neurobehavioral scores (toxicity effect) and 2) worsen or show less improvement over the first week of life (withdrawal effect). Neurobehavioral testing was performed with the BNB and 5–7 postpartum. The data supported those of other controlled studies that did not find early effects of prenatal cocaine exposure but added to the understanding that effects obs to be related to acute toxicity or cocaine withdrawal. The investigators cautioned that the uncertainty of persistent effects of cocaine exposure warranted long-term follow-up. Although most cocaine-exposed infants do not require treatment, if excessive irritability occurs, treatment with short courses of phenobarbital may be warranted. Because these infa reported to be hyporeactive once the initial irritability subsides, they should be provided with an individualized program of structured physical contact, including gentle handling with social talking, and eye contact without overstimulation (Center for Substance Abuse Treatment 1993a). Intervention programs provided by trained personnel should include the pare possible. Breast-feeding by a cocaine-using mother poses risks of acute neonatal intoxication (Chaney et al. 1988; Chasnoff et al. 1987) (in contrast to opiate use) and is therefore c Similar to the action of cocaine, amphetamine and methamphetamine block the reuptake of neurotransmitters. Use of these drugs during pregnancy has been associated with a high rate; reductions in birth weight, length, and head circumference; associated congenital malformations; and abnormal neurological signs, muscle tone problems, abnormal cry patter feeding, and seizures (Eriksson et al. 1978, 1981; Oro and Dixon 1987; Smith et al. 2003).

Barbiturates Maternal use of phenobarbital at a dosage of at least 90 mg/day for 12 weeks before delivery has been reported to produce a neonatal abstinence syndrome marked by hyperactivit excessive crying, tremulousness, hyperreflexia, vomiting, and diarrhea (Blumenthal and Lindsay 1977; Desmond et al. 1972; Hill et al. 1977). This complex of signs is similar to opi syndrome (American Academy of Pediatrics 1998). The abstinence syndrome usually develops by age 4–8 days and should be treated with phenobarbital when symptoms cannot be conservative measures. A more prolonged abstinence syndrome, similar to the subacute withdrawal described occasionally with heroin exposure, may persist for 2–6 months. Barbi breast milk, but breast-feeding need not be discouraged.

Hallucinogens The effects of marijuana ( 9 -tetrahydrocannabinol) on the human fetus and neonate have been studied by Fried and colleagues (Fried 1995; Fried et al. 1983, 1998) for several deca linked maternal marijuana use with reduced fetal growth, preterm birth, and an increase in neonatal tremors and startle responses. Marijuana has been shown to affect the infant's visual stimulation and may cause developmental problems (Fried et al. 1998). Lysergic acid diethylamide (LSD) has been reported to cause chromosomal breakage, spontaneous ab prematurity. Phencyclidine, or 1-(1-phenylcyclohexyl)piperidine, also known as PCP and "angel dust," has been noted in limited studies to cause hypertonia, hyperreflexia, and trem 1980; A. A. Strauss et al. 1981).

Alcohol Despite ongoing educational campaigns, alcohol use during pregnancy continues to be a major health problem. Data from the 2002 Centers for Disease Control and Prevention's Beh Surveillance System (BRFSS) indicated that approximately 10% of pregnant women used alcohol and approximately 2% engaged in binge drinking or frequent use of alcohol. Alcoho itself or as part of a larger pattern of polysubstance use. Comprehensive management of the pregnant alcohol user should begin with preconception counseling and extend througho Biological variability makes it impossible to define a safe level of alcohol consumption during pregnancy; thus, total abstinence should be recommended. Alcohol abuse is generally d consumption of seven or more alcoholic drinks per week or consumption of three or more alcoholic drinks on multiple occasions (Finnegan and Kandall 2005; Hanson et al. 1978; So 1989; Streissguth and Finnegan 1996). The recently adopted terminology of fetal alcohol spectrum disorders denotes that alcohol-related effects may range from severe, devastating, and lifelong to less apparent and sub

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Centers for Disease Control and Prevention codified diagnostic criteria for the most severe manifestations, called fetal alcohol syndrome, which is thought to occur in 0.2–1.5 per 1,0 alcohol syndrome, which may escape detection despite its catastrophic nature, should include Dysmorphology. All three dysmorphic features (small philtrum, thin vermillion border, small palpebral fissures) should be present. Other facial dysmorphisms seen in fetal alc include hypoplastic maxilla, short upturned nose, micrognathia or retrognathia, and, less commonly, ptosis, strabismus, epicanthal folds, microphthalmia, posterior rotation o lip or palate. Other reported malformations involve the cardiac system, genitourinary and gastrointestinal tracts, skin, and joints. Growth. Prenatal or postnatal growth deficits in height or weight occur. Central nervous system. Abnormalities are seen, which may be structural (small head size, neuroimaging abnormalities), neurological (including seizures), or functional (test substantially below that expected for age, schooling, or circumstances). Less devastating effects of fetal alcohol exposure have been reclassified as partial fetal alcohol syndrome, alcohol-related birth defects, and alcohol-related neurodevelopmental diso Intrauterine exposure to alcohol also has been reported to produce neonatal signs consistent with withdrawal (Coles et al. 1984; Nichols 1967; Pierog et al. 1977). Alcohol-exposed n hyperactivity, irritability and excessive crying, tremors, poor sucking, and even seizures. Administration of phenobarbital in dosages of 5–10 mg/kg/day, dependent on the severity, regimen of slow tapering of the medication appears to control acute symptoms in the newborn.

Nicotine Long-term maternal smoking has been linked to increased rates of placenta previa, abruptio placentae, placental infarcts, and placental changes caused by vasoconstriction. Elevate monoxide in smokers also may adversely affect the delivery of oxygen to the fetus transplacentally. Many studies have shown a reduction in birth weight by approximately 150–200 cigarettes smoked. Hypertonia has been reported in neonates born to smoking mothers. Children born to mothers who smoke have increased rates of sudden infant death syndrom and death up to age 5 years, primarily from respiratory disorders such as bronchiolitis and pneumonia. Neonatal withdrawal also can occur in infants exposed to heavy maternal sm pregnancy (Godding et al. 2004).

Selective Serotonin Reuptake Inhibitors The increasing use of SSRIs to treat maternal depression during pregnancy has recently raised concerns about their effects on the fetus and newborn. Commonly used SSRIs include fluoxetine, paroxetine, sertraline, and venlafaxine. Fetal exposure to SSRIs has not been reported to be associated with major congenital malformations. Both anecdotal reports and series of patients tie maternal SSRI use during pregnancy to a neonatal syndrome that may be the result of a direct toxic effect or abstinence (Wisner et and Stephens 2004). Nordeng et al. (2001) reported a series of cases of neonatal abstinence syndrome in infants exposed to SSRIs (citalopram, fluoxetine, paroxetine) in the third t Withdrawal symptoms occurred within a few days after birth and lasted up to 1 month. Most of the infants required treatment. Symptoms included irritability, constant crying, shive tonus, eating and sleeping difficulties, and convulsions. In a prospective study (Zeskind and Stephens 2004), SSRI-exposed infants had a shorter mean gestational age, were more m and tremulous, and showed fewer rhythms in heart rate variability. In addition, the infants showed fewer changes in behavioral state, fewer different behavioral states, a lower pea and significantly more rapid eye movement sleep, which was characterized by longer continuous startles or arousals. The Food and Drug Administration is also assessing reports of r cyanosis, apnea, seizures, temperature instability, feeding difficulty, and vomiting in SSRI-exposed neonates. In a recent Israeli study, Levinson-Castiel et al. (2006) noted that 30% infants had withdrawal symptoms—most commonly, tremor, gastrointestinal problems, hypertonicity, sleep disturbances, and high-pitched cry. Although none of the infants require highest Finnegan withdrawal score did not occur until 48 hours after birth, suggesting the need for observation of such infants. The long-term effects of prolonged exposure to SSRIs neonates who develop severe symptoms, have yet to be determined.

Buprenorphine Several studies have been reported regarding the use of buprenorphine in opiate-dependent pregnant women. Buprenorphine does not interfere with fertility and appears to be safe regard to reproductive, teratogenic, and toxicity profiles. In a 1998 report in nine patients, Fischer et al. (1998) found that buprenorphine administration in opiate-dependent pregna efficacious and well tolerated. Babies born exposed in utero to buprenorphine had birth weights and Apgar scores within the normal range and no evidence of neonatal abstinence. In study with more patients, Fischer et al. (2000) reported similar findings, except that 50% of the neonates had mild to moderate abstinence symptoms of very short duration. In con report (Kayemba-Kay's and Laclyde 2003) found that 85% of their infants had abstinence symptoms, and all but one infant had to be treated. In follow-up of the infants, the investig transient lower limb hypertonia, jerky movements, and jitteriness that lasted 3–9 months. Overall milestones were within normal limits. Although current data are limited, pregnant women taking buprenorphine have not had adverse effects, and infants born to these women have been delivered at term with birth we range. Observations have varied concerning frequency, intensity, and duration of abstinence in newborns exposed in utero to buprenorphine (Loustauneau et al. 2002). Illicit drug u in 40% of the cases, confounding the data with regard to the role buprenorphine plays in the occurrence of abstinence symptoms. Neonatal symptoms following buprenorphine expo appear within 12–24 hours, peak at approximately 72–96 hours, and last 15–21 days. Nicotine exposure appears to exacerbate the severity of neonatal abstinence. Buprenorphine i milk, and the plasma-to-breast milk ratio is 1:1. Because of its poor bioavailability, the infant is exposed to one-fifth to one-tenth of the total amount available; therefore, the infant buprenorphine compared with other opiates (Johnson et al. 2001; Nanovskaya et al. 2002). With current studies in progress on buprenorphine exposure in the perinatal period (The funded by the National Institute on Drug Abuse, Lester 2006), we should soon have data to clarify further the use of this medication in pregnant women and its effect on neonatal ab

CONCLUSION Perinatal substance abuse is a problem of major public health importance for women and children. Societal moral attitudes that have stigmatized and dehumanized women who use pregnancy (Kandall 1996) have placed barriers in the way of obtaining optimal medical and obstetrical care. These considerations apply to women of all races and socioeconomic sta health result can be obtained once these barriers have been removed and women are able to find appropriate services in a supportive, multidimensional treatment facility. Although learned over the past several decades from research in the field of perinatal substance abuse, continued evidence-based studies are essential to determine the intricacies of neonata syndrome and the overall immediate and long-term effects of in utero substance exposure. To delineate the multifactorial aspects of perinatal substance abuse will require many mo researchers and a large funding commitment by government agencies.

KEY POINTS Because polysubstance use is common, proper evaluation and treatment of the substance-exposed infants rest with accurate assessment of maternal drug-taking patterns. Neonatal opiate abstinence, consisting of central nervous system, respiratory, gastrointestinal, and autonomic signs, is best treated with an opiate such as tincture of opium, with scale used as a guide to management. Neurotoxicity secondary to stimulant (cocaine, amphetamines) exposure consists of mainly neurological and neurobehavioral findings; the use of a supportive and comforting indiv usually makes specific pharmacotherapy unnecessary. Recent reports linking selective serotonin reuptake inhibitors to fetal and neonatal problems underscore the need for vigilance whenever new drugs are prescribed during pregnan Because more women consume alcohol during pregnancy than they do all illicit drugs combined, it is important to remember that fetal alcohol spectrum disorders range from subt are permanently disabling.

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Chapter 42. Prescription Drug Abuse

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Wilson M. Compton, Richard Denisco: Chapter 42. Prescription Drug Abuse, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.35 6700. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Prescription Drug Abuse Wilson M. Compton, M.D., M.P.E. Richard Denisco, M.D., M.P.H.

PRESCRIPTION DRUG ABUSE: INTRODUCTION Pharmaceutical products have been abused throughout the ages, and the current epidemic of prescription drug abuse in the United States represents the newest wave of a long-standing problem (Compton and Volkow 2006a). The extent of the problem is staggering, with national surveys showing that in 2004, approximately 15 million Americans, age 12 years and older, used a psychotherapeutic drug for a purpose other than medical use (Colliver et al. 2006). Past-year prevalence rates among twelfth grade students documented that prescription drugs were among the most abused illicit substances: 9%–10% reported Vicodin abuse, 4%–5% reported OxyContin abuse, 8%–9% reported amphetamine abuse, 6%–8% reported sedative abuse, and 5%–7% reported Ritalin abuse in each of the past several years (Johnston et al. 2007). Thus, prescription drug abuse has reemerged recently as a major and costly public health threat (Birnbaum et al. 2006). Furthermore, prescription drug abuse presents unusual difficulties for clinicians for two reasons: first, the medical system is the origin of the substances in many cases; and second, the boundary between therapeutic use, misuse, and addiction can be quite vague. Overall, physicians are in a unique situation of having to prescribe the optimal medication dosage to minimize the symptoms of the disease, such as when treating pain with opioids, hyperactivity with stimulants, or anxiety with sedatives. Simultaneously, physicians must monitor their prescribing practices to reduce the risk of substance abuse and addiction. We explore various factors for the increases in substance abuse for each class of drug. The division of drugs into classes is based on the pharmacological category: opioids (analgesics), stimulants, and sedatives and tranquilizers. Other classes of medications can be misused (e.g., anticholinergics, laxatives, neuroleptics, antidepressants); however, this chapter is limited to the three major drug classes mentioned earlier. Chemistry, physiology, detoxification, and treatment details can be found in the chapters specific to the major drug class. Although those aspects are the same between licit and illicit compounds of the same drug class, many other aspects of prescription drug abuse are different and are addressed in this chapter.

GENERAL ISSUES Definitions Despite data indicating high rates of prescription drug abuse, a major limitation of the existing research is that the terms misuse, abuse, dependence, and addiction are used in idiosyncratic ways. To make the nomenclature consistent, a minimum guideline would be for each researcher and author to specify their definitions clearly. In this chapter, abuse is defined as any intentional use of opioids outside of a physician's prescription for a bona fide medical condition, excluding accidental misuse. Note that our use of the term abuse is distinct from the abuse diagnosis specified in DSM-IV-TR (American Psychiatric Association 2000). However, addiction in this chapter is synonymous with the standard DSM-IV-TR diagnosis of dependence, which is a psychiatric syndrome defined as including compulsive use, impaired control, tolerance, withdrawal, and continued use despite physical and psychological problems caused or exacerbated by use (American Psychiatric Association 2000).

Historical Perspective on the Scheduling of Prescription Drugs

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Medication abuse can be dated to antiquity, particularly with regard to the intentional misuse of opioids. More recently, in the late nineteenth century, many Civil War veterans developed an addiction to opioids, which began with exposure to opioids in the treatment of pain from war-related injuries. Simultaneously, the patent medicine industry with its liberal use of opioids and cocaine was burgeoning. This situation was addressed in the United States with the enactment of the Harrison Act in 1914. More recently, the Controlled Substances Act (CSA) was enacted into law as Title II of the Comprehensive Drug Abuse Prevention and Control Act of 1970. The CSA is the comprehensive legislation designed to regulate the manufacture, importation, possession, and distribution of certain drugs and their precursor compounds. Schedules (classifications), mainly based on the compound's addictive potential, were created. Two federal departments, the Department of Justice and the Department of Health and Human Services (which includes the Food and Drug Administration), now determine which drugs are added or removed from the various schedules. In particular, the U.S. Drug Enforcement Administration (DEA) within the Department of Justice is the agency responsible for enforcing the controlled substances laws and regulations of the United States and was formed as part of the CSA (Drug Enforcement Administration 1970). Scheduling decisions are mandated to be made on the criteria of potential for abuse, accepted medical use in the United States, and potential for addiction. According to the DEA Web site, Schedule I and II drugs have a high potential for abuse (Drug Enforcement Administration 1970, 2003, 2006). They require high-security storage and detailed records and have a quota on manufacturing, among other restrictions. Schedule I drugs are available for research only and have no approved medical use. Schedule II drugs are available only by written prescription (nonrefillable) and require a form for ordering. Schedule III and IV drugs are available only by prescription but are allowed five refills in 6 months and may be ordered verbally (with a follow-up written prescription). Most Schedule V drugs are available over the counter. Factors considered in scheduling decisions include the actual or relative potential for abuse, pharmacological effects and abuse history of the drug, whether the compound is a precursor or analogue to a controlled substance, and the overall risk to the public health.

Epidemiology of Prescription Drug Abuse As seen in Figure 42–1, according to the National Survey on Drug Use and Health, approximately 6% of persons in the United States age 12 years or older (14.8 million) abused prescription drugs in 2004 (Colliver et al. 2006). The most commonly abused drugs were analgesics, followed by tranquilizers and stimulants. Abuse of these substances was most prevalent in young adults (ages 18–25 years), followed by adolescents (ages 12–17 years) and adults (age 26 years or older). In general, males had higher rates of abuse, with an important exception that adolescent females (ages 12–17 years) were somewhat more likely than adolescent males to have abused any prescription drug (9.9% vs. 8.2%), analgesics (8.1% vs. 7.0%), tranquilizers (2.6% vs. 1.9%), and stimulants (2.6% vs. 1.9%) in the past year. FIGURE 42–1. Past-year nonmedical use of prescription psychotherapeutic drugs among persons age 12 years or older, by drug type: percentages, 2002–2004.

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Includes methamphetamine.

Source. Reprinted from Colliver JD, Kroutil LA, Dai L, et al: Misuse of Prescription Drugs: Data From the 2002, 2003, and 2004 National Surveys on Drug Use and Health. Rockville, MD, Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2006. Another source of data is the yearly surveys of eighth, tenth, and twelfth grade students conducted by the University of Michigan's Institute for Social Research under a program called Monitoring the Future. This series of surveys was started in 1975 and provides detailed information about trends in drug abuse for youths in the United States. This study has documented major shifts in drug abuse trends, with decreases during the 1980s from the peaks seen in the late 1970s, followed by increases in the early 1990s, and a gradual decline since the late 1990s (Johnston et al. 2007). Superimposed on this general trend are specific drugs that have followed different trajectories. For example, past-year prevalence of sedative abuse has been increasing among twelfth graders for the past decade, and many prescription-type drugs are abused by numerous youths. Examination of the past-year prevalence for major categories indicates that prescription-type drugs were among the most commonly reported in the most recent data—past-year abuse of Vicodin was reported by 9.7% of twelfth graders, amphetamines by 8.1%, sedatives and tranquilizers by 6.6%, Ritalin by 4.4%, and OxyContin by 4.3% (Table 42–1) (Johnston et al. 2007). Additional analyses of the Monitoring the Future data performed by McCabe et al. (2005) further confirmed the growing pattern of abuse among adolescents; illicit users of prescription opioid analgesics were significantly more likely to be male, to be white, and to have lower grade point averages. Illicit users of opioid analgesics also reported higher rates of cigarette smoking, alcohol use, marijuana use, other illicit drug use, and problem behaviors. McCabe et al. (2007) examined prescription drug abuse among undergraduate students. They investigated the medical use, illicit use, and diversion of four distinct classes of abusable prescription medications (sleeping medication, sedative or anxiety medication, stimulant medication, and pain medication) in a random sample of undergraduate students attending a large, public, midwestern research university in the United States in 2003. They found that the prevalence of illicit use within the past year was highest for pain medication, followed by stimulant medication, sedative or anxiety medication, and sleeping medication. Women generally reported higher past-year medical use rates.

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However, undergraduate men reported higher illicit use rates. Medical users of stimulants for attentiondeficit/hyperactivity disorder (ADHD) were the most likely to be approached to divert their medication. When the investigators adjusted for confounding variables, the study also found that illicit users of prescription drugs were more likely to use other drugs than were students who did not use prescription drugs illicitly (McCabe et al. 2006b). This study documents that those who abuse prescription drugs are more likely to abuse other types of drugs as well, thus compounding the complexities of treatment. When correlates of drug abuse are examined, demographics including race and ethnicity are generally considered. According to the National Survey on Drug Use and Health (NSDUH) (Figure 42–2), rates of past-year prescription drug abuse were significantly higher among Native Hawaiian or other Pacific Islander (10.1%) and American Indian or Alaskan Native (8.1%) persons compared with black or African American (3.9%) and Asian (3.0%) persons. Rates for white (6.7%), Hispanic or Latino (6.3%), and "two or more races" (7.5%) participants were in between the other rates. In student surveys, Asian and African American students reported lower rates of illicit use of prescription drugs than did white or Hispanic students (McCabe et al. 2006b, 2007). FIGURE 42–2. Past-year nonmedical use of any prescription psychotherapeutic drug, by race/ethnicity: annual averages based on 2002–2004.

Source. Reprinted from Colliver JD, Kroutil LA, Dai L, et al: Misuse of Prescription Drugs: Data From the 2002, 2003, and 2004 National Surveys on Drug Use and Health. Rockville, MD, Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2006. Similarly, according to the National Epidemiologic Survey on Alcohol and Related Conditions, American Indian or Alaskan Native participants had a significantly greater odds ratio for use of all four categories of prescription drugs (except sedatives) as compared with white participants, whereas the odds for black, Hispanic, and Asian participants were lower than for white participants for all four classes (Huang et al. 2006).

Comorbidity In general, addictive disorders show a remarkably strong association with psychiatric disorders

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(Compton et al. 2007; Grant et al. 2004; Regier et al. 1990). Within this overall context, significant variation in the degree of association depends on both the particular substance disorders and the particular psychiatric disorders. For example, DSM-IV-TR dependence disorders generally have stronger associations than DSM-IV-TR abuse (Compton et al. 2005; Conway et al. 2006). In the general population household survey, the National Epidemiologic Survey on Alcohol and Related Conditions (N = 43,093), associations of lifetime nonmedical substance use disorders and Axis I and II disorders were overwhelmingly positive and statistically significant for each nonmedical drug use disorder and all other DSM-IV-TR Axis I and II disorders (Huang et al. 2006). Among the mood disorders, bipolar I disorder showed the strongest association with prescription drug use disorders. Among the anxiety disorders, panic with agoraphobia was the disorder with the strongest association. Among the personality disorders, antisocial personality had the strongest associations. Finally, in addition to comorbidity with psychiatric disorders, abuse of or dependence on one type of prescription drug was very likely to be associated with a clinically significant drug use disorder related to another prescription drug, illicit drug, or alcohol (Huang et al. 2006; McCabe et al. 2006a). For example, individuals with alcohol use disorders constituted less than 9% of the total sample but accounted for more than one in every three abusers of prescription drugs. Furthermore, the past-year co-occurrence of alcohol use disorders and prescription drug abuse was more concentrated among young adults ages 18–24 years than among individuals age 25 years and older (McCabe et al. 2006a). Less is known about the timing of onset of comorbid disorders. In one study, a prominent pathway from psychiatric disorder to prescription drug abuse was documented. Longitudinal data from 6,439 participants in the 1998 and 2001 waves of Healthcare for Communities, a nationally representative telephone survey, showed that respondents with a common mental health disorder in 1998 (major depression, dysthymia, generalized anxiety disorder, or panic disorder) were more likely to report opioid abuse in 2001 than were those without any of these disorders (odds ratio = 1.96; 95% confidence interval = 1.47–2.62) (Sullivan et al. 2006). Thus, persons with psychiatric disorders may be particularly vulnerable to the development of prescription drug abuse. Overall, common mental health disorders and problem drug use are associated with abuse of prescription drugs. Clinicians need to assess the patient carefully for co-occurring disorders whenever either psychiatric illness or prescription drug abuse is identified.

Medical System Issues Prescription drugs are legal compounds, manufactured and distributed by the medical system before their diversion occurs. The list of the medications that are diverted into abuse is lengthy (Table 42–2). Thus, prescription drug abuse is inexorably linked to medical practice in ways quite different from most other drug abuse. This also means that prescription drug abuse engenders a false perception as being inherently less risky than the abuse of street drugs. This perception is believed to be at least one of the forces driving the teenage prescription drug abuse epidemic (Friedman 2006).

OPIOIDS (ANALGESICS) Chronic pain is common, with one recent study reporting that 26% of all Americans age 20 years and older had some type of pain lasting more than 24 hours in the previous month, and 10% of all Americans surveyed had pain lasting more than 1 year (Centers for Disease Control and Prevention, National Center for Health Statistics 2006). Furthermore, Stewart et al. (2003) found that 13% of the total U.S. workforce experienced a loss in productive time during a 2-week period as a result of a common pain condition. This resulted in an estimated $61.2 billion worth of lost productive time alone. The majority (76.6%) of lost productive time was explained by reduced performance while at work, not work absence. Because opioids are a common and useful treatment for pain, the high prevalence of chronic pain indicates that many persons will be exposed to opioids chronically, and some will develop addiction in the process. Thus, the difficulty of addressing the treatment of pain while minimizing the risk of addiction will continue to present particular complexities to clinicians. A brief description of the history of pain treatment is useful because the intersection of pain treatment

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and opioid abuse is particularly relevant for clinicians. Opioid drugs have been used for the treatment of pain, and problems with their use have occurred for thousands of years. As described earlier, regulation, including criminal prosecution, has occurred in the last hundred years. By the 1940s, additional regulatory controls had been implemented in the United States (Ballantyne and Mao 2003). As a result, physicians became reluctant to prescribe opioids and the public became fearful of using the medications even as prescribed and even when the pain was from an acute traumatic injury or a terminal condition (Cordell et al. 2002; C. S. Hill 1996; Wilson and Pendleton 1998). A turning point came during the 1980s when the World Health Organization began advocating for progressive treatment of terminal cancer pain. Opioid treatment became established as an effective, necessary, and acceptable means of treating pain caused by a terminal disease. By the end of the twentieth century, largely through the efforts of hospital accrediting agencies and practice guidelines, opioid therapy had been firmly established as an invaluable and accepted treatment for acute pain, and pain became the "fifth vital sign" (McQuay 1999; Phillips 2000; Portenoy 1996). Through the efforts of pain-control advocates, subspecialty accreditation was established by the American Board of Medical Specialties, and clinical practices were instituted for pain management. Nevertheless, one of the most difficult issues now facing physicians who treat chronic pain is whether and how to prescribe opioid therapy for chronic pain that is not associated with terminal disease, including pain experienced by the increasing number of patients with cancer in remission who need long-term opioid therapy. Many of the issues involved in the treatment of pain due to cancer in remission are the same as those in the treatment of chronic pain that is unrelated to a malignant condition. Pain relief is the expected end point of opioid therapy, but there is no consensus on whether pain relief without other benefits, such as functional improvement, is a reasonable and sufficient outcome of chronic pain treatment. Therefore, the other desirable end points that constitute an acceptable outcome of opioid therapy for chronic (nonterminal) pain conditions remain under discussion (Ballantyne and Mao 2003). During the latter part of the twentieth century, scientific research led to a better understanding of the actions of opioids, affording physicians greater options with regard to duration of action, route of delivery (e.g., transdermal, intrathecal, or epidural), and chemical structure (such as synthetic or semisynthetic formulations designed to reduce side effects). However, widely accepted evidence-based practice guidelines are not established. Therefore, current guidelines are based on consensus from long-standing clinical observations and practices. Recommendations generally include a cautious approach to dose escalation in order to control pain and the discontinuation of opioids if treatment goals, including patient compliance, are not met (Portenoy and Foley 1986). Yet, as noted earlier, even the goals of treatment are not uniformly agreed on. For example, is improvement in subjectively reported pain a sufficient goal, or must functional improvement also occur? Certainly in some conditions the pathology of the disease is such that functional improvement is not an obtainable goal. One of the significant challenges facing physicians and other practitioners in busy general medical practice settings is the demands of patients who have complex medical, socioeconomic, and legal problems for increasing doses of opioids. As a consequence, very large doses of opioids are prescribed for patients with chronic pain that is not associated with terminal disease, sometimes without any real improvement in the patient's pain or level of functioning (Ballantyne and Mao 2003). It has long been recognized that problems of addiction can arise from the use of prescription opioids (Goldman et al. 1998; Himmelsbach 1934; Joranson et al. 2000; Weppner et al. 1976; Wilford 1990). Although many questions remain with respect to the extent of the problem and the characteristics of individuals who develop these problems, increasing medical use of opioid analgesics makes this an imperative topic for research (Joranson et al. 2000). Further adding to the complexity of these issues is that patients with severe, debilitating pain may be undertreated because of concerns about addiction (Morgan et al. 1994; Portenoy 1996; Weissman and Haddox 1989; Zenz and Sorge 1991). Understanding the extent and unique features of prescription

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opioid problems is needed to optimize the use of these agents (Brands et al. 2004). Although abuse of and addiction to opioid agents are not new phenomena (De Quincy 1996), the scale, range, and growth of the problem are new. Epidemiological surveys in 2006 of youths in the United States indicated that opioid analgesics were among the most frequently abused illicit drugs among secondary students (twelfth graders), second only to marijuana (Johnston et al. 2007). Furthermore, in the past few years, we have seen a marked increase in the use of opioid medications in the United States and an even greater increase in problems associated with such use (Compton and Volkow 2006b; Paulozzi and Ryan 2006). This upsurge in use and problems is particularly concerning because it seems to represent an expanded pathway to opioid addiction (Siegal et al. 2003). According to recent epidemiological data, 4.7% of U.S. household residents older than age 12 years (11.0 million) abused an opioid medication in 2004, and more than 10% of these persons (1.5 million) endorsed the symptoms of a DSM-IV-TR opioid use disorder (Colliver et al. 2006). New cases of opioid analgesic abuse occurred in more than 2 million persons in 2005 (Substance Abuse and Mental Health Services Administration 2006a). From another perspective, between 1998 and 2002, the number of opioid analgesic drug mentions (i.e., excluding heroin and morphine) in medical examiner cases increased in 28 of 31 reporting areas of the United States (Substance Abuse and Mental Health Services Administration 2004). Furthermore, there has been a 10-fold variability in sales of some opioid medications in the United States during the past 15 years, with a linear relation between total opioid analgesic sales and drug poisoning mortality (Paulozzi and Ryan 2006). Recently, accidental drug poisonings were shown to be implicated in more than 20,000 deaths per year in the United States, with opioids related to a large portion of these deaths (Centers for Disease Control and Prevention 2007). Thus, the relation of prescription opioid drug abuse to death is of increasing concern. In data from emergency departments, mentions associated with opioid drugs, another indicator of problems, increased 135% from 1995 to 2002 and 18.5% from 2001 to 2002 (Substance Abuse and Mental Health Services Administration 2003). The increase in opioid analgesic abuse is especially worrisome because at the doses that these substances are sometime abused, they can result in respiratory depression and death. In addition, opioid abuse is particularly problematic for two populations: 1) adolescents, because of uncertain implications for future addiction and 2) the elderly because of increased sensitivity to toxic effects. Like other drug-related conditions, opioid analgesic abuse is mostly concentrated in adolescents and young adults (Substance Abuse and Mental Health Services Administration 2006a); however, little is known about opioid effects in adolescence. Most of what we know about opioid abuse and addiction has been learned from heroin addiction in 20- to 40-year-old individuals. Given rapid brain development during adolescence, early exposure to opioids may result in neurobiological changes and behavioral consequences that may differ from those we have seen in adults (Compton and Volkow 2006b). As previously noted, abuse of prescription opioids among young people is common. In a study with 4,580 college students, lifetime prevalence of prescription opioid abuse was 14.3%, and the past-year prevalence was 7.5% (McCabe et al. 2007). No gender differences were found, but white students were more likely than black and Asian students to report prescription opioid abuse. The reason cited most often for nonprescribed use of prescription opioids was "to relieve pain" (cited by 40%). Other typical motives included "gives me a high" and "experimentation." Despite no overall gender differences, undergraduate men were about two times more likely than undergraduate women to report lifetime nonmedical use of prescription opioids to get high and to experiment. Patients with chronic pain are frequently prescribed opioids, and this exposure is associated with risk of opioid misuse. In one study of opioid-treated chronic pain patients (N = 196), the strongest predictors of misuse were self-reported histories of previous alcohol or cocaine abuse and previous criminal drug- or alcohol-related convictions. Age was also predictive, but the effect was not large. Gender, race, literacy, disability, and measures of socioeconomic status were not associated with misuse. In addition, no relation between pain scores and misuse was found (Ives et al. 2006).

Differences From Heroin Abusers

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In a treatment sample in Canada (N = 679), prescription opioid abusers had higher levels of use of benzodiazepines, higher levels of depression, and more reports of chronic pain than did heroin abusers (Monga et al. 2007). In a study of patients admitted to methadone maintenance treatment, a detailed retrospective chart review of new admissions from 1997 to 1999 (N = 178) identified four groups: 24% had used prescription opioids only, 24% had used prescription opioids initially and heroin later, 35% had used heroin first and prescription opioids subsequently, and 17% had used heroin only (this group was significantly younger: mean age = 26 years, P <0.01). Subjects reported regular use of prescription opioids at higher-than-therapeutic dosages. For example, in the "prescription opioid only" group, the reported mean number of codeine- and oxycodone-containing tablets consumed daily was 23 tablets and 21 tablets, respectively. No significant differences were found among the groups in measures of social stability. Those dependent on prescription opioids alone were less likely to use illicit non-opioid drugs or to inject drugs (Sigmon 2006). Those who used prescription opioids only or initially were more likely to have ongoing pain problems and to be involved in psychiatric treatment (Brands et al. 2004). A similar pattern was seen in the national survey of treatment admissions, which indicated that 12% of the patients admitted with primary prescription opioid abuse reported intravenous as their primary route, compared with 63% of the patients admitted for heroin abuse (Substance Abuse and Mental Health Services Administration 2006b). Overall, it appears that patients with only prescription opioid dependence (i.e., opioid dependence without heroin dependence) may have less severe opioid addiction but have quite complex comorbidity. Furthermore, patients addicted to prescription opioids appeared to be more stable compared with those addicted to heroin, reporting fewer family and social problems and less income from illegal sources (Brands et al. 2004). Thus, they may be particularly good candidates for antagonist treatment, such as naltrexone, and they may be particularly well suited for outpatient office buprenorphine (Fiellin 2006).

Chronic Opioid Side Effects Opioids affect multiple organ systems, including the endocrine system. These alterations include tolerance (probably the most troublesome clinical problem), sedation, respiratory depression, meiosis, gastrointestinal hypomotility, and hyperalgesia (increased sensitivity to pain or pain with normally nonnoxious stimuli). The effect of morphine on the hypothalamic-pituitary-adrenal axis is a reduction in plasma cortisol levels, with a similar dose-dependent relation anticipated with the prescription opioids. The effect of opioids on the hypothalamic-pituitary-gonadal axis includes a decrease in testosterone and estrogen levels. Testosterone replacement is often prescribed for individuals receiving methadone maintenance therapy after laboratory confirmation of low testosterone levels. The physician or health care provider treating patients receiving long-term opioid therapy should be aware of the multiple systemic effects of opioids, which are not ameliorated with time (Ballantyne and Mao 2003).

STIMULANTS Recent data from the NSDUH indicate that an estimated 21 million persons age 12 years or older in the United States, or about 9%, have used prescription stimulants nonmedically at some point in their lifetimes (Colliver et al. 2006). This estimate includes an estimated 12 million persons reporting nonmedical use of methamphetamine, which is often produced illegally but is also potentially available as a prescription agent. Furthermore, just as increased abuse of opioids is associated with increased prescribing of opioids in general, high rates of abuse of prescription stimulants may be related to recent increases in prescribing of these agents for ADHD. One key difference is that the problems of abuse of prescription stimulants used to treat ADHD may be particularly apparent in friends or peers of persons with ADHD rather than the individuals with the disorder themselves, as is the case with opioids (Compton and Volkow 2006b; Volkow and Swanson 2003). To summarize, ADHD is a common neuropsychiatric syndrome with onset in childhood, usually becoming apparent (and thus coming to medical attention) during the first few years of grade school (Goldman et al. 1998). Hyperactivity in children was first described clinically in 1902, and the first report of stimulant use to treat hyperactivity in that condition was in 1937. ADHD may be associated with

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several comorbid psychiatric conditions, impaired academic performance, and both patient and family emotional distress. It was previously thought that the disorder remitted before or during adolescence, but it has become well established that the illness frequently persists into adulthood (Biederman et al. 1996; J. C. Hill and Schoener 1996). Pharmacological treatment, particularly with stimulant medication, is a typical intervention, although other forms of treatment (e.g., behavior therapy, parent training) are important parts of good clinical care. Despite a great amount of interest, and frequent heated debate, by both the lay and the scientific communities, various aspects of ADHD continue to generate controversy. This controversy centers on facts concerning the diagnostic and treatment features of the condition. From a diagnostic standpoint, ADHD is a disease of children, who are a vulnerable population, and this diagnosis is based solely on patient history and behavioral assessment, without use of laboratory or radiological confirmation. From a treatment standpoint, ADHD has an early onset and extended course, which often necessitates treatment over many years; this treatment often includes stimulant medications that have abuse or diversion potential (Goldman et al. 1998). The relation between substance use disorders and ADHD is complex. Children with ADHD who do not have comorbid conditions have a risk for a substance use disorder that is no different from the risk for children without ADHD up to about age 14 years (Goldman et al. 1998). The risk of developing substance use disorders in those with ADHD is increased in adolescents, and the risk ratio increases further in adulthood, regardless of whether comorbid conditions are present. Persistence of ADHD symptoms and family history of both ADHD and substance use disorders are risk factors for their development. A highly potent risk factor is the presence of comorbid conduct disorder or bipolar disorder (Goldman et al. 1998). There is debate about whether long-term treatment of ADHD may decrease the risk of subsequent development of substance use disorders (Biederman et al. 1996; Taylor et al. 1996). Although longitudinal studies have shown the effectiveness of pharmacological treatment for ADHD, considerable concern remains about diversion of these drugs for nonmedical or illicit use (Herman-Stahl et al. 2006; Kroutil et al. 2006). Despite this controversy, youths in the United States are frequently given stimulants for ADHD—more frequently than are youths in western European countries (Goldman et al. 1998). Analogous to the situation for chronic pain, the number of prescriptions for treatment of ADHD in children and adults has increased markedly since 1990. For example, the amount of methylphenidate approved for production in the United States has increased more than eightfold—from 1,768 kg in 1990 to 14,957 kg in 2000 (Kroutil et al. 2006; White et al. 2006).

Epidemiology of Stimulants Amphetamines, a class of psychotherapeutic stimulants, have had a relatively high prevalence of use in the youth population for many years. Among twelfth graders in the United States (Johnston et al. 2007), use of amphetamines increased in the last half of the 1970s and reached a peak in 1981, 2 years after marijuana use peaked. After 1981, a long and steady decline in use of amphetamines by twelfth graders began, which did not end until 1992. As with many other illicit drugs, amphetamine use reemerged in the 1990s, with the annual prevalence starting to increase by 1992 among eighth graders and by 1993 among tenth and twelfth graders. Use peaked in the lower two grades by 1996 and in twelfth grade by about 1997. Since those peak years, use remained stable for several years and has decreased somewhat since 2003. Abuse of Ritalin (methylphenidate) was added to the Monitoring the Future student surveys in 2001; rates of Ritalin abuse have been fairly stable over the past 5 years, with an annual prevalence of 4.4%–5.1% in twelfth graders, 3.4%–4.8% in tenth graders, and 2.4%–2.9% in eighth graders. According to the 2002 NSDUH, abuse of ADHD stimulants most frequently involved methylphenidate and dextroamphetamine. Of the estimated 3.2 million persons who abused any prescription stimulant in the past year, slightly more than half (1.7 million) were ages 12–25 years. However, this age group composed more than 80% of the 0.8 million abusers of ADHD stimulants. Females constituted fewer

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than one-half of past-year abusers of any prescription stimulant (1.5 million) and ADHD stimulants (0.3 million) but constituted a slight majority (0.9 million) of abusers of nonmethamphetamine stimulants (Kroutil et al. 2006). A recent study of students found that approximately three-fourths (75.8%) of the 269 past-year illicit users of prescription stimulants reported using an amphetamine-dextroamphetamine combination agent (e.g., Adderall) in the past year, and approximately one-fourth (24.5%) reported using methylphenidate (e.g., Ritalin, Concerta, Metadate). Students who used these drugs as study aids preferred the slow-release drug Adderall to Ritalin. These empirical data were the first to support the frequent media attention on Adderall as the drug of choice for high school and college students who were abusing stimulants (Teter et al. 2006). Thus, studies that rely solely on methylphenidate use as an indicator for illicit use of prescription stimulants may underestimate the prevalence of stimulant-type prescription drug abuse. In a college student population, Hispanic and white students had higher rates of illicit prescription stimulant use than did Asian and African American students, but no overall gender differences in use were found (Teter et al. 2006). In the overall population studied in NSDUH, gender differences also were not found, with regard to abuse of both prescription and nonprescription stimulants. Further exploration of certain age subgroups in the NSDUH showed that males were more likely than females to have abused prescription stimulants in certain age groups (Kroutil et al. 2006). However, in other age subgroups, adolescent girls (ages 12–25 years) used methamphetamine (usually illegally produced, nonprescription stimulant) more than did boys, with much of this difference attributable to girls using methamphetamine for appetite control (Herman-Stahl et al. 2006; Kroutil et al. 2006).

Motives to Use Stimulants College students abuse prescription stimulants for a variety of reasons, with academic performance being one of the most often cited reasons, especially among women in college (Teter et al. 2006). White et al. (2006) used data from 2002 and also found that the reasons for abusing or misusing stimulant medication included improving attention, partying, reducing hyperactivity, and improving grades (sometimes a combination of the reasons was cited [e.g., stay up to party and then use again to stay up to cram]). A lack of appreciation on the part of the students for the potency and potential health effects of stimulants was noted. Again, because these are medical substances, they were perceived to be "safe." Males were more likely than females to sell or give away their stimulant medication (Poulin 2001). One study found that 16% of schoolchildren in rural Wisconsin and Michigan who were prescribed stimulant medication were approached to sell, give away, or trade their stimulant medication (Musser et al. 1998). Another study of high school adlescents, also in the Midwest, found that of those who reported prescription stimulant use, 23.3% reported being approached to sell, give, or trade their prescription drugs (McCabe et al. 2004).

SEDATIVES AND TRANQUILIZERS The category of sedative-hypnotics and tranquilizers is often divided into separate classes of drugs based on their intended primary purpose of either relief from anxiety or relief from insomnia. This division is arbitrary and often is based on only dose administered or the time of administration (i.e., at bedtime or not), and for that reason, we consider them as one class. Prescription sedatives and tranquilizers have been abused for decades, whether it was the earlier agents, such as the barbiturates and chloral hydrate, or the benzodiazepines since the 1960s. Some have proven to be highly problematic and addictive (e.g., methaqualone and the short-acting barbiturates), but all have significant abuse liability. Even the newest hypnotic agents, such as zolpidem and zopiclone, which have lower abuse potential compared with many earlier agents, have been associated with misuse and abuse (Hajak et al. 2003). The primary indications for the prescription of this class of medications are anxiety and insomnia. In

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contrast to the opioid and stimulant drug classes, no changes in medical practice patterns have occurred that would account for increases in the abuse-to-use ratio that periodically occur with these drugs.

History One of opium's many properties that made it popular in the nineteenth century was its effectiveness as an anxiolytic. Just after the turn of the century, concerns about the addictive potential of opium, laudanum, and related opioids led to a search for alternative sedating agents. The bromides and chloral hydrate replaced opium and its derivatives for these purposes. Barbiturates were introduced in the 1930s and gained great popularity. By the 1950s, the addictive potential of barbiturates was becoming apparent. Phenothiazines and meprobamate became available during this period. As had been the pattern, these medications were thought to be less addictive and safer medications than their predecessors for the treatment of anxiety and insomnia. However, the phenothiazines, although much less liable for abuse, had significant side effects that made their use inappropriate for this patient population, and meprobamate often did not have sufficient potency. Thus, the need for a drug with mid-range potency and a reduced side-effect profile was great. Benzodiazepines fit this profile, starting in the early 1960s with chlordiazepoxide and then with diazepam. Over time, these medications became the most widely prescribed of any drug class in the United States. In the 1970s, a historically important drug was introduced—methaqualone—as another attempt at producing a less abusable and safer sedative. This drug is chemically unrelated to the other classes of sedatives. Unfortunately, methaqualone had a high abuse potential. Therefore, it was reclassified to Schedule I and taken off the market in the United States in the early 1980s. Most recently, nonbenzodiazepine partial -aminobutyric acid (GABA)A agonists such as zolpidem and zaleplon, "z-hypnotics," have been introduced as hypnotic agents with minimal side effects. Although the chemical structures of these compounds do not resemble those of benzodiazepines, their therapeutic efficacy appears to be a result of agonist effects on the benzodiazepine site of the GABAA receptor. These substances are effective as hypnotic agents with minimal side effects, although cases of abuse have been reported even for these agents (Brunton et al. 2006; Hajak et al. 2003).

Epidemiology During the 1980s, abuse of sedatives and tranquilizers decreased among youths, with abuse declining by 75% among twelfth graders over the 15-year interval between 1977 and 1992. However, since 1992, abuse of sedatives has increased, and annual prevalence more than doubled among twelfth graders—from 2.8% in 1992 to 7.2% in 2005 (Figure 42–3). There has been a trend for simultaneous use of benzodiazepines with other drugs, which is consistent with the observation that benzodiazepines are often used in conjunction with other drugs or alcohol; for example, alprazolam use became popular to "come down" from or ameliorate the effects of smethylenedioxymethamphetamine ("ecstasy") or amphetamine use or to ameliorate withdrawal symptoms from other drugs such as opioids or alcohol (Johnston et al. 2007). FIGURE 42–3. Percentage of high school seniors reporting nonmedical use of sedatives in past year.

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Source. Reprinted from Johnston LD, O'Malley PM, Bachman JG, et al: Monitoring the Future, National Survey Results on Drug Use, 1975–2006, Vol. I: Secondary School Students. Bethesda, MD, National Institute on Drug Abuse, 2007. A study of slightly older individuals (college students) by McCabe et al. (2005) showed very similar results, with 7.8% lifetime abuse of benzodiazepines and 4.5% past-year abuse. College students more likely to abuse benzodiazepines were white, had both male and female sexual partners, and reported higher rates of substance use and other risky behaviors. In addition, benzodiazepine abuse was less likely among college students in the North Central region of the United States and those attending historically black colleges and universities (McCabe et al. 2005).

CONCLUSION In the United States, pain is often undertreated, but prescription opioid abuse is escalating in conjunction with increasing numbers of prescriptions. Similarly, abuse of stimulants increased as prescriptions for youths with ADHD have increased. Even sedatives and tranquilizers are commonly abused. Possible initiatives to combat prescription drug abuse will require strategies used for drugs that are always illegal, in combination with new tactics specifically tailored to prescription medications. Effective drug abuse prevention strategies targeted to family interventions and reducing general drug abuse risk factors while strengthening protective factors are warranted (National Institute on Drug Abuse 2005). Furthermore, specific campaigns to encourage patients to dispose of medication when a medical condition has resolved appear reasonable as a way to diminish potential for diversion. An additional concern is the potential for access to prescription agents through the Internet (Forman et al. 2006). To address this concern, a unified approach by many stakeholders may be necessary. Overall, in this chapter, we have shown some of the evidence that prescription drug abuse is common. Most common is abuse of opioid analgesics, followed by tranquilizers and stimulants. As with other substances, comorbidity is the rule rather than the exception. Co-occurrence of prescription drug abuse and addiction with other substance use disorders and many psychiatric conditions is common. Notably, the reasons for abuse of the different categories of prescription drugs and for comorbidity vary according to gender. In particular, younger males appear more likely to abuse these substances for their intoxicating properties, whereas females abuse them for health-related issues (pain and weight control). Abuse of these substances presents unusual difficulties for physicians both because physicians themselves are the source of the substances in some cases and because the distinctions among

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therapeutic use, medical misuse, abuse, and addiction can be quite subtle. A further complexity relates to the legal controls of these substances such that prescriptions and monitoring for signs of abuse are the responsibility of the health care system. Thus, physicians are in a unique situation in dealing with prescription drug abuse compared with other illicit substances, alcohol, and tobacco.

KEY POINTS Prescription drug abuse is common. Prescription drug abuse has a major relation to medical practice. Nomenclature is difficult and confusing; distinguishing use from misuse from abuse from addiction is complex for both clinicians and researchers. Treatment is based on the pharmacological class of the substance of abuse.

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Siegal HA, Carlson RG, Kenne DR, et al: Probable relationship between opioid abuse and heroin use (letter). Am Fam Physician 67:942–945, 2003 [PubMed] Sigmon SC: Characterizing the emerging population of prescription opioid abusers. Am J Addict 15:208–212, 2006 [PubMed] Stewart WF, Ricci JA, Chee E, et al: Lost productive time and cost due to common pain conditions in the US workforce. JAMA 290:2443–2454, 2003 [PubMed] Substance Abuse and Mental Health Services Administration: Emergency Department Trends From the Drug Abuse Warning Network, Final Estimates 1995–2002. Rockville, MD, Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2003 Substance Abuse and Mental Health Services Administration: Mortality Data From the Drug Abuse Warning Network. Rockville, MD, Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2004 Substance Abuse and Mental Health Services Administration: Results From the 2005 National Survey on Drug Use and Health: National Findings. Rockville, MD, Office of Applied Studies, 2006a Substance Abuse and Mental Health Services Administration: Treatment Episode Data Set (TEDS): Highlights—2005. Rockville, MD, National Admissions to Substance Abuse Treatment Services, Office of Applied Studies, 2006b Sullivan MD, Edlund MJ, Zhang L, et al: Association between mental health disorders, problem drug use, and regular prescription opioid use. Arch Intern Med 166:2087–2093, 2006 [PubMed] Taylor E, Chadwick O, Heptinstall E, et al: Hyperactivity and conduct problems as risk factors for adolescent development. J Am Acad Child Adolesc Psychiatry 35:1213–1226, 1996 [PubMed] Teter CJ, McCabe SE, LaGrange K, et al: Illicit use of specific prescription stimulants among college students: prevalence, motives, and routes of administration. Pharmacotherapy 26:1501–1510, 2006 [PubMed] Volkow ND, Swanson JM: Variables that affect the clinical use and abuse of methylphenidate in the treatment of ADHD. Am J Psychiatry 160:1909–1918, 2003 [Full Text] [PubMed] Weissman DE, Haddox DJ: Opioid pseudoaddiction—an iatrogenic syndrome. Pain 36:363–366, 1989 [PubMed] Weppner RS, Wells KS, McBride DC, et al: Effects of criminal justice and medical definitions of a social problem upon the delivery of treatment: the case of drug abuse. J Health Soc Behav 17:170–177, 1976 White BP, Becker-Blease KA, Grace-Bishop KA: Stimulant medication use, misuse, and abuse in an undergraduate and graduate student sample. J Am Coll Health 54:261–268, 2006 [PubMed] Wilford BB: Abuse of prescription drugs. West J Med 152:609–612, 1990 [PubMed] Wilson JE, Pendleton JM: Oligoanalgesia in the emergency department. Am J Emerg Med 7:620–623, 1998 Zenz M, Sorge J: Is the therapeutic use of opioids adversely affected by prejudice and law (abstract)? Recent Results Cancer Res 121:43–50, 1991 [PubMed]

SUGGESTED READING Ballantyne JC, Mao J: Opioid therapy for chronic pain. N Engl J Med 349:1943–1953, 2003 Colliver JD, Kroutil LA, Dai L, et al: Misuse of Prescription Drugs: Data From the 2002, 2003, and 2004 National Surveys on Drug Use and Health. Rockville, MD, Substance Abuse and Mental Health Services Administration, Office of Applied Studies, 2006 Compton WM, Volkow ND: Major increases in opioid analgesic abuse in the United States: concerns and

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strategies. Drug Alcohol Depend 81:103–107, 2006b Huang BD, Dawson DA, Stinson FS, et al: Prevalence, correlates, and comorbidity of nonmedical prescription drug use and drug use disorders in the United States: results of the National Epidemiologic Survey on Alcohol and Related Conditions. J Clin Psychiatry 67:1062–1073, 2006 National Institute on Drug Abuse: Prescription drug abuse. 2007. Available at: http://www.nida.nih.gov.ezproxy2.library.usyd.edu.au/drugpages/prescription.html. Accessed March 8, 2007. Zacny J, Bigelow G, Compton P, et al: College on Problems of Drug Dependence taskforce on prescription opioid non-medical use and abuse: position statement. Drug Alcohol Depend 69:215–232, 2003 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 43. Substance Use Disorders Among Physicians

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J. Wesley Boyd, John R. Knight: Chapter 43. Substance Use Disorders Among Physicians, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.357067. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Substance Use Disorders Among Physicians J. Wesley Boyd, M.D., Ph.D. John R. Knight, M.D.

SUBSTANCE USE DISORDERS AMONG PHYSICIANS: INTRODUCTION In years past, the prevalence of addictive disorders in the medical profession was widely exaggerated. In fact, physicians have rates of substance abuse and dependence that are very similar to those of the general population. Physicians' patterns of use, however, differ in that physicians most often misuse prescription drugs and do so for reasons of self-treatment. Physicians have greater access than most to very potent psychoactive medications and are subject to unique stresses, and when they become impaired as a result of psychoactive substance use, other people may be placed in jeopardy as well. In this chapter, we present the key features of the problem of substance abuse among physicians and a structured approach to intervention, treatment, and monitoring that has a high rate of success and allows the great majority of physicians with substance use disorders to return safely to medical practice. Dr. Knight acknowledges grant support from the National Institute on Alcohol Abuse and Alcoholism (K07 AA013280) and from the Maternal and Child Health Bureau (5T20MC000-11-06). We dedicate this chapter to Dr. Michael B., who shared his experience, strength, and hope with so many other physicians until his untimely death from a carotid aneurysm. He died clean and sober, before the miracle could be even half-completed, and we still miss him.

DEFINITIONS AND TERMINOLOGY Historically, the term impaired physician was applied to physicians with substance use disorders, irrespective of the substance of abuse. More recently, however, the term impaired physician has been broadened to include physicians whose ability to practice medicine has been adversely affected for any reason, including physicians with physical disabilities, certain forms of mental illness (including, most prominently, major depression, bipolar disorder, and attention-deficit/hyperactivity disorder [ADHD]), neurocognitive and/or emotional impairments arising as a result of illnesses such as HIV/AIDS or diabetes mellitus, and behaviors arising from other reasons that prevent the physicians from being able to practice medicine with reasonable skill and safety. Impaired physician has also come to include physicians who exhibit disruptive behaviors (Pfifferling 1997), including either words or actions that have the potential to interfere with quality patient care. Disruptive words and actions can include inappropriate anger or resentment, inappropriate words or actions directed toward another person, and inappropriate responses to patients' needs or staff members' requests. Given that physicians with many of these disorders and problems are, in fact, able to continue working if they receive treatment of some kind and or monitoring, we feel that the term impaired physician is archaic, demeaning to those physicians with the problems just listed, and ought to be replaced with language that describes the nature or source of the problem without simultaneously implying that the physician is either impaired or unable to safely practice medicine. Despite the numerous ways in which physicians can potentially compromise patient care, in this chapter we will focus our attention entirely on substance use disorders among physicians. Substance use disorder, as defined by DSM-IV-TR (American Psychiatric Association 2000), is a category that includes both substance abuse and substance dependence. We use the term misuse to refer to use of any illicit

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drug, to problematic drinking, or to use of a psychoactive medication for a reason other than that for which it was prescribed or when it was not prescribed in the usual course of the practice of medicine by one's own treating physician (e.g., self-prescribing). Among physicians, problems regarding substance use may arise from acute intoxication or withdrawal symptoms following intoxication. Withdrawal can take many forms, including feeling sick or hungover from excessive drinking, feeling agitated as a result of withdrawal from depressant drugs, or feeling lethargic after overuse of stimulants.

EPIDEMIOLOGY Rates of substance use disorders among U. S. physicians are similar to rates in the general population, with the lifetime prevalence of substance dependence reported to be between 8% and 15% (Blondell 1993; Brewster 1986; Clare 1990; McAuliffe et al. 1984; Skipper 1997). The most extensive survey of physician substance use was the 1992 Physician Substance Use Survey (PSUS), which polled 9,600 physicians about their own use of psychoactive substances. The PSUS reported an 8% lifetime rate of substance use disorders (Hughes et al. 1992). Other studies generally have reported higher rates. One possible reason is that the PSUS relied on physicians' self-reports and, as such, might have underestimated actual rates of use. The PSUS and other studies found that anesthesiologists and emergency medicine physicians are at greater risk compared with physicians from other specialties for developing substance use disorders (Hughes et al. 1992, 1999; Mansky 1996). This finding is supported by the observation within state physician health monitoring programs that these two fields of medicine are significantly overrepresented (Hughes et al. 1999; Knight et al. 2007; Mansky 1996). Surgeons and pediatricians report lower rates of substance use and also tend to be underrepresented in state physician health monitoring programs (Hughes et al. 1999; Knight et al. 2007). The PSUS also found that physicians are more likely than nonphysicians to consume alcohol, more likely to use analgesics and tranquilizers, and less likely to use illicit drugs (Hughes et al. 1992). Among physicians who misuse drugs, emergency medicine physicians tend to use more illicit drugs, anesthesiologists tend to misuse opioids, and psychiatrists are more likely to misuse benzodiazepines. It is likely that availability and familiarity are contributing risk factors for medical specialists. A large proportion of physicians who reported misusing drugs in the PSUS reported the reason as "self-treatment," which may represent an occupational hazard for the medical profession at large.

WARNING SIGNS AND SYMPTOMS Among physicians, symptoms of substance misuse may first appear outside of the workplace—often at home or in the physician's social or financial dealings—long before they become apparent in the workplace (Centrella 1994). Because of this phenomenon, when symptoms appear in the hospital or medical office, it is often the case that the substance use has been active for a long time. It is therefore not surprising that physicians often seek treatment late in the course of a substance use disorder. One study of physicians found that the mean duration of substance-related problems before receiving treatment was 6–7 years (Brooke et al. 1991). Early attention to presenting signs and symptoms of physician substance misuse is therefore important, even though many signs and symptoms are nonspecific (Table 43–1). The earliest signs may include disruptions in personal and family life, irregular work hours, loss of interest in professional or recreational activities, falling farther behind in charting and documentation than other physicians, or unusual prescribing practices. Certain physical changes might also suggest a substance use problem. These signs include deterioration in physical appearance, visible weight changes, excessive fatigue, significant changes in sleep patterns (including sleeping much more or much less than usual), coming to work bleary-eyed, smelling of alcohol while on duty, or the appearance of needle marks, bruises, or bandages. Signs of injection drug use, however, may be subtle. Our experience has shown that physicians are quite knowledgeable about injections and may take great care to conceal injection marks by using veins in the lower extremities or genital area. Sometimes, physicians with substance use disorders will make direct statements about how they are

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feeling. Statements that should provoke concern include expressing constant sadness or tearfulness, excessive anxiety or irritability, unprovoked anger or hostility, hopelessness or worthlessness, and feelings of isolation. When signs of substance misuse become manifest in the workplace, symptoms may include deterioration in the quality of work, repeatedly being late for meetings and appointments, having recurring absences, continually seeking special accommodations, repeatedly having trouble in getting along with staff and patients, and not responding to pages when on call. Although none of these warning signs alone can confirm the presence of a substance use disorder, their presence should be cause for concern and warrants further exploration and investigation. Little has been published about the relation between specific drugs of abuse and the severity of physician impairment. To further complicate this issue, physicians who are asked directly may minimize the effects that drug use has had on their ability to practice. Factors influencing the level of physician impairment likely include the pattern of use (e.g., morning use versus evening or weekend use), the amount of the substance that is self-administered, and the degree of tolerance to the substance in question (American Psychiatric Association 2000). Some tolerant individuals may show fewer signs of impairment when the drug is present in their serum compared with when the serum level declines and they show the negative physiological and cognitive concomitants of acute withdrawal (American Psychiatric Association 2000). Drugs that have steeper pharmacokinetic curves (e.g., injectable opioids and inhalants) are likely to produce greater and more obvious degrees of impairment in a shorter time. Drugs with longer onset and duration of action (e.g., benzodiazepines) may produce more subtle impairment, and their use, therefore, may go undetected for a longer period. Long-acting drugs also may produce protracted periods of symptomatic withdrawal, which requires close medical monitoring and management during the early stages of treatment (Eickelberg and Mayo-Smith 1998). Withdrawal seizures may occur days or even weeks after the discontinuation of long-acting benzodiazepines or barbiturates, and it is recommended that they be slowly tapered rather than stopped abruptly during detoxification.

CONFIRMING THE DIAGNOSIS A consulting physician who is asked to see a colleague who may be impaired should perform a complete medical and psychosocial history, a physical examination, and appropriate diagnostic tests. Before beginning this assessment, however, it is recommended that the consulting physician inform the colleague and any referring individuals about the extent to which confidentiality can be assured and who will have access to the medical record of the evaluation. Specific release forms may need to be signed. The consulting physician and other evaluators may or may not have a doctor–patient relationship with the physician who is misusing substances, and this should be discussed in advance to avoid later misunderstanding. Once everyone involved understands the conditions of confidentiality, the assessment can proceed. The "patient" history should include questions about negative changes in performance at work or at home; use of substances in situations in which it is hazardous (e.g., driving after drinking); any legal, social, or interpersonal problems that might be substance-related; loss of control over use of substances (e.g., drinking more than planned); tolerance and/or withdrawal symptoms; cravings and attempts to taper use or quit; and other substance-related physical or psychological problems (American Psychiatric Association 2000). Physicians who misuse prescription drugs should be asked how they obtained them (e.g., stealing of samples or office supplies, diverting from patients in the hospital, conspiring with patients to share prescriptions, writing fraudulent prescriptions, ordering from pharmaceutical suppliers, Internet orders), and early consideration should be given to consultation with an attorney. Collateral history from professional colleagues and hospital or office coworkers and staff is often most helpful, but care must be taken to protect privacy to the greatest extent possible, and the interviewing physician should obtain signed releases to confer with these individuals in accordance with federal confidentiality regulations (i.e., 42 Code of Federal Regulations [CFR], Part 2). In our experience, the value of collateral history from family members is much more variable. Spouses and significant others may give inaccurate information out of a misinformed desire to protect the physician or, when the physician's

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misuse of substances has been disruptive to the family, may exaggerate symptoms out of anger. Asking close family members to give collateral histories also may have a harmful effect on family relationships, and we recommend that it be avoided in most circumstances. Physical findings may include any of the usual indicators of acute or chronic substance use, depending on the specific substances that have been used. A thorough mental status examination should be performed, although the results are usually unremarkable. Making a diagnosis of substance abuse or dependence is not especially difficult if the physician is forthcoming with information and freely discusses his or her pattern of substance use. It can be much more difficult, however, when the physician denies or minimizes use. When suggestive signs and symptoms are present but the physician denies using, we recommend immediately obtaining laboratory testing for the substances in question. The operative word in this recommendation is "immediately" because the window of detection for most drugs of abuse is narrow (12–72 hours). Because laboratory testing for drugs is a technically complex and continually changing science, we recommend consultation with a toxicologist prior to testing whenever possible. If a toxicologist is not available, we recommend that urine and blood be immediately collected under federally mandated collection and chain-of-custody procedures (Vogl 1996) and that specimens are securely stored until the correct test(s) can be ordered. The toxicologist should be consulted about the type of testing that should be performed for the drugs that are suspected (i.e., immunoassay versus gas chromatography/mass spectrometry), the optimal body substrate (i.e., urine, serum, or hair) to be sampled, and the window of detection (i.e., number of hours following use during which the laboratory test result will be positive), so that negative test results can be properly interpreted. If there is a question about long-term use instead of immediate intoxication, hair testing can yield up to 3 months of information about substance use. Hair testing should not be performed, however, for drugs that can be smoked (i.e., marijuana, cocaine) because external contamination of the hair by smoke in the environment can cause a false positive result (DuPont et al. 1995). Immediate laboratory testing provides the physician with a means of refuting any false allegations of substance use. When urine is collected, the temperature of the specimen must be immediately checked to minimize the possibility of substitution, specific gravity and creatinine must be measured to exclude the possibility of in vivo or in vitro dilution, and confirmatory testing must be performed on all positive screens with gas chromatography and/or mass spectrometry (Vogl and Bush 1997). The greatest care must be taken when performing laboratory testing for drugs of abuse in physicians because physicians may face serious professional and legal sanctions if the test result indicates drug use. A differential diagnosis should be considered before making a final diagnosis of substance abuse or dependence. The differential diagnosis should include diabetes mellitus (especially when alcohol on the breath or other erratic behaviors have been reported), thyroid disease, other hormone irregularities, and psychiatric disorders ranging from ADHD to bipolar disorder to major depression. Although it is rare, incipient psychosis should be considered in some cases . Finally, as with all patients, physicians with substance use disorders may have co-occurring medical and psychiatric disorders, so a thorough diagnostic workup should be part of every routine assessment. When legitimate doubts exist about the accuracy of reports of physician substance use, we recommend early referral to a physician health committee or state physician health program. Before making the referral, the referring clinician should prepare a detailed listing of the concerns, taking care to state exactly what was seen or heard and by whom and taking care to avoid generalizations and drawing conclusions. For example, it is much more appropriate to record, "Nurse Smith stated that when Dr. Jones arrived in the emergency department, his speech was slurred, his eyes appeared bloodshot, and she thought that she smelled something like alcohol on his breath" than to state "Dr. Jones was drunk while seeing a patient in the emergency department."

INTERVENTION Our clinical experience unfortunately indicates that clinicians face significant barriers to starting

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treatment for physicians with substance use disorders. One barrier is the longstanding culture of tolerance and denial in the medical profession. We often see our colleagues in ourselves, and many of us are not enthusiastic about initiating a process that we fear might cause the professional ruin of one of our own. Nonetheless, early intervention can be lifesaving for both the physician and his or her patients. We therefore recommend that an intervention be arranged at the earliest possible opportunity whenever there is a reasonable basis to believe that a physician has a substance use disorder. Unfortunately, many physicians still see addiction as a moral failing rather than as a treatable brain disease, even though it has been well established as the former by the scientific community (Comerci and Schwebel 2000; Leshner 1997; Wise 2000). The principles of directive interventions that we recommend are summarized in the mnemonic acronym FRAMER (Table 43–2), which is a method of how best to frame one's concerns about a colleague. The intervention should occur in a private location and at the earliest possible time after the sentinel incident but not when the physician is acutely intoxicated. Preparation is important. First, the clinician must gather the facts, including documentation of oral complaints and any written complaints or notes. These should be factual statements of what has been observed and should not draw any conclusions about the basis of the behavior in question. The tone should be factual and not accusatory. Second, the clinician must determine his or her responsibility for reporting a colleague who is suspected of misusing substances. If a substance use disorder is confirmed, does state law require either individual physicians or health care facilities to report the physician to the state's licensing board? If so, is there a clause within state law that allows a physician not to report a colleague if that colleague voluntarily enters an approved treatment and monitoring program? Medical staff bylaws, other regulations, or ethical principles also may mandate reporting colleagues who one either suspects or knows to have a substance use disorder. The third principle is to bring in another person to the meeting with the physician of concern. There is strength in numbers, and it is advisable to have a witness present who can verify the exact nature of the conversation. A member of the state's physician health program would be an ideal person to have present. If that is not possible, someone who is familiar with state regulations and treatment options should be present. This could be the physician's department chief, chair of the hospital wellness committee, an addiction specialist, or a health care organization's chief medical officer. The clinician should open the meeting with a monologue in which he or she lists, in a matter-of-fact way, the exact observations that have led to concern. This is an intervention, not a discussion or a debate. If the physician interrupts, the clinician should politely ask him or her to let the clinician finish what he or she has begun to say, after which he or she will extend the same courtesy. The goal is to prevent the intervention from deteriorating into an argument. If the physician denies any problems, the clinician should insist on a comprehensive, independent evaluation to assess the extent of any problems and determine whether treatment is necessary. If the physician admits to having a problem, the clinician should tell him or her how much he or she appreciates his or her honesty but insist that the physician enter a treatment program immediately. It is usually best to insist that the physician cease practice as soon as possible and arrange for crosscoverage of his or her patients, but this may vary according to the exact nature and scope of the problem. When the physician accepts the recommendation for evaluation or treatment, the clinician must set a deadline by which it must be completed and insist on a report back from the program that summarizes the pertinent findings and any recommended additional treatments. The intervention team should obtain a signed release form from the physician of concern before the evaluation so that the referring physician can speak with the evaluator prior to the assessment, provide the evaluator with the pertinent facts, summarize the questions at hand, and receive any pertinent information from the evaluator (Physician Health Services 2003). Every health care facility is required by the Joint Commission on Accreditation of Health Care

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Organizations to have a process by which physician health matters can be addressed, which, when implemented, usually means that hospitals create a physician health or wellness committee. These committees should provide reasonable assurances of confidentiality, concern themselves with healthrelated issues only, and remain separate from administrative and disciplinary committees. These committees often provide educational programs for medical staff and residents and are a valuable resource for physicians with routine health problems. However, we recommend that, when faced with questions of patient safety or physician impairment, these committees should consult with the state physician health program as early as possible.

INITIAL TREATMENT, AFTERCARE, AND MONITORING Few scientific studies have been published on what kind of treatment is best for physicians with substance use disorders, and we found only one study suggesting that longer programs have better long-term rates of abstinence (Smith and Smith 1991). Nonetheless, many physicians with substance use disorders are referred to residential treatment programs for "professionals" lasting 2–4 months. This practice is controversial, and referred physicians may object to the high cost and disruption to family and professional life. There is little reason to believe that physicians will respond less favorably to treatment than nonphysicians will, so we recommend that they be matched to treatment programs that are state licensed, that provide an intensive initial assessment (including substance use, medical, psychological, psychiatric, family, and occupational components), and that offer a full spectrum of treatment services (e.g., individual therapy, group therapy, psychopharmacology, support groups). For those physicians who receive a referral to residential treatment, initial treatment usually consists of close medical observation for any signs of withdrawal, with provision of medication and other treatment as needed. After this initial period of medical stabilization, the physician enters into an intensive psychosocial rehabilitation program, which includes individual and group therapy, Alcoholics Anonymous (AA) and/or Caduceus (a support group for professionals in recovery) meetings, psychological evaluation (or neuropsychological testing if indicated), psychopharmacological evaluation and treatment if indicated, and, often, family meetings. Some of these residential programs for physicians are exceptionally thorough. Health insurance, however, seldom covers more than a fraction of the cost, and the significant expense can be prohibitive for younger physicians, those still in residency or fellowship training, and those physicians whose substance use has taken a significant financial toll. Most long-term residential programs provide an extensive aftercare plan, which includes recommendations for individual therapy, medications, attendance at AA or Caduceus meetings in the physician's home community, and monitoring by the state physician health program. All of these recommendations should be initiated before the physician returns to the medical workplace.

STATE PHYSICIAN HEALTH PROGRAMS State medical boards and professional societies have responded to the problem of physician impairment by developing physician health monitoring programs, aimed at ensuring that physicians with substance use disorders obtain proper treatment and remain abstinent so that they can safely remain in or return to medical practice (American Medical Association 2003). A listing of state programs and contact information is available through the Web site of the Federation of State Physician Health Programs (http://www.fsphp.org/). State physician health programs provide or facilitate independent assessments for physicians and provide guidance to hospital administrators and physician health committees. They are knowledgeable about state licensing regulations, treatment resources for substance abuse and dependence, and aftercare and monitoring. They are also available to contract with physicians who agree to treatment and complete abstinence from alcohol and drug use and to provide for monitoring and advocacy. The specifics of substance use disorder monitoring contracts vary from state to state, but most require participation in an individualized treatment plan and structured monitoring for a minimum of 3 years. Treatment includes individual psychotherapy, recommended medications (e.g., naltrexone), and attendance at AA or Caduceus meetings. Monitoring includes periodic meetings with physician health

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program staff, regular observation by and meetings with professional colleagues at the workplace (including an agreement to notify the program if they observe any concerning or unusual behaviors), periodic structured self-reports, and random laboratory testing for alcohol and drugs. Physicians recovering from addiction report that assistance with recovery is the most important component of state monitoring programs (Knight et al. 2002). The monitoring contracts stipulate that violation of the terms of the contract, which may be relapse to use of psychoactive substances, treatment noncompliance, or both, will be reported to the state licensing agency, department chairs, hospital administrators, and others with administrative authority over the physician. Conversely, physician health programs provide advocacy for compliant physicians with hospitals, credentialing, and regulatory agencies as needed to allow for a safe and timely return to medical practice. Physician health programs often require completion of a structured treatment program as the first step in the contract process.

SPECIAL ISSUES FOR MONITORED PHYSICIANS Disclosure Physicians who are monitored by state physician health programs may need guidance on when and to whom to disclose their status and how much information to disclose. Most physician health programs comply with federal confidentiality rules and will not disclose any information without specific 42 CFR Part 2–compliant, signed release forms. Some, including the Massachusetts Physician Health Services (PHS) program, function under peer-review protection, which offers an additional layer of protection against disclosure of confidential information. Nonetheless, monitored physicians will encounter situations in which they are asked to disclose their own past substance-related treatment or monitoring contract information as part of a hiring, credentialing, or licensing application form. The question often arises in a hiring situation, for example, as to when such a confidential disclosure should be made to minimize the chances of discrimination on the basis of having a substance-related disorder. In general, we advise physicians to answer all direct questions honestly but to try to avoid making a disclosure of confidential information until a face-to-face interview and to delay the disclosure until they are sure that they are genuinely interested in the position being offered. When the physician is making the disclosure, we suggest that he or she quickly give the basic facts (e.g., "I want you to know that I have a history of abusing prescription drugs"), then move quickly to a description of what he or she has done about it (e.g., "I entered into an intensive treatment program for physicians and completed the 3-month stay. Immediately after completing the program, I signed a monitoring contract with the state physician health program, and I have done everything they required and more"), and end with a description of how the experience has changed him or her (e.g., "Since completing treatment, I have been completely free from any use of alcohol or drugs, and I have a new and better understanding of myself and others; it has made me a better physician"). Physicians with substance use disorders should consult with an attorney before completing medical license applications or other forms that include ambiguous questions about past use of substances, treatment, and monitoring.

Illnesses Monitored physicians may need to interrupt laboratory testing because of illnesses, and states vary in their requirements for authorizing medical leaves from testing. Treatment of certain illnesses, such as ADHD, anxiety disorders, and those associated with chronic pain, also create special challenges for state programs and monitored physicians. State programs require physicians to abstain completely from use of all drugs and alcohol, including both illicit drugs and psychoactive prescription drugs. Most monitoring contracts include provisions that allow physicians to receive treatment for a legitimate medical problem with stimulant medications, tranquilizers, and narcotic analgesics as long as the prescription is written by a usual treating physician who is aware of the monitoring contract and the contracting physician provides the program with a copy of the prescription. These precautions are included because programs tend to view even legitimate use of psychoactive medications as creating a high risk for relapse at best and as drug-seeking behavior at worst. In addition, it is very difficult to monitor physicians who require

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such medications for long periods of time. Chronic pain patients, for example, will have positive urine test results for opioids, and it is virtually impossible to differentiate by laboratory test alone those physicians who take their medications as directed from those who abuse them. Nonetheless, ample evidence indicates that those with co-occurring substance use disorders and ADHD can safely take stimulant medications (Levin et al. 2006, 2007; Riggs et al. 2004; Schubiner et al. 2002) and that those with co-occurring substance use disorders and chronic pain can safely take narcotic analgesics (Dunbar and Katz 1996; Jamison et al. 1998; Jovey et al. 2003; Kennedy and Crowley 1990). Physicians being monitored for recovery from substance use disorders should not lose their right to receive effective treatment for mental disorders or relief from chronic pain. However, we recommend that physicians undergoing monitoring take simple precautions when a co-occurring illness requires treatment with a psychoactive drug: 1) have one prescribing physician and one pharmacy where all prescriptions are filled, 2) allow open communication among all treating physicians (primary care and specialists), 3) fully disclose to treating physicians the history of substance misuse and terms of the monitoring contract, 4) discuss treatment with a therapist who is knowledgeable about substance use disorders and an AA or Caduceus sponsor, and 5) take psychoactive medications exactly as prescribed at set intervals and avoid as-needed dosages.

PROGNOSIS Physicians treated and monitored for substance use disorders have high rates of success, as confirmed by several published reports (Table 43–3). Nonetheless, most published studies are neither blinded nor case-controlled and include small samples of physicians drawn from a single state. Furthermore, in reviewing some of the published reports (Crowley 1986; Gallegos et al. 1992; Geyser 1988; Gualtieri et al. 1983; Morse et al. 1984; Reading 1992; Shore 1987; Smith and Smith 1991; Vogtsberger 1984), the studies were inconsistent with one another about basic issues such as what constitutes success and the length of time physicians were followed. Some studies defined success as the physician being able to return to work; others defined success as complete abstinence from alcohol or drugs; and still others allowed for a brief relapse. The follow-up intervals in these published reports varied from as little as 5 months to as long as 9 years. In our experience, physicians often have a brief relapse once or twice prior to maintaining a substantial period of abstinence, so that a better measure of success might require a longer rather than a shorter period of observation. Table 43–4 presents the 3- to 5-year outcomes of substance use disorder monitoring contracts in the Massachusetts PHS program (Knight et al. 2007). PHS defines success as complete and continuous abstinence from any use of alcohol or other drugs as indicated by weekly random urine tests, quarterly self-reports, and collateral reports from professional colleagues and supervisors. The overall success rate of the PHS program was 75%, but first contracts had a success rate of only 56%, and second and third contracts had success rates of only 27% and 32%, respectively. These data indicate that a substantial proportion of physicians participating in the PHS program experience early relapses but eventually go on to complete a 3-year monitoring program successfully (Knight et al. 2007). However, compared with men, women had significantly shorter time to first relapse (log-rank test for equality of survival distribution, P = 0.001). This finding is of great concern, especially considering a recent report of high suicide rates among women physicians (Knight et al. 2007; Schernhammer 2005). More attention should be given to gender-specific treatment and monitoring services within state monitoring programs. Most other published studies of physician treatment and monitoring programs report success rates in the 75%–85% range. These rates are far higher than those reported for general treatment populations (Baggaley and Morgan-Jones 1993; Eklund et al. 1994; Noda et al. 2001). We attribute these high success rates to the highly structured programs that physicians enter when they sign monitoring agreements, as well as early and aggressive intervention in the face of relapse. Another factor is likely the high cost of failure (e.g., loss of medical license, loss of income, public embarrassment), and conversely the significant reward for maintaining sobriety (i.e., ability to continue in medical practice).

LEGAL CONSIDERATIONS

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Some important legal considerations should be kept in mind when addressing physician substance use. In many states, individual physicians and health care organizations are required to report a physician to the licensing board if they have reasonable suspicion that the physician is impaired by alcohol or another drug. (Massachusetts health care providers are also required to report physicians whose ability to practice medicine safely has been compromised by physical disabilities or mental instability.) In Massachusetts, this reporting requirement exists regardless of whether the physician's work performance is impaired and extends to those physicians who are "habitually drunk" or who have "been addicted to, dependent on, or a habitual user of narcotics, barbiturates, amphetamines, hallucinogens, or other drugs having similar effects" (Massachusetts Board of Registration in Medicine 2007). Failure to report such a physician can result in sanctions against the individual physicians or health care facilities who failed to make the report. Many states allow for a confidential referral to a physician health program instead of a report to the licensing board. This is commonly referred to as a diversion program, and in states where this provision exists, the diversion program should be preferentially used. Doing so allows the physician with the substance use disorder the possibility of obtaining much needed help without immediate fear of the legal and professional difficulties that can arise when the licensing board becomes involved. If the physician refuses to enter the diversion program, then most states require that the licensing board be notified about the physician. Some physicians who misuse substances engage in illegal acts to procure their drug(s), whether through self-prescribing, diverting stock medications for their own use, stealing medications from patients, prescribing for fictional patients or family members, or purchasing drugs through the Internet or on the street. In these situations, we strongly urge physicians to obtain legal counsel early, preferably from an attorney who is experienced in dealing with physicians, hospitals, and state boards of medicine as well as the police, prosecuting attorneys, and the U. S. Drug Enforcement Administration. Obtaining an attorney who both knows these agencies and is licensed in the state where the alleged offenses occurred is essential. We have witnessed a few physicians who have wasted money employing attorneys who knew little of these issues or who were out-of-state and unfamiliar with the local licensing board's rules, regulations, and usual practice. Another legal consideration is whether to self-report information to the state licensing board about a possible infraction of their rules or some other wrongdoing. Recovered physicians should be judicious about what they report to the licensing board, but they should never withhold information or lie. This constitutes perjury and, when discovered, invariably leads to a disciplinary procedure and harsher treatment than if the physician had been truthful with the board in the first place. We strongly recommend that physicians consult with an attorney before making any self-report to the licensing board and before completing license renewal or other credentialing forms and questionnaires.

ETHICAL CONSIDERATIONS In addition to legal concerns, several ethical issues arise when dealing with medical colleagues who are or might be misusing substances. Ethical dilemmas arise when basic principles are in conflict with one another. For example, we have a duty in general to respect the autonomy of others, but in the case of someone who is actively misusing psychoactive substances, honoring this duty can result in harm. If we decide, for example, that someone's behavior is dangerous enough to warrant a forced intervention, our prima facie duty to respect the autonomy of others is outweighed by other competing principles —namely, those of beneficence (defined as "doing good") and nonmaleficence (alternatively defined as "preventing harm" or "not inflicting harm on others"). The potential tension between beneficence and nonmaleficence might be especially pronounced when we are not certain about a physician's behavior and when it might not be clear how best to proceed such that one does good and prevents as much harm as possible to all parties involved (including the physician, his or her family, and his or her patients). We have certainly witnessed interventions in ambiguous cases that resulted in public scrutiny, loss of professional income, jeopardized housing, and

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sudden deprivation of a panel of patients of their treating physician. At times, it is difficult to conclude that, all things considered, good had been accomplished. That said, one cannot know in these circumstances what harm might have resulted if the intervention had been postponed and the physician were allowed to continue to misuse alcohol or drugs. We have seen other cases in which inaction led to greater harm to family members and patients, incarceration of the physician, or the death of the physician. Physicians are not usually trained to observe and evaluate fellow physicians. Our objectivity when dealing with fellow physicians might be compromised. Also, with a colleague, it might be more difficult to draw a line between casual use and abuse, or even dependence. There are many "slippery slopes" in medicine, and we might be tempted to give our colleagues the benefit of the doubt (compared with our patients) and avoid confrontation. Others might raise legitimate concerns that in forcing an intervention on someone, we are acting paternalistically. Furthermore, especially in those situations in which physicians are working in the same clinic or practice, the referring physician should be reasonably concerned that his or her motives might at times be impure. Bringing a colleague down in some manner might serve to improve our own standing in some way—such as by increasing our own patient panel or improving our status within our medical institution. Can a physician be certain about the purity of his or her motivations when confronting a colleague?

PREVENTION What strategies might be used to try to prevent substance misuse before it begins? Given the number of physicians with substance use disorders who reported that their problem began when they were attempting to treat themselves for a medical problem (or psychological problem), our first recommendation for prevention is that all physicians should have a primary care physician and never self-prescribe. We also recommend that, except in true emergencies, physicians not prescribe for their immediate family members. When either self-treating or treating one's immediate family, there is too much potential for poor judgment and an appearance of wrongdoing. In many states, prescribing for self and family is prohibited or tightly regulated by the licensing board. In Massachusetts, for example, physicians are prohibited from prescribing Schedule II drugs for immediate family members and Schedule II–IV drugs for themselves. Physicians also should make their own wellness a high priority. Engaging in hobbies apart from medicine, regularly participating in recreational activities, attending social events, and taking vacations are all important determinants of health and well-being. We also recommend that physicians seek appropriate care for medical or psychiatric problems as soon as they arise. The same applies to misusing substances. A clinician who believes that he or she might have a problem in any of these areas should obtain an evaluation at the earliest possible opportunity. Physicians who are healthier are better doctors across many measures: they are more likely to counsel their patients against smoking, to exercise regularly, to eat a healthy diet, and to drink in moderation if at all (Abramson et al. 2000; Frank et al. 2003). They also create and maintain better working environments for those around them.

CONCLUSION Physicians are not immune to substance use disorders and have prevalence rates of substance abuse and dependence that are similar to those of the general population. Unlike the general population, however, physicians are much more likely to misuse prescription drugs and to do so for reasons of self-treatment. Impairment resulting from psychoactive substance use causes risk to the physician and his or her family, professional colleagues, and patients. Early intervention is needed, and the best approach is one that is highly structured and that leads to an independent evaluation with a required report back. Residential programs of 2–4 months in duration are often recommended, but controversy exists as to whether this level of intensity is needed in all cases. Aftercare plans should include monitoring by the state physician health program, and these programs have high rates of success. Help is available, and it works.

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KEY POINTS The term impaired physician historically referred not only to physicians with substance use disorders but also to those with medical, psychiatric, or behavior disorders that impede the ability to practice medicine safely and effectively. This term is now considered archaic and should be replaced by more accurate, less pejorative language. Physicians are vulnerable to substance abuse and dependence at rates comparable to those of nonphysicians. Signs and symptoms of a substance use disorder often present first at home and other nonprofessional settings. When problems manifest themselves in the medical workplace, the substance use usually has been occurring for years. The effect of a physician's substance misuse can extend far beyond the personal toll on the physician and may extend to professional colleagues, patients, and family members. Early intervention for or prevention of physician substance misuse is vitally important. Dealing with a colleague who has a substance use disorder often requires consideration of both legal and ethical issues. Every state in the United States has a physician health program. State physician health programs provide or facilitate independent assessments for physicians with substance use disorders, provide guidance to hospital administrators and physician health committees, and contract with physicians who agree to treatment and complete abstinence from alcohol and drug use to provide monitoring and advocacy. Physicians in monitoring programs should not be deprived of appropriate treatment for other psychiatric disorders or pain. Stimulant medications, tranquilizers, and narcotic analgesics can be safely prescribed with appropriate safeguards and open communication among all treating physicians. The success rates for physicians who undergo substance abuse treatment are quite high, with most programs reporting positive outcomes in the 75%–85% range. Recovering physicians should consult with an attorney before making a self-report to the state licensing board and when answering confidential health-related questions on license renewal, job application, and hospital or insurance credentialing forms.

REFERENCES Abramson S, Stein J, Schaufele M, et al: Personal exercise habits and counseling practices of primary care physicians: a national survey. Clin J Sport Med 10:40–48, 2000 [PubMed] American Medical Association: Federation of State Physician Health Programs. 2003. Available at: http://www.fsphp.org. Accessed January 4, 2004 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision. Washington, DC, American Psychiatric Association, 2000 Baggaley MR, Morgan-Jones D: Long-term follow up study of military alcohol treatment programme using post-treatment career as an outcome measure. J R Army Med Corps 139:46–48, 1993 [PubMed] Blondell RD: Impaired physicians. Prim Care 20:209–219, 1993 [PubMed] Brewster J: Prevalence of alcohol and other drug problems among physicians (review). JAMA 255:1913–1920, 1986 [PubMed] Brooke D, Edwards G, Taylor C: Addiction as an occupational hazard: 144 doctors with drug and alcohol problems. Br J Addict 86:1011–1016, 1991 [PubMed] Centrella M: Physician addiction and impairment—current thinking: a review. J Addict Dis 13:91–105, 1994 [PubMed]

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Clare AW: The alcohol problem in universities and the professions. Alcohol Alcohol 25:277–285, 1990 [PubMed] Comerci GD, Schwebel R: Substance abuse: an overview. Adolesc Med 11:79–101, 2000 [PubMed] Crowley TJ: Doctors' drug abuse reduced during contingency-contracting treatment. Alcohol Drug Res 6:299–307, 1986 Dunbar SA, Katz NP: Chronic opioid therapy for nonmalignant pain in patients with a history of substance abuse: report of 20 cases. J Pain Symptom Manage 11:163–171, 1996 [PubMed] DuPont R, Griffin D, Siskin B, et al: Random drug tests at work: the probability of identifying frequent and infrequent users of illicit drugs. J Addict Dis 14:1–17, 1995 [PubMed] Eickelberg SJ, Mayo-Smith MF: Management of sedative-hypnotic intoxication and withdrawal, in Principles of Addiction Medicine, 2nd Edition. Edited by Graham AW, Schultz TK, Wilford BB. Chevy Chase, MD, American Society on Addiction Medicine, 1998, pp 441–455 Eklund C, Melin L, Hiltunen A, et al: Detoxification from methadone maintenance treatment in Sweden: long-term outcome and effects on quality of life and life situation. Int J Addict 29:627–645, 1994 [PubMed] Frank E, Bhat Schelbert K, Elon L: Exercise counseling and personal exercise habits of US women physicians. J Am Med Womens Assoc 58:178–184, 2003 [PubMed] Gallegos KV, Lubin BH, Bowers C, et al: Relapse and recovery: five to ten year follow-up study of chemically dependent physicians—the Georgia experience. Md Med J 41:315–319, 1992 [PubMed] Geyser MR: The impaired physician: the Arizona experience. Fed Bull 75:77–80, 1988 [PubMed] Gualtieri AC, Consentino JP, Becker JS: The California experience with a diversion program for impaired physicians. JAMA 249:226–229, 1983 [PubMed] Hughes PH, Brandenburg N, Baldwin DC Jr, et al: Prevalence of substance use among US physicians. JAMA 267:2333–2339, 1992; erratum in JAMA 268:2518, 1992 [PubMed] Hughes PH, Storr CL, Brandenburg NA, et al: Physician substance use by medical specialty. J Addict Dis 18:23–37, 1999 [PubMed] Jamison RN, Raymond SA, Slawsby EA, et al: Opioid therapy for chronic noncancer back pain: a randomized prospective study. Spine 23:2591–2600, 1998 [PubMed] Jovey RD, Ennis J, Gardner J, et al: Use of opioid analgesics for the treatment of chronic noncancer pain—a consensus statement and guidelines from the Canadian Pain Society 2002. Pain Res Manage 8:3A–14A, 2003 Kennedy JA, Crowley TJ: Chronic pain and substance abuse: a pilot study of opioid maintenance. J Subst Abuse Treat 7:233–238, 1990 [PubMed] Knight JR, Sanchez LT, Sherritt L, et al: Monitoring physician drug problems: attitudes of participants. J Addict Dis 21:27–36, 2002 [PubMed] Knight JR, Sanchez LT, Sherritt L, et al: Outcomes of a monitoring program for physicians with mental and behavioral health problems. J Psychiatr Pract 13:25–32, 2007 [PubMed] Leshner AI: Addiction is a brain disease, and it matters [see comments]. Science 278:45–47, 1997 [PubMed] Levin FR, Evans SM, Brooks DJ, et al: Treatment of methadone-maintained patients with adult ADHD: double-blind comparison of methylphenidate, bupropion and placebo. Drug Alcohol Depend 81:137–148, 2006 [PubMed]

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Levin FR, Evans SM, Brooks DJ, et al: Treatment of cocaine dependent treatment seekers with adult ADHD: double-blind comparison of methylphenidate and placebo. Drug Alcohol Depend 87:20–29, 2007 [PubMed] Mansky PA: Physician health programs and the potentially impaired physician with a substance use disorder. Psychiatr Serv 47:465–467, 1996 [PubMed] Massachusetts Board of Registration in Medicine: 243 Code of Massachusetts Regulations. 2007. Available at: http://www.massmedboard.org/regs/243cmr.htm. Accessed January 27, 2007 McAuliffe WE, Rohman M, Wechsler H: Alcohol, substance use, and other risk-factors of impairment in a sample of physicians-in-training. Adv Alcohol Subst Abuse 4:67–87, 1984 [PubMed] Morse RM, Martin MA, Swenson WM, et al: Prognosis of physicians treated for alcoholism and drug dependence. JAMA 251:743–746, 1984 [PubMed] Noda T, Imamichi H, Kawata A, et al: Long-term outcome in 306 males with alcoholism. Psychiatry Clin Neurosci 55:579–586, 2001 [PubMed] Pfifferling JH: Managing the unmanageable: the disruptive physician. Fam Pract Manag 4:76–78, 83, 87–92, 1997 Physician Health Services: How to make a referral to PHS. 2003. Available at: http://www.massmed.org/phs/referral.html. Accessed June 29, 2004 Reading EG: Nine years experience with chemically dependent physicians: the New Jersey experience. Md Med J 41:325–329, 1992 [PubMed] Riggs PD, Hall SK, Mikulich-Gilbertson SK, et al: A randomized controlled trial of pemoline for attentiondeficit/hyperactivity disorder in substance-abusing adolescents. J Am Acad Child Adolesc Psychiatry 43:420–429, 2004 [PubMed] Schernhammer E: Taking their own lives—the high rate of physician suicide. N Engl J Med 352:2473–2476, 2005 [PubMed] Schubiner H, Saules KK, Arfken CL, et al: Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 10:286–294, 2002 [PubMed] Shore JH: The Oregon experience with impaired physicians on probation. JAMA 257:2931–2934, 1987 [PubMed] Skipper GE: Treating the chemically dependent health professional. J Addict Dis 16:67–73, 1997 [PubMed] Smith PC, Smith JD: Treatment outcomes of impaired physicians in Oklahoma. J Okla State Med Assoc 84:599–603, 1991 [PubMed] Vogl W: Urine Specimen Collection Handbook for Federal Workplace Drug Testing Programs (DHHS Publ No SMA-96-3114). Rockville, MD, Center for Substance Abuse Prevention, Substance Abuse and Mental Health Services Administration, 1996 Vogl WF, Bush DM: Medical Review Officer Manual for Federal Workplace Drug Testing Programs (DHHS Publ No SMA-97-3164). Rockville, MD, Center for Substance Abuse Prevention, Substance Abuse and Mental Health Services Administration, 1997 Vogtsberger KN: Treatment outcomes of substance-abusing physicians. Am J Drug Alcohol Abuse 10:23–37, 1984 [PubMed] Wise RA: Addiction becomes a brain disease. Neuron 26:27–33, 2000 [PubMed]

SUGGESTED READING

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Dilts SJ, Gendel MH: Substance use disorders, in The Handbook of Physician Health: The Essential Guide to Understanding the Health Care Needs of Physicians. Edited by Goldman LA, Myers M, Dickstein LJ. Chicago, IL, American Medical Association, 2000, pp 118–137 Talbott GD, Gallegos KV, Angres DH: Impairment and recovery in physicians and other health professionals, in Principles of Addiction Medicine, 2nd Edition. Edited by Graham AW, Schultz TK, Wilford BB. Chevy Chase, MD, American Society of Addiction Medicine, 1998, pp 1263–1280 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 44. Gay Men and Lesbians

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Robert Paul Cabaj: Chapter 44. Gay Men and Lesbians, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.357658. Printed 1 0/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Gay Men and Lesbians Robert Paul Cabaj, M.D.

GAY MEN AND LESBIANS: INTRODUCTION Gay men and lesbians, as well as bisexual men and women and transgender people, require a special consideration in any literature focused on substance use, abuse, and treatment. Gay men and lesbians (the groups most studied) have higher rates of alcohol use and drug use than the general population, have higher rates of mood and anxiety disorders, and may respond best to gay-sensitive and gay-affirmative treatments. In addition, gay men are more likely to use and abuse "club drugs" and, in particular, methamphetamine—the use of which in some cities is described as at epidemic or crisis levels. Furthermore, risky behaviors, such as unprotected anal intercourse or sharing needles, that expose people to HIV and AIDS often occur under the influence of alcohol and drugs, so gay men who use such drugs may be at greater risk. Finally, transgender people—although not as well studied—seem to have very high rates of substance use and will need specific help when entering treatment. The literature on substance use and abuse among gay men and lesbians is extensive and continues to grow. The focus has been mainly on the following areas: the extent of the use or abuse; the psychodynamic, psychological, and emotional issues related to substance use and abuse; the association with exposure to HIV; the explosive use of methamphetamines; health needs of transgender individuals; and clinical interventions. Bisexual men are included in some studies, but very little literature is available specifically on bisexual women. A homosexual or bisexual sexual orientation is not a mental illness or psychopathology. Understanding the variations of sexual orientation and the range of adjustments individuals and society in general have to sexual orientation is as important as understanding the influence and importance of culture, ethnicity, race, and gender on the psychological development of a person and the way substance abuse issues may be shaped or express themselves. The study of sexual orientation is therefore not a study of pathology but of the various ways people adjust to differences that are not always well accepted or tolerated by most people.

A SHORT REVIEW OF THE MODERN UNDERSTANDING OF SEXUAL ORIENTATION This chapter is written with the assumption that the reader has a basic understanding of modern thinking about sexual orientation and some understanding of the lives of gay men and lesbians. This brief section reviews the evolution of current thinking. In 1973, the American Psychiatric Association's (APA's) Board of Trustees—after extensive scientific review, debate, and analysis of research undertaken by the National Institutes of Health—removed homosexuality per se as a mental illness from DSM-II (American Psychiatric Association 1968; Bayer 1987). Homosexuality is now seen as normal variation of human sexual and affectional (loving) expression; sexual orientation is a complex phenomenon with many variations along a spectrum of heterosexuality to homosexuality. A nonpathological view of homosexuality as well as homosexual and bisexual men and women removed the stigma of mental illness and opened up vast areas of study, research, hypothesis, and knowledge about sexual orientation itself, the expression of sexual desire, and the psychological and social forces that influence the lives of people with homosexual and bisexual sexual orientations, including the nature of bias and prejudice resulting from intolerance to differences.

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Historically, homosexuality as a specific category was not described in the medical or psychiatric literature until the early 1870s. Psychiatry and the fledgling psychoanalytic movement made homosexuality a topic of special interest and focus. Although Freud himself did not consider homosexuality a mental illness (E. Freud 1960), his writing on the subject was extensive and at times contradictory (S. Freud 1920/1955; Lewes 1988). European and American psychoanalysts published articles and books about homosexuality and gay men (and lesbians to a much more limited extent) into the 1970s, almost all assuming homosexuality was psychopathological and looking for causes, such as the way mothers raised their sons or fears gay men might have of the opposite sex (Bieber et al. 1962; Deutsch 1932; Fenichel 1945; Radó 1969; Socarides 1978). The change in viewing homosexuality as a normal variation of human sexual expression began with the famous Kinsey studies that examined sexual behavior of men and women in America, noting much more frequent homosexual sexual acts than anyone had ever imagined, such as 37% of males having at least one homosexual experience to orgasm between adolescence and old age (Kinsey et al. 1948, 1953). Even though the surveys were of only behavior, they led to studies of sexual orientation itself as well as of gay men, lesbians, and bisexual people. Evelyn Hooker (1957) is credited with one of the first studies to show no psychological differences between gay men and matched heterosexual men, and she went on to lead the APA's efforts to evaluate the research that supported the APA's diagnostic change. The psychoanalytic literature began to reflect these new perspectives, with a pioneering psychoanalytic review in 1986 that not only critiqued past thinking but also proposed some new approaches based on cross-cultural, biological, and newer psychoanalytic approaches, including object relations and other theories (Friedman 1986). Literature by Isay (1989), Drescher (2001), and many other psychoanalysts and other mental health professionals since have helped reshape the focus to the issues that gay men and lesbians face in society because of their differing sexual orientation rather than the assumption of a psychopathological orientation. The APA has remained in the lead with books and articles that reflect the new understanding (Cabaj and Stein 1996). Lesbians also have received more direct study and review than in the past (Magee and Miller 1997). It seems clear that people do not choose a sexual orientation; it is somehow "built in" (Bell et al. 1981). What "causes" one's sexual orientation is a common focus of study, but literature also looks at the effects of antigay bias and internalized homophobia, as is discussed later in this chapter. The biological studies, for the most part, seem to grow out of the confusion between sexual orientation and gender identity—most studies have tried to show some physical trait in gay men that must be like that of women, and vice versa for lesbians, because of the prejudicial view that if a man wishes to be with a man, he must somehow be like a woman, and a woman wishing to be with a woman must in some way be like a man. The biological studies to date have been inconclusive (Pillard 1998). Familial studies have shown some promise in understanding the origins of sexual orientation and are discussed later in this chapter (Pillard 1996). Combined with other studies on twins and heritability (Whitam et al. 1993), this body of research helps underline the probable genetic substrate of sexual orientation in all people, with different genetic influences for male homosexuality, male heterosexuality, female homosexuality, female heterosexuality, and, possibly, even for bisexuality. Although a complex set of behaviors and feelings such as those seen with homosexuality could not be explained by any single factor, the genetic basis may be the foundation on which other biological, familial, and societal influences work to shape the development and expression of sexual orientation in adult men and women.

EPIDEMIOLOGY OF SUBSTANCE USE AND ABUSE BY GAY MEN AND LESBIANS Research continues on the extent of alcohol and other substance use (including nicotine) and the incidence of substance abuse in the gay and lesbian population. Most studies, some focused on just men, some on just women, and some on gay youths (Corliss et al. 2006; Diamond and Wilsnack 1978; Drabble et al. 2005; Gruskin and Gordon 2006; Gruskin et al. 2001; Guss and Drescher 2000; Hall 1993;

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Hughes 2003, 2005; Lewis et al. 1982; Lohrenz et al. 1978; McKirman and Peterson 1989a; Mosbacher 1988; Pillard 1988; Saghir and Robins 1973; Skinner 1994; Ziyadeh et al. 2007); reviews of surveys (Hughes and Wilsnack 1997; Weinberg and Williams 1974); and the experiences of most clinicians working with gay men and lesbians (Cabaj 1997; Finnegan and McNally 1987) estimate an incidence of substance abuse of all types at approximately 30%, with ranges of 28%–35%. This estimate contrasts with an incidence of 10%–12% for the general population. The higher rates seem to hold across age ranges as well as different cultural and ethnic backgrounds for gay men and lesbians, although different substances may be used by different populations (Grov et al. 2006; Hughes et al. 2006). The numerous studies and reports varied in quality, however; some had significant methodological problems, including poor or absent control groups, unrepresentative population samples (some studies gathered subjects from only gay and lesbian bars), or a failure to use uniform definitions of substance abuse or of homosexuality itself. One major problem in studies that attempt to determine prevalence and incidence of substance use or abuse among gay and lesbian people is the limited data on the actual numbers of gay people. Because of stigma and fear, gay people may not be forthcoming about their sexual orientation in surveys and studies, and the actual percentage of gay people in the population is not clear. Nonetheless, regardless of where the sample was taken—urban or rural, various socioeconomic settings, in the United States or other countries—the rates of substance use were strikingly uniform, but some variation was reported. For example, Stall and Wiley (1988) used very simple screening questions and noted greater substance use but no greater alcohol use among gay men as compared with heterosexual men in San Francisco, California. McKirman and Peterson (1989a) reported that heavy alcohol use was not greater for gay men and lesbians than for heterosexual persons sampled but did note that fewer gay men and lesbians abstained from alcohol use, and a greater number of gay men and lesbians were moderate alcohol users. Transgender people are benefiting from increasing research about health and risk issues. Studies seem to indicate that substance use is even higher in this population (the rate is reported as high as 60% in some studies [Seil 1996; Skidmore et al. 2006]), so a review of substance use and abuse with all transgender people is essential for a complete assessment of behavioral health needs. In addition, transgender people may experience higher rates of depression and suicidality, may be greater victims of violence, have limited access to health care, and place themselves at higher risk in sexual situations and therefore have higher rates of HIV infection and AIDS compared with those in the general population (Clements-Nolle et al. 2001; Fitzpatrick et al. 2005). Alcohol abuse has been the focus of most studies of gay people. Club drug and methamphetamine use has begun to dominate the literature, reflecting the heavier use, especially by gay men, since the early 1990s (Goode and Troiden 1979; Green and Halkitis 2006; Halkitis and Palamar 2006; Kelly et al. 2006; Klitzman 2006; Klitzman et al. 2000; Lampinen et al. 2006; Parsons et al. 2006; Shoptaw 2006; Wainberg et al. 2006).

FACTORS THAT CONTRIBUTE TO THE PREDISPOSITION TO SUBSTANCE USE AND ABUSE Many factors contribute to the prominent role of substance use and abuse in gay men and lesbians. Many years ago, some psychoanalysts postulated that homosexuality was a cause of alcoholism (Israelstam and Lambert 1983). Current thinking focuses on several factors: genetics; biological contributions; and the psychological effects of heterosexism (an ideological system that denies, ignores, denigrates, or stigmatizes any nonheterosexual form of emotional and affectional expression, sexual activity, behavior, relationship, or socially identified community) and homophobia, both internal (selfloathing, fear, or resistance to accepting and expressing sexual orientation by gay men, lesbians, and bisexual persons) and external, which is better described as antigay bias (fear and loathing of gay men and lesbians or of homosexuality itself).

Biological and Social Factors

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In looking at the etiology of sexual orientation, growing evidence indicates that homosexual orientation may have genetic, biological, and biochemical components (Bailey and Benishay 1993; Bailey and Pillard 1991; Pillard 1988, 1998; Pillard and Weinrich 1986; Pillard et al. 1982). In addition, some of these studies (Pillard 1988; Pillard et al. 1982) found that gay men have a greater than normal chance of having an alcoholic father (and a mother with mood disorders). Parallel research supports the genetic, biological, and biochemical contributions to substance use disorders. Perhaps there may be some genetic links? The possibility seems unlikely, however. The aforementioned familial studies and others (Bell and Weinberg 1978; Bell et al. 1981) imply that the genetics of male and female homosexuality are different, yet rates of substance abuse are the same for gay men and lesbians. (The familial studies indicate that a gay male is much more likely to have a gay male brother compared with the rates expected in the general population but no more likely to have a lesbian sister, and the opposite is true for lesbians—they are more likely to have a lesbian sister but no more likely to have a gay brother [Pillard 1996].) Societies or cultures in turmoil or undergoing social change have higher rates of alcoholism (Cassel 1976; Vaillant 1983). Gay men and lesbians continue to face great societal stress from factors such as antigay discrimination, limited social acceptance, struggles over legally recognized relationships or marriage, and job protection. Continuing societal antigay bias, risk of verbal and physical attacks, the effect of HIV on gay men and lesbians, and ongoing internalized homophobia for some further add to the stress—and may help explain the higher drug and alcohol use as well as the higher rates of suicidal behaviors seen among gay men and women (see the "Suicidality" subsection in this chapter) (Amadio 2006; Israelstam and Lambert 1989; McKirman and Peterson 1989b; Nawyn et al. 2000; Noell and Ochs 2001). Such societal bias over the years caused most gay people to adopt a "ghetto mentality," creating their own social fabric and outlets, including neighborhoods and towns that may be more welcoming and comfortable to live in and visit. The social outlets available to gay men and lesbians, however, tend to be bars, private homes, clubs, gay-travel programs, and organized parties known as "circuit parties" during which alcohol and other drugs (especially club drugs such as methylenedioxymethamphetamine [MDMA; "ecstasy"], -hydroxybutyrate [GHB], nitrate inhalants [known as "poppers"], and ketamine) play a prominent role. Some alcohol- and drug-free alternatives such as coffeehouses, bookstores, and clean-and-sober clubs cater to gay men, lesbians, and bisexual persons, but gay bars are still the most recognized place for gay people to meet or visit when coming to a new town. People just coming out as gay or lesbian may only know about gay bars, and their use of alcohol and drugs may be influenced by meeting someone there who uses or abuses alcohol and drugs.

Gay Identity Formation Exploration of the links between the use or abuse of substances and gay identity formation may help explain the process by which many gay people turn to alcohol and drug use. Most gay people have internalized homophobia because they are brought up in a society that is, to varying degrees, antigay. The coming-out process may be delayed or very difficult to negotiate, depending on the intensity of internalized homophobia. The gay person may believe—influenced by familial, religious, cultural, and local societal factors—that homosexuality is a sin, an illness, unnatural, or evil or that it will lead only to sadness, loneliness, and isolation. Identity development as a gay or lesbian person, and the concomitant coming-out phenomena, is a complex process that continues throughout the entire life cycle and has been formulated in various ways (Cass 1996; Coleman 1982; de Monteflores and Schultz 1978; Hanley-Hackenbruck 1988; McDonald 1982). Coming out is easiest to understand as a series of steps an individual negotiates at his or her own time and pace. First, the individual becomes aware that his or her own sexual orientation is different from that of the majority. Second, that person can accept the difference and begin to integrate it into a self-concept, including grappling with the negative feelings that may be associated. Third, the individual may choose to act on these feelings (although some people with strong homoerotic feelings never

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engage in sexual intercourse with others of the same sex). Finally, the person makes a series of lifelong decisions about whether to let others know and whom to let know. The psychology of difference—learning to live in a society that does not accept difference readily —shapes the identity development of many children who will grow up to be gay or lesbian. De Monteflores (1996), in particular, described how difficult it is to grow up different. A person of color cannot hide skin color, and the difference is obvious to all, but a person with a homosexual orientation, while aware of being different, may not be recognized as different by anyone else. In a society that promotes and supports heterosexuality, the sense of difference in these children may be confusing and alienating, leading to social isolation and denial of natural feeling. For those children who are gender discordant in behavior (i.e., who act more like the opposite sex in terms of gender role expectations), self-esteem and other aspects of the personality may be profoundly damaged from being shunned, humiliated, and derided by their peers (Hanson and Hartmann 1996). The vast majority of parents of gay men and lesbians are heterosexual and raise their children either assuming that they will be heterosexual or not thinking about their sexual orientation at all. For the pregay or prelesbian child (i.e., the child who will grow up to be gay or lesbian), the difference between internal feelings and parental expectations may create a major psychological challenge. The child who will grow up to be gay or lesbian wants the love and acceptance of his or her parents and other caregivers. If the parents cannot respond to or give support for what is unfamiliar or uncomfortable for them, they will either ignore those attributes of the child that suggest difference or try to change them. This rejection and criticism, both real and perceived, leads to pain, denial, isolation, and fear. As a coping mechanism, pregay or prelesbian children commonly learn to disconnect and dissociate from their true selves and sexual orientation and adapt to parental expectations by creating and presenting a "false self" or an internal identity that is not a genuine reflection of the true nature and feelings. For the gay child, that awareness of being different—having affectional and sexual longings that are different from those of the others around him or her—is usually evident quite early in life, especially in men. Alice Miller's (1981, 1984) description of parents who form, and deform, the emotional lives of their talented or different children has strong parallels with the development of many gay children. Parental reactions help to shape and validate the expression of the needs and longings of their children because parents more frequently reward what is familiar and acceptable to them and tend to discourage or deemphasize behavior and needs they do not value or understand. Harm occurs when a parent is too depressed, preoccupied, narcissistic, or under the influence of drugs or alcohol to respond to the actual needs and wants of the child. Children eventually learn to behave the way parents expect and to hide or deny the longings or needs that are not rewarded. Dissociation and denial may become major defenses in the personality structure of such children because they learn early that their feelings and needs are not acceptable and must be hidden and suppressed. Thus, the psychological effects of being different profoundly shape the way sexual identity develops and then is expressed by gay people as they emerge from childhood. In addition, these children are unlikely to have clear and positive role models of gay adults available to them. In adolescence, sexual feelings emerge with greater urgency, but there is rarely any context or permission for their expression. Adolescents in particular often reject and isolate those who are different and encourage conformity, which further support denial and suppression of the emerging homosexual feelings. As a result, the gay or lesbian adolescent may even further split off awareness of affect and behavior related to his or her homosexuality (Martin 1982). When adolescents who have disconnected themselves from any awareness of their homosexual feelings become aware of such feelings, they may work even harder to suppress these feelings by isolating themselves and avoiding situations that may stir up their longings. Some of these youths may devote extraordinary energy to academic or career success to cover up their underlying shame and sense of being defective; others may become depressed, isolated, guarded, and lonely, expecting to be rejected and ignored if their true feelings were to be revealed (Hetrick and Martin 1987). Often these young

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people become ashamed not only of their sexual feelings but also of their bodies, their social interactions, and other aspects of themselves. Although not all gay men and lesbians have the same degree of difficulty traversing childhood and integrating an often stigmatized sexual identity into a healthy personality structure, most will show some residual signs of this difficult developmental path. Substance use serves as an easy relief, can provide acceptance sexually, and, more importantly, mirrors the "comforting" dissociation developed in childhood. Alcohol and other drugs cause dissociation from feelings and anxiety, mimicking the emotional state many gay people had to develop in childhood to survive. These "symptom-relieving" aspects help fight the effects of homophobia; substance use can allow "forbidden" behavior, allow social comfort in bars or other unfamiliar social settings, and provide comfort through the dissociative state itself. Some gay people cannot imagine socializing without alcohol or other mood-altering substances. Many gay people had their early homosexual experiences while drinking or under the influence of drugs. Some gay people who experience shame for being gay find that using alcohol and drugs may be the only way that they feel they can allow themselves to act on their sexual feelings. This association is a very powerful behavioral link—the pleasure and release of substance use and the pleasure and release of sexual intercourse—and very difficult to change or unlink later in life. For gay men especially, sexual activity and intimacy are often split off or dissociated from each other. Substance use may allow people to act on feelings long suppressed or denied but also mirrors the dissociative experience and makes integration of intimacy and love more difficult. Sexual activity and substance use provide an instantly gratifying relief or satisfaction of longings and needs but can be challenges to love and intimacy. For many men and women, this linking of substance use and sexuality persists and may become part of the coming-out process and the formation of a social and personal identity. Many gay people continue to feel self-hatred; the use of mood-altering substances temporarily relieves this self-loathing, but then the self-loathing is reinforced in the drug withdrawal period. Alcohol and many other drugs can cause depression, leading to a further worsening of self-esteem. The internal state that accompanies internalized homophobia and the internal state that occurs with substance abuse are very similar—the "dual oppression" of homophobia and substance abuse (Finnegan and McNally 1987). The following traits can be seen in both states: denial; fear, anxiety, and paranoia; anger and rage; guilt; self-pity; depression, with helplessness, hopelessness, and powerlessness; self-deception and development of a false self; passivity and the feeling of being a victim; inferiority and low self-esteem; self-loathing; isolation, alienation, and feeling alone, misunderstood, or unique; and fragmentation and confusion. These close similarities make it very difficult for gay men or lesbians who cannot accept their sexual orientation to recognize or successfully treat their substance abuse.

ASSESSMENT, INTERVENTION, AND TREATMENT CONSIDERATIONS Treatment must generally focus on recovery from substance abuse and from the consequences of homophobia and usually requires self-acceptance of one's sexual orientation. To reverse and treat the denial and dissociation described earlier, if so experienced, the gay man or lesbian will need to address his or her own acceptance of self as a gay person (although no one should be forced to come out publicly if not ready). In the assessment of a gay man or lesbian presenting for behavioral health services, clinicians need to be aware of the higher incidence of substance abuse in this population and, accordingly, routinely screen for symptoms of alcoholism or other substance abuse. In formulating a treatment plan for gay men or lesbians who have a substance abuse problem, the clinician needs to explore the following in the assessment of each individual: the stage in the life cycle; the degree and effect of internalized homophobia; the stage in the coming-out process and the experience of coming out; the support and social network available; the current relationship, if any (including a married spouse of the opposite sex if that is the case), and the history of past relationships; the relationship with the family of origin; the degree of comfort with sexuality and expression of sexual feelings; career and economic status; and

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health factors, including HIV status. Given that gay men and lesbians engage in psychotherapy more often than does the general population (Jones and Gabriel 1999), any current psychotherapy must be addressed. Most clinicians working with addicted patients recognize that psychotherapy alone will not treat substance abuse and, in fact, may actually be harmful and not indicated (Vaillant 1983). Traditional individual psychotherapy can be isolating and lonely and may create the false hope that understanding and insight will lead to recovery. Often, the insights lead to rationalizations for continuing to abuse substances. (If a patient is already in therapy when recovery begins, the therapy need not stop, but the work will need to be much more supportive and focused on the here and now and the recovery process itself, while the emotional and neurological systems begin to heal.) Inpatient and outpatient detoxification and rehabilitation programs often lack knowledge about gay people and do not address sexual orientation, and the staff members may be unaware that they have gay and lesbian patients (Hellman et al. 1989). Finding a sensitive way to address sexual orientation and making gay and lesbian patients feel welcome and accepted are necessary at all levels of care. If treatment in a formal substance abuse program is indicated, the program should at least be gay-sensitive—aware of, knowledgeable about, and accepting of gay people in a nonprejudicial fashion. The ideal program would be gay-affirmative—actively promoting self-acceptance of a gay identity as a key part of recovery. Twelve-step recovery programs and philosophies are the mainstays in abstaining from drug and alcohol use (living clean and sober) for most substance abusers. Many larger communities now have gay and lesbian Alcoholics Anonymous (AA), Narcotics Anonymous (NA), Cocaine Anonymous (CA), Methamphetamine Anonymous (MA), and Al-Anon meetings. AA, as an organization, clearly embraces gay men and lesbians, as it embraces anyone concerned about a substance abuse problem (Kus 1987). Some groups parallel and similar to AA have formed to meet the needs of gay men and lesbians, such as Alcoholics Together, and many big cities sponsor "round-ups"—large 3-day weekend gatherings focused on 12-step programs, lectures, workshops, and drug- and alcohol-free socializing. Most 12-step programs recommend avoiding emotional stress and conflicts in the first 6 months of recovery. Discussions about the conflicts around acknowledgment of sexual orientation and living comfortably as a gay person are necessary for recovery, even if these topics are emotionally laden and stressful. Some of the suggestions and guidelines of 12-step programs and most treatment programs may be difficult for some gay men and lesbians to follow. For example, giving up or avoiding old friends, especially fellow substance users, is difficult for the gay person who has limited contacts who relate to him or her as a gay person; it is also difficult to stay away from bars or parties if they are the only gay social outlets available. Special help on how not to drink or use drugs in such settings may be necessary. Many gay people mistakenly link AA and religion (as do many). Because many religious institutions denounce or condemn homosexuality, gay men and lesbians may be especially resistant to 12-step programs. An increasingly popular model is a combination of the harm reduction and relapse prevention models of intervention—especially with HIV-positive, substance-abusing gay men (American Medical Association 1996; Brettle 1991; Fernandez and Levy 1994; Springer 1991; Strang 1992). Sobriety and recovery are always the ultimate goal, but realistic steps along the way to that goal are promoted, such as reducing use, encouraging use of clean needles, encouraging adherence to safer-sex guidelines, discovering situations that trigger substance craving, and using a type of behavior modification to avoid these situations. Even if every single sexual contact or needle-sharing incident is not safe, every reduced-risk encounter is a harm reduction event. Every time drugs and alcohol are not used when they usually would be used, better judgment, awareness, or even recovery may follow. Many localities now have gay, lesbian, and bisexual health or mental health centers, almost all with a

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focus on recovery and substance abuse treatment. National organizations, such as the National Association of Lesbian and Gay Addiction Professionals, the Association of Gay and Lesbian Psychiatrists, the Gay and Lesbian Medical Association, the Association of Lesbian and Gay Psychologists, and the National Gay Social Workers, can help with appropriate information.

SPECIFIC ISSUES IN THE TREATMENT AND RECOVERY OF GAY MEN AND LESBIANS Relationships Many other factors affect the treatment of gay men and lesbians. Many gay men and lesbians are in long-term relationships, and treatment for these individuals clearly must focus on relationships, parenting, and family concerns. The literature is extensive on the topic of what constitutes a gay or lesbian couple or an extended family as well as on the topic of couples and family therapy with gay men, lesbians, and bisexual individuals (Cabaj 1988a; Cabaj and Klinger 1996; McWhirter and Mattison 1984a, 1984b). The principles and techniques of couples and family therapy are the same as with heterosexual patients and may need to be part of the recovery process. Same-sex relationships are not readily accepted or even acknowledged in America, and gay people are still fighting for the right to same-sex marriage (Cabaj and Purcell 1998). Although many people view marriage and recognized and sanctioned relationships as a religious or civil rights issue, the mental health aspects of such relationships are increasingly being recognized (Pawelski et al. 2006). Understanding the effect of internalized homophobia, antigay bias, and the issues involved when two people of the same sex—and similar culturally determined gender role expectations—attempt to meet, bond, and establish relationships will help when working with a gay couple or family with substance abuse concerns. Because many gay, lesbian, and bisexual people have children, children also may have a role in the treatment and recovery process in gay men and lesbians.

Violence As noted earlier, lesbians and gay men are also subject to the possibility of violence and hate crimes directed at them because of their sexual orientation (Herek et al. 1999; Huebner et al. 2004; Klinger and Stein 1996; Otis and Skinner 1996). Such violence ranges from verbal to physical attacks; many victims of such violence turn to alcohol or drug use, and such an attack may result in relapse for a person already in recovery or an increase in use by someone currently using drugs. Domestic violence is also a real possibility with gay couples and is greatly underreported (Island and Letellier 1991; Schilit et al.1990). As with all couples, a link exists between drug or alcohol use and domestic violence. Finally, gay people are subject to physical and sexual abuse when growing up or in situations in which they may be exploited by others; a higher risk for alcohol and drug use is associated with such abuse.

HIV and AIDS HIV infection and AIDS are still major health concerns for gay men especially—and gay men of color increasingly—and lesbians to a more limited extent. Treatment centers and programs may resist talking about safer sex because it is uncomfortable to talk about such matters (Cabaj 1989). Some counselors may view discussions about safer sex and other prevention issues as detracting from recovery issues. However, like discussing sexual orientation itself, discussions about both safe sex and other HIV-infection prevention efforts are essential to recovery and may be lifesaving. Most gay men know what safer sex is, and in most reviews of gay men and safer-sex practices, the great majority of men who were knowledgeable about safer sex failed to practice it while under the influence of some substance (Calzavara et al. 1993; Leigh 1990; Leigh and Stall 1993; Paul et al. 1994; Stall 1988; Stall et al. 1986). The type of drug used also may play a role in increased risk. For example, ecstasy use does not seem to be associated with risky sexual activity as much as methamphetamine use does—although both are very popular in gay social settings (Schilder et al. 2005).

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Alcohol and drug use is a major complication in health maintenance for the HIV-infected person—trying to take a complicated regimen of medications on a specific schedule can be quite challenging. Gay men, who are depressed or have damaged self-esteem and shame because of internalized homophobia, may put themselves at risk for HIV infection, consciously or unconsciously, via risky sexual practices, especially under the influence of drugs or alcohol, or by sharing needles (Cabaj 1998; Perry and Fishman 1993).

Attempts to Change Sexual Orientation Early recovery may be a time when gay men and lesbians blame their sexual orientation for their substance abuse (and other problems) and may express a desire to try and change their sexual orientation. No evidence indicates that people can change their actual orientation, but they can certainly change behaviors, even if only temporarily. Gay men or lesbians who are distressed about their sexual orientation may be quite vulnerable to exploitation by therapists and programs that purport to change sexual orientation. A summary of issues basic to understanding sexual orientation noted earlier makes clear that sexual orientation is a very complex phenomenon, with probable genetic, biological, social, familial, and cultural forces in its origins and expression, and psychological and psychodynamic forces may result from having a particular sexual orientation and the adjustment to and acceptance of it. Sexual orientation, therefore, is not a result of how someone is raised. Sexual behavior, on the other hand, and the adjustment to one's sexual orientation are very much dependent on how and in what setting one is raised. Some therapists and clergy promote interventions that attempt to change sexual orientation. These approaches are sometimes called "conversion" or "reparative therapies." Nicolosi (1991) and Socarides and Volkan (1991) strongly advocated such approaches, the former using reparative approaches and the latter psychoanalytic techniques. These approaches assume that homosexuality is pathological and the result of deficient parental upbringing. Instead of exploring and understanding internalized homophobia and the consequences of antigay bias in gay and lesbian people who are troubled by their sexual orientation, advocates of such treatments take a "shame-based" approach and usually share concern with the patient that his or her sexual orientation is, indeed, a major problem and that the orientation can be changed. Confounding gender role expectation with sexual orientation, these interventions assume that the gay man did not have enough masculine support or modeling from his father and the lesbian did not have enough feminine support or modeling from her mother. The advocates of such treatments claim a high success rate for those people who truly wish to change their sexual orientation, but very few objective data or clinical materials support such types of treatments (reviewed in Drescher and Zucker 2006). What appears to happen as a result of such interventions is that someone is able to change sexual behavior temporarily—that is, the way they act on sexual feelings—but not change basic sexual orientation, maintaining same-sex sexual fantasies and desires, and usually returning to homosexual behavior over time. A heightened focus on the issue occurred when Spitzer (2003) reported the results of a telephone survey of people who reported that they had wanted to change sexual orientation and a handful who said that they did. Drescher and Zucker (2006) focused on the extremely flawed nature of the survey, and Spitzer himself has condemned the use of the study to indicate that true change in sexual orientation is possible. Gay-, lesbian-, and bisexual-supportive therapists, in fact, report significant emotional and psychological harm from such attempts to change sexual orientation, with resulting depression, shame, anxiety, guilt, and suicidality (Haldeman 1994). Interventions that attempt to treat something that is not an illness, try to change something that most likely cannot change, and cause emotional harm in the process seem at best without merit and at worse unethical, and such attempts seem even more exploitative if done with gay men and lesbians in recovery or with active substance use or abuse.

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If a person truly is troubled by his or her sexual orientation, exploration of the source of the distress and attempts to relieve the conflicts would be much more beneficial than suggesting the possibility of change, which is highly unlikely to occur. The internalized homophobia or external antigay pressure usually can be addressed in treatment and would help a gay man or lesbian far more than creating a deepened sense of shame and fear of acting on sexual and loving feelings. Families also may benefit from such sensitive explorations, and if family members are a major source of the conflict for the person, family therapy can be very beneficial. If religious or faith-based pressure is a major part of the conflict, the gay man or lesbian may need help in being directed to a minister, priest, rabbi, or someone who can speak to the particular concerns of the religion in question and who is sensitive to and aware of the conflicts facing gay, lesbian, and bisexual people.

Gay and Lesbian Youths For some adolescents who do come out as openly gay or bisexual, life can be quite difficult. Many face taunts or threats from their peers that can vary in intensity. Their families, as well as their friends, may reject them, and some gay youths run away from home. Such gay youths may end up homeless, may start using drugs, and may turn to "survivor sex" for pay as street workers. Some gay youths who were living on the street reported to me that they were trying to acquire HIV infection on purpose so that they would qualify for medical and social services as well as disability incomes and housing programs. Gay youths are also at greater risk for suicidal thinking and behavior, as discussed in the "Suicidality" subsection later in this chapter.

Aging Gay Men and Lesbians Older gay people face the same issues as all older people but may feel more isolated and disconnected from others if alone, having grown up during a time of even more prejudice against gay people (the era when homosexuality was still considered a mental illness or a perversion). Many gay people, however, have developed strengths from years of battling antigay bias that serve them well in coping with older life (Berger and Kelly 1996). Gay men and lesbians at any age—but especially as they get older—may deal with the loss of a long-term relationship; such "gay widows" may have few social supports. Of course, drug and alcohol use may be a major part of an older gay person's life, and interventions must take into account both his or her being older and being gay.

Suicidality Suicidal thinking, suicide attempts, and completed suicides are major concerns for all people who use or abuse substances, but the concern and risk are even higher for gay men and lesbians—especially for adolescents and young adults. All ages have been studied—with the greatest focus on youths—and the studies indicate that the incidence of completed suicides in gay men and lesbians is as high as three times the national average, and as many as 30% of gay and bisexual people may have attempted suicide (S. D. Cochran and Mays 2000; Garofalo et al. 1999; Paul et al. 2002; Rotheram-Borus et al. 1994). The increased rates seem related to the struggles around acceptance in the face of antigay bias and self-esteem damaged by internalized homophobia, although the studies that indicate that lesbian, gay, bisexual, and transgender people have higher rates of mood disorders may be an additional risk factor (Mills et al. 2004).

Personal Attitudes of Providers Clinicians and counselors must be aware of their own personal attitudes regarding homosexuality. If a provider is uncomfortable with gay people or is outright antigay and cannot get help in working out these attitudes with a supportive colleague or supervisor, the person seeking help would be better off referred to another provider or staff member for help (Cabaj 1988b). Gay men and lesbians facing recovery from substance abuse should not have to fight homophobia in a health care system to obtain quality care.

Socioeconomic and Other Factors

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Many substance abusers are from poor or limited economic backgrounds. Although gay men in general and lesbians to a lesser extent may be socioeconomically above the national average, gay chronic drug users may have lost their jobs or economic supports, especially when methamphetamine is the drug of abuse. Limited insurance, limited treatment options, and limited ability to avail themselves of the social services and enrollment in public assistance profoundly influence the care of many gay substance users, especially those with HIV or AIDS. Minority status may further limit access to care or add to the wariness of seeking care from mainstream systems of care. Economic and societal forces often keep some gay minority substance abusers on the edges of society, with little hope of breaking out of the setting they are in—a setting that often supports easy drug or alcohol use, whether it be the "gay ghetto" imposed by homophobia or geographic and racial ghettos. A brief list of additional treatment issues facing all people in recovery—with special effect on gay men and lesbians—include the following: how to have safer sex while clean and sober; how to adjust to clean and sober socializing, without the use of alcohol or drugs to hide social anxiety; how to deal with employment problems and adjust to the effect of being out as a gay person at work; how to work with the family of origin regarding acceptance of the sexual orientation of their gay or lesbian child; how couples will adjust to the damaging effects substance use may have had over the years; determining the negative effect of codependent relationships; how to maintain confidentiality in record keeping, especially around discussion in the medical record of sexual orientation or HIV status; dealing with child custody issues when necessary; diagnosis and treatment of additional medical problems; and legal problems. Finnegan and McNally (1987) address many of these concerns in greater detail.

Issues Specific to Lesbians As described earlier, the incidence of substance abuse is equally high for gay men and lesbians, but lesbians who abuse substances may have additional social struggles and concerns. Compared with gay men, lesbians are more likely to have lower incomes, and lesbians are more likely to be parents—up to one-third of lesbians are biological parents (Kirkpatrick 1996). Lesbians face the prejudices aimed at women as well as those for being gay, including the stronger reaction against and willingness to ignore female substance abusers (Banks and Gartrell 1996); lesbians are more likely to come out later in life (Herbert 1996); and lesbians more often have bisexual feelings or experiences (Bell and Weinberg 1978; Bell et al. 1981) and, as a result, are at greater risk for HIV infection via a heterosexual sexual route in addition to possible injection drug use and the less risky woman-to-woman sexual contact transmission. A few surveys noted earlier have focused on lesbian substance abuse, including one survey in the general population (J. Bradford, C. Ryan, "Mental Health Implications: National Lesbian Health Care Survey," unpublished report for the National Lesbian and Gay Health Foundation, Washington, DC, 1987) and one in lesbian medical students (Mosbacher 1993). Both continue to indicate high use of alcohol and other drugs in lesbians and a greater concern over a problem with alcohol and drug use than in similar heterosexual populations. Use of alcohol may be greater than drugs, but that varied by culture and location, and alcohol plays a role across all age groups for lesbians (Hughes et al. 2006). The following discussion focuses on gay men more specifically. Some of the issues also apply to lesbians, but the factors involved in being "male" and "gay" in our society compared with being "female" and "lesbian" may limit applications to lesbians for all the topics discussed.

Issues Specific to Gay Men Being male brings its own social and cultural pressures in addition to those about being gay. Cultural expectations about what it means to be male, regardless of sexual orientation, add social and personal pressures. These cultural expectations—basically gender role expectations—vary by culture and ethnicity. Gay men of color may face quite different problems from those faced by white gay men. In general, though, a cultural stereotype of being male in America seems to be the expectation of being powerful, masculine, independent, emotionally reserved, career motivated rather than relationship

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motivated, and sexually driven with a focus on obtaining orgasm and having multiple partners. Boys and men who do not seem to fit this stereotype—or who do not wish to act like this stereotype—may have trouble fitting in or being socially accepted. Part of societal heterosexism stems from confusion about what homosexuality is and what gay men are. Because most heterosexual individuals cannot imagine what it is like to be gay, to be attracted to someone of the same sex, they often assume that a gay man must be in some way like a woman. If a man wants to be with another man emotionally or sexually, then they think that the gay man must see himself as a woman. Many cultures, especially Latin-based cultures, cast great stigma on any man who appears to be in any way like a woman. As noted, many gay people feel shame about being gay, which may contribute to the use of drugs and alcohol; the comfort to be openly gay or have sexual contact that might be considered shameful or subject to scorn by others may be enhanced by the use of drugs and alcohol.

TYPES AND PATTERNS OF SUBSTANCES ABUSED Any and all types of drugs and alcohol may be used and abused by gay men or lesbians. However, certain drugs may be more associated with this population (especially gay men) than other drugs. In the last decade or more, the use and abuse of methamphetamine (also known as "speed," "crystal," "tina," "crank," and other names) has emerged as a particular problem for gay men. Although use is not exclusive to gay men (adolescents across the United States and younger urban Asian and Latina women are also noted to be high users), it results in multiple psychological and medical concerns for gay men in particular. The use of the drug is highly associated with sexual activity and is popular at "circuit parties," at which large numbers of gay men gather for partying, dancing, and sexual activity (often accompanied by drug use), and with men seeking sexual partners over the Internet ("party and play"). Why gay men in particular are more likely to use and abuse methamphetamine may be linked to the sexual enhancement aspect of the drug, but there appear to be many reasons, including the aspects of internalized homophobia described earlier. Green and Halkitis (2006), for example, reported an affinity linked to lower self-esteem and social awkwardness many gay men experience, tied to expectations of peak sexual performance, especially in urban gay subculture. Gay men of color are also at risk for use of methamphetamine, including a population that usually is not associated with excessive substance use—Asian and Pacific Islanders (Choi et al. 2005; Nemoto et al. 2002). There are many routes of administration, including oral inhalation, nasal insufflation, absorption through the rectal mucosa, and intravenous use. Methamphetamine is experienced as heightening sexual feelings and duration of sexual activity, as well as sexual disinhibition, allowing some men to have sexual intercourse for 12 hours or more. Methamphetamine users are at risk for increased exposure to HIV with multiple sexual partners, unprotected anal intercourse (sexual intercourse without condoms), and injection drug use (Gorman et al. 1995; Mansergh et al. 2001, 2006a). Some men who specifically wish to become infected with HIV (for a variety of psychological reasons) find that using methamphetamine and having unprotected sexual intercourse is a particularly successful route to accomplish their goal (Halkitis et al. 2006). Those gay men who prefer to have unprotected anal sex with all of its risks (known as "barebacking") are also more likely to use methamphetamines (Mansergh et al. 2002). The use of methamphetamines has clearly been linked to a higher risk for HIV infection as a result of the many factors already discussed (Colfax and Guzman 2006; Shoptaw 2006; Shoptaw and Reback 2006). One study focused on gay male HIV-positive methamphetamine users who were sexually compulsive and on the high rates of unsafe sexual activity that puts so many others at risk (Semple et al. 2006). Other studies suggest that the use of sildenafil and methamphetamine contribute to the higher HIV risk (many users of methamphetamines have transient erectile dysfunction, so they use sildenafil as well) (Fisher et al. 2006; Mansergh et al. 2006b). Many urban areas have started to address the concerns specific to gay men, and some treatment

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programs are emerging for gay methamphetamine abusers. Who is likely to seek treatment is not clear because many of the gay men who use methamphetamine do so with others, and users often face social pressures to continue using even when problems develop. Many men enter treatment only after experiencing great financial consequences or major health problems (B. N. Cochran and Cauce 2006). Several types of treatment have been studied, and more studies are focusing specifically on gay men (Wainberg et al. 2006). Contingency-management types of behavioral modifications are showing promise as successful interventions (Rawson et al. 2004; Shoptaw et al. 2005). In San Francisco, a program called PROP (Positive Reinforcement Opportunity Project), a variation of contingency management with rewards for staying clean, is under way to determine whether gay men have specific needs that need to be addressed (studies are just beginning, so no data have been reported at time of publication, but the program is based on interventions discussed in Shoptaw et al. 2006 and Roll et al. 2006). The role of outpatient treatment alone or in combination with other interventions also needs additional study (Levounis and Ruggiero 2006). Traditional 12-step programs are increasing with a focus specific to methamphetamine in many urban areas, and Methamphetamine Anonymous (or Crystal Anonymous) groups are forming. As noted earlier, circuit parties are very popular with a segment of gay men, and drug use is quite prominent and extensive in those settings. Drugs such as ecstasy, "special K," GHB, "blue nitro," and other designer drugs are very popular, in addition to alcohol, amphetamines, marijuana, and cocaine. The parties are scheduled throughout the year as frequently as monthly, and local clubs have weekly events that are like circuit parties in terms of late nights and prominence of drug use (Mansergh et al. 2001). Many people state they only use at these parties and do not recognize how often they are actually using drugs. Methamphetamine use is widespread and growing in such venues. Finally, "poppers," or inhaled amyl nitrate or variants of it, are used by people of all sexual orientations. However, it has been noted for many years that they play a significant role in sexual activity for many gay men and have even been linked to some of the rare physical conditions seen with HIV and AIDS, especially Kaposi's sarcoma (Goode and Troiden 1979; Romanelle et al. 2004).

CONCLUSION Substance use plays a prominent role in the lives of many gay men and lesbians. Understanding the culture of being gay will help substance abuse professionals and treatment programs meet the specific needs of such people. Although the developmental issues described may not apply to all gay men and lesbians, the effects of internalized homophobia and societal antigay bias can be seen in almost all gay people and shape the clinical picture and issues that providers will need to address for successful treatment and recovery. Understanding the many issues discussed in this chapter will help frame the best approach to the individual gay man or lesbian who is abusing drugs or alcohol. The specific concerns noted—most important, the higher rate of alcohol and substance use and abuse, the higher risk of suicidality, the effect of HIV and AIDS, and the explosive use of methamphetamine—should be included in all assessments and, if relevant, shape the best treatment intervention.

KEY POINTS Substance use plays a prominent role in the lives of many gay men and lesbians, and gay men and lesbians have higher rates of substance use and abuse than in the general population. The higher rates of use and abuse can be explained by a combination of biological, social, environmental, and developmental factors. The internalized homophobia most gay and lesbians must confront in their own lives may have created a psychological structure with the overdevelopment of the defense mechanisms of denial, suppression, and repression. The effects of drugs and alcohol have a natural ability to support denial, suppression, and repression.

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Antigay bias seen throughout society contributes to many life stressors and creates a "ghetto mentality" for many gay men and lesbians—encasing themselves in social environments that feel protective but are often associated with drug and alcohol use. Although all types of drugs and alcohol are used by those gay men and lesbians who use, the explosive use of methamphetamine has been especially noteworthy among gay men. Recovery for most gay men and lesbians requires self-acceptance of their sexual orientation (which may have been a source of conflict). The ideal treatments for gay men and lesbians will be gay-affirmative or, at a minimum, gay-sensitive.

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SUGGESTED READING Bell AP, Weinberg MS, Hammersmith SK: Sexual Preference: Its Development in Men and Women. Bloomington, Indiana University Press, 1981 Cabaj RP: Substance abuse and HIV disease: entwined and intimate entities, in New Treatments for Chemical Dependency. Edited by McCance-Katz EF, Kosten TR. Washington, DC, American Psychiatric Press, 1998, pp 113–149 Cabaj RP, Purcell DW (eds): On the Road to Same-Sex Marriage: A Supportive Guide to Psychological, Political, and Legal Issues. San Francisco, CA, Jossey-Bass, 1998 Cabaj RP, Stein TS (eds): Textbook of Homosexuality and Mental Health. Washington, DC, American Psychiatric Press, 1996 Drescher J: Psychoanalytic Therapy and the Gay Man. Hillsdale, NJ, Analytic Press, 2001 Finnegan DG, McNally EB: Dual Identities: Counseling Chemically Dependent Gay Men and Lesbians. Center City, MN, Hazelden, 1987 Guss JR, Drescher J (eds): Addictions in the Gay and Lesbian Community. Binghamton, NY, Haworth, 2000 Isay RA: Being Homosexual: Gay Men and Their Development. New York, Farrar, Straus & Giroux, 1989 Magee M, Miller D: Lesbian Lives: Psychoanalytic Narratives Old and New. Hillsdale, NJ, Analytic Press, 1997 Shoptaw S, Reback CJ, Peck JA, et al: Behavioral treatment approaches for methamphetamine dependence and HIV-related sexual risk behaviors among urban gay and bisexual men. Drug Alcohol Depend 78:125–134, 2005 Wainberg ML, Kolodny AJ, Drescher J (eds): Crystal Meth and Men Who Have Sex With Men: What Mental Health Care Professionals Need to Know. Binghamton, NY, Haworth Medical, 2006

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Chapter 45. Minorities

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Joseph Westermeyer, Dan Dickerson: Chapter 45. Minorities, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.357974. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Minorities Joseph Westermeyer, M.D., Ph.D. Dan Dickerson, D.O., M.P.H.

MINORITIES: INTRODUCTION The term minority refers here to groups within the population who differ from others in their cultural or ethnic characteristics and may be liable to different—often inferior—policy or procedure. Culture refers to the sum total of a group's ways of living, including the group's material culture, worldview, social organization, symbols, status, child-raising methods, language, technology, and citizenship. The term ethnicity, as used in multiethnic societies, applies to peoples from diverse cultural backgrounds who share a common national culture. Distinctive characteristics include identity with a national origin, religious practice, language besides English spoken in the home or neighborhood, dress, diet, nonnational holidays or ceremonial events, traditional family rituals, and use of disposable income and free time (Keyes 1976). Subculture refers to groups within a culture that have distinctive group characteristics but that cannot exist independently of the population at large. Substance use, abuse, or commerce can foster highly cohesive and distinctive subcultures, such as "bottle gangs," tavern culture, cocktail lounge culture, opium den culture, and crack house culture (Bourgois 1989; Dumont 1967; Weibel-Orlando 1985; Westermeyer 1974a). Cross-cultural can refer to the comparison of psychosocial characteristics across two or more cultural groups or, in the medical context, to treatment in which the clinician and the patient belong to different cultures (Comas-Diaz and Griffith 1988). Comparisons across cultures are often termed etic, whereas noncomparable, culture-specific elements or patterns are termed emic (Lefley and Pedersen 1986).

PREHISTORY The development of psychoactive substances began millennia before written records (Table 45–1) (Westermeyer 1988). People of Africa, Asia, and Europe prepared beverage alcohol from fruits, grains, tubers, and mammalian milk. They also grew opium, cannabis, and some plants with stimulant properties, such as khat (also spelled chat or qat) in the Red Sea area (Griffiths et al. 1997), kola in other parts of Africa, kratom in Southeast Asia, and betel across South Asia to Oceania (Burton-Bradley 1977). The champions of psychoactive substance invention were the peoples of the Americas (see Table 45–1). Before 1500 A.D., they developed several hundred stimulant or hallucinogenic compounds, including tobacco (containing nicotine), coca leaf (containing cocaine), coffee (containing caffeine), and peyote (DuToit 1977). American Aztecs and Papago prepared beverage alcohol from cacti and other plants. These methods are still used commercially today (Anawalt and Berdan 1992; Waddell and Everett 1980).

Routes of Administration People in Africa, Asia, and Europe consumed psychoactive substances primarily by ingesting them. They also chewed some substances—for example, betel nut and khat (Getahun and Krikorias 1973). Again, the peoples of the Americas before 1500 A.D. were foremost in developing innovative means for consuming drugs. They discovered several other routes of administration besides eating, drinking, and chewing (Negrete 1978)—namely, snuffing, smoking, and rectal clysis (Furst 1972; Furst and Coe 1977). Chewing, smoking, snuffing, and clysis avoided first-pass metabolism in the liver and accelerated onset

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of drug effect. After 1500 A.D., medical practitioners used these routes of administration to administer medication.

Social Controls Laws regarding substance use and abuse appeared in the earliest codes of law (Anawalt and Berdan 1992). The Aztecs' laws governed when and how much alcohol could be imbibed, taking into account one's social status, role, and age; the punishments for breaking the laws ranged up to and included death. Other formal methods of control have included taxes, limitations on hours of sale and locations for sale, prescribing laws for certain substances (e.g., opiates), and illegal status for some psychoactive substances. Religious, cultural, and ethnic prescriptions and proscriptions have long affected alcohol and drug use (Westermeyer 1999). Typical patterns of informal social control have included the following: Substance use restricted to ceremonies or holidays Substance use restricted to large group or extended family events Proscription of taboo substances by certain groups (e.g., prohibition of alcohol use by some Christians, Hindus, and Muslims)

HISTORY Before 1500 A.D., sporadic cases of alcoholism and addiction were recognized over many centuries. Prior to that time, commerce in wine, tobacco, and probably other substances occurred locally, within early nation-states, and along established trade routes (Westermeyer 1998). Around 1500 A.D., improved methods of shipbuilding and new navigation technology led to safer and less expensive international commerce. These changes resulted in the exchange of psychoactive substances across thousands of miles. These and other changes in the post–1500 A.D. world produced two momentous substance abuse epidemics, one associated with opium in Asia and one associated with alcohol in Europe (Table 45–2). Alcohol abuse among the aboriginal peoples of the Americas and Australia may have constituted a third post-1500 epidemic (Brady 1995; Manson et al. 1992). The Industrial Revolution, development of large plantations for certain plant products, and disruption of tribal societies during a period of empire building also contributed to these epidemics. Tobacco smoking, which spread rapidly around the world during the 1500s, may have set the stage for the subsequent Asian opium epidemic. Tobacco smoking reached the China Sea within decades of its discovery by Europeans in North America. Asian people smoked tobacco in tobacco houses, the meeting places of the day. Tobacco houses subsequently became associated with political sedition and were outlawed in many Asian countries. Tobacco raising and smoking went underground and continued. Around the same time, opium—previously known as an herbal medication—began to be smoked in social settings (Strang et al. 1997). By the 1600s, the Asian opium epidemic was well under way, dwarfing the tobacco smoking habit that preceded it. Commercial interests, huge profits, and international politics fueled the epidemic, which was also fostered by local corruption and an absence of cultural strictures against opium use (Fields and Tararin 1970; Merrill 1942; Terry and Pellens 1928). Attempts at addressing the opium epidemic included enactment of antiopium laws, establishment of government ministries charged with eliminating opium production and commerce, and formation of private antiopium societies that aided addicted people trying to quit using opium and that warned the general public about opium. By the mid-1900s, an estimated 18 million Chinese people were addicted to opium (Fields and Tararin 1970). Democratic, leftist, and rightist governments in China, Japan, both Koreas, and Taiwan also reversed their opium endemics around the same time (i.e., the 1950s and 1960s). The opiate endemic continues in Thailand, Laos, Burma, Malaysia, Bangladesh, Pakistan, India, Afghanistan, and several countries in the Middle East (Westermeyer 1982). The gin epidemic began in England around the 1600s and continued for almost two centuries, with some vestiges remaining until the 1900s. It involved rum and gin from the Caribbean, where it could be

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purchased cheaply (because of slave labor) and then used as ballast in ships returning from commercial voyages. Although mead (a honey beer) had been drunk traditionally in England, the population had limited experience with distilled beverage alcohol. During the development of the gin epidemic, the Industrial Revolution was also under way, with a massive shift of the population from farms and small towns to industrial towns of various sizes. Because a calorie of alcohol cost less than a calorie of carbohydrate in bread, potent economic forces favored the use of gin and rum as food. Because workers were thought to perform better after moderate drinking, taverns were open briefly in the morning and again at noon so that workers could imbibe before and during work (Thurn 1978). So severe and widespread was alcohol abuse that fetal alcohol effects were first recognized during the epidemic (Rodin 1981). Public and private efforts gradually brought the gin epidemic under control in the seventeenth, eighteenth, and nineteenth centuries. An import duty on beverages reduced economic incentives to drink. Eight-page booklets detailed the family, health, and social consequences of excessive drinking. Around this time, abstinence-oriented Christian denominations developed, leading eventually to the founding of Alcoholics Anonymous in the twentieth century (Aaron and Musto 1981). During World War II, tens of millions of young men were transported long distances from home and exposed to years of combat. This tremendous undertaking affected not only the combatants but also many civilian populations in Asia. Combatants were exposed to beverage alcohol, amphetamines, opiates, and other drugs not known in their native lands (Tamura 1989). Marked increases in alcohol and drug abuse occurred in many parts of the world following this conflict. The first pandemic of youthful drug abuse began in the mid-1900s and involved all continents (Cameron 1968). Returning home to high unemployment, lost youth, and devastated countries, many combatants used nontraditional forms of psychoactive substances. A youth culture with its own nontraditional dress, music, mores, morals, and drugs appeared in many countries during the latter half of the twentieth century (Deutsch 1975; Maddahian et al. 1986). The resurgence of fundamentalist (and abstinenceoriented) Buddhist, Christian, and Islamic sects across the globe may have its roots in societal responses to youth culture, including youthful drug use and abuse (Galanter and Westermeyer 1980), just as widespread drug use may have been a response to fundamentalist religiosity (Westermeyer and Walzer 1975). Colleges and universities, recognizing the onset of alcohol abuse among young students, have been attempting to establish new social mores among students (National Institute on Alcohol Abuse and Alcoholism 2002). Migration also has contributed to major shifts in alcohol and drug use. Hispanic migration to North America has resulted in increased rates of alcoholism among women (Caetano 1987) (see Table 45–2). Immigrants and refugees have brought their traditional drug use patterns, such as addiction to opium and khat (Westermeyer et al. 1991).

From Cottage Industry to High-Technology Industry Before the 1800s, much of the production and distribution of drugs of abuse depended on high-labor, low-technology methods. Substances such as opium and alcohol were produced in agricultural settings with human and animal power. Rapid, efficient intercontinental sailing ships and navigation technology had stimulated intercontinental trade in substances after 1500, but local distribution depended largely on human and animal transport. Because the technology of the day was widely known and available to virtually anyone, alcohol and drugs were produced and distributed mostly on a small scale to meet local needs. Distribution was effected through local barter and shopkeepers. Until the opium and gin epidemics, few producers, shippers, or retailers depended solely on alcohol or drugs for their livelihoods. As cottage industry techniques gave way to myriad technological advances, new substancefocused occupations and even industries evolved. New social and health problems also appeared (Westermeyer 1988). Since the early 1800s, advancing technology has resulted in more efficient and rapid means of drug

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administration. The development of the syringe and hollow needle permitted the user to avoid the first-pass effect of the liver and consume the entire drug dose. Cigarette production fostered all-day tobacco smoking and dependence. Some drugs can be administered via skin patches. These new methods of administration have resulted in new medical and public health challenges (Davoli et al. 1997). Parenteral drug administration has produced epidemics of drug-related maladies (e.g., AIDS, hepatitis B and C). These infectious disease outbreaks among drug injection users have led to increased drug smoking and snuffing in recent years (Perez-Jimenez and Robert 1997).

Concentration of Traditional Substances Alcohol distillation and the preparation of hashish oil were early inventions to increase potency. During the 1800s, chemical concentrates of opium (morphine and heroin) and coca leaves (cocaine) were developed. These concentrates facilitated the use of these substances by snorting, smoking, and parenteral injection. Whereas crude plant compounds had limited shelf lives and were bulky, odoriferous, and easily detected, heroin and cocaine had long shelf lives and were highly compact and much less odoriferous. These concentrated compounds lent themselves to prolonged storage, smuggling, and secretive retail commerce (Westermeyer 1982). In addition, some new compounds (such as heroin) crossed the blood-brain barrier more rapidly than traditional mixtures and therefore came to be in greater demand.

Synthetic Psychoactive Substances In the 1800s, synthetic psychoactive substances began to be produced. Soon after the development of the gaseous anesthetics nitrous oxide, chloroform, and ether, recreational users began using them. Early abusers were principally medical and pharmaceutical workers. Development of the petroleum industry during the later 1800s and early 1900s led to inexpensive, readily available industrial, cleaning, and fuel compounds that could produce relaxation or an altered state of consciousness. Abusers of petroleum chemicals have included industrial workers, gas station workers, mechanics, unemployed individuals, children and adolescents, alcoholic and addicted prisoners, aboriginal peoples, and military inductees in basic training or at a bivouac (Beauvais et al. 1985; Westermeyer 1987). In the early 1900s, invention of synthetic sedatives and stimulants brought the newly developing pharmaceutical industry into the picture as a producer of addictive drugs. By the 1930s, barbiturate addiction was appearing in industrialized countries. Sporadic cases of amphetamine abuse were seen before World War II, but the use of these drugs by the military catapulted them into widespread use in some countries, producing the first amphetamine epidemics after the war (Tamura 1989). In preparation for World War II, various pharmaceutical houses developed synthetic opioid drugs, anticipating that raw opium might not be available during conflict. This process led to the development of many synthetic opioids with various durations of action—from methadone at one extreme to the short-acting drug fentanyl at the other. In the later 1900s, "outlaw" chemists synthesized new compounds with psychoactive properties, the so-called designer drugs that were supposed to have specific desirable effects.

Smuggling and Distribution of Illicit Substances Smuggling involves actions by individuals sophisticated in operating illegally at one or more national boundaries. World War II, which displaced millions of people, created a huge reservoir of such persons in many countries around the world, and refugee movements since that time have done the same. Although the vast majority of these people are law-abiding, the drug trade draws a sufficient number of people, keeping it not only viable but also active and largely successful. Small airplanes, cigarette boats, and extensive ship, boat, and truck traffic have enabled the transportation of illicit substances over great distances with relative ease (Simmons and Gold 1973). Community-level retail distribution of illicit substances remains a cottage industry around the world, featuring:

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Low capital investment for starting up (e.g., a storefront or car, a gun, a day's or week's supply of drugs) A relationship and/or shared identity between buyer and seller Multiple distribution and sales points (so that inactivation of one point does not eliminate the trade) High profits relative to investment Reduced risk through corruption of police and elected officials

ETHNIC IDENTITY AND SUBSTANCE USE Culturally prescribed use, in which an individual must use a psychoactive substance under certain cultural circumstances, exists among many ethnic groups in the United States. Examples include consumption of wine at Jewish Passover seders and at Catholic masses and peyote chewing at ceremonies of the Native American Church (La Barre 1964). Prescribed use subserves religious and social ends. Duration of use and dosages are also prescribed. Failure to use the substance can be considered unfriendly or deviant. Forbidden use or taboo for some substances exists in all societies. Use of certain substances is forbidden under any circumstances. Examples include heroin in the United States, alcohol in Saudi Arabia, and coffee or cola drinks among Mormons. Taboo tends to work well as long as the individual remains affiliated with the ethnic group proscribing the use; separation from the group tends to erode the taboo. Because no society can enculturate its members into the safe, healthful use of all available substances, most psychoactive substances are forbidden or available only under specific circumstances (e.g., through medical prescriptions). Substances have taken on symbolic meaning in some instances. Psychoactive substances have come to represent certain values, attitudes, identities, or characteristics. One form of substance-related symbolism involves ethnic identity (Carstairs 1954). For example, among many Jewish people, drunkenness or alcoholism is seen as non-Jewish. Many Muslims consider any use of alcohol to be sinful (Chafetz 1964). Throughout history, substances have at times possessed political symbolism. For example, the Irish long distilled the illicit whiskey poteen to avoid English taxation and English manufactured beverage alcohol (Connell 1961). In recent decades, cannabis has been a symbol of rebellion against established order (Cameron 1968). Substance use also has functioned as a social bridge between and within groups. In parts of Latin America, drinking establishments have served as meeting places for persons of differing class and ethnic backgrounds (Heath 1971). Likewise, in parts of Africa, beer gardens have served as egalitarian social venues for people of different races and tribes (Wolcott 1974).

CULTURAL RISK FACTORS Lack of prescription or proscription, in which the culture or ethnic group neither requires nor forbids use of a substance, leaves the decision to use to the individual (Baasher 1981). This in-between state generally predisposes individuals to substance abuse and dependence, especially abuse of and dependence on highly addictive substances such as alcohol, cocaine, opiates, and tobacco. Norm conflict occurs when ideal norms and behavioral norms differ within a culture. One ideal norm may be that substance use does not occur, whereas behavioral norms may imply that such use is expected. As the gap between ideal and behavioral norms increases, the presumed conflict increases. Norm conflicts occur because individuals rather than entire societies make the choices regarding substance use (Westermeyer 1999). Pathogenic use patterns can occur as a behavioral norm, especially in groups with norm conflict regarding substance use. An example of such a pathogenic use pattern is bingeing on alcohol. This pattern exists among some northern European groups, some Native American tribes, some island communities in the Pacific, and many American college students. It is likely to lead to pathological use of alcohol among vulnerable persons; in some groups, lifetime risk of alcohol abuse can occur in up to

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half of the men and a quarter of the women (Boehnlein et al. 1992–1993; Robin et al. 1998). Technological changes can render a traditional use pattern unsafe. Particularly at risk are societies that formerly accepted very heavy intoxication at ceremonial times or that permitted alcohol or drug use during certain types of work. For example, a heavy drinker riding home in an oxcart from a New Year celebration may be relatively safe and is unlikely to harm others. The same person riding a bicycle or a motorcycle, or driving a car or a truck, is at serious risk of harming himself or herself and others. Intoxicated mariners today risk the lives of hundreds of people (e.g., in the case of a ferryboat) or risk damaging an entire ecosystem (e.g., in the case of an oil tanker). Even low blood levels of psychoactive substances can impede certain highly complex tasks, such as landing an airplane. Inadequate ensocialization occurs if the society's prescriptions and proscriptions regarding substances are not taught to children. Teaching occurs initially by role modeling and later through supervised use in ritual settings. To be effective, this aspect of culture must be taught in a consistent fashion during infancy, childhood, and adolescence. Some ethnic groups do an excellent job of ensocializing their children into appropriate prescriptions and proscriptions regarding substances (Bennett and Ames 1985). Individuals who leave their ethnic groups of origin are at risk for substance abuse if they migrate to groups that foster pathogenic substance use (Eaton and Weil 1955). Disenfranchised groups can play major roles in the drug trade. Examples of these groups include the Chiu Chao minority in Hong Kong, Hmong and Iu Mien minorities in Laos and Thailand, Corsicans and Sicilians in Europe, and Middle Eastern refugees and immigrants in parts of Latin America. Funds raised by such groups through the drug trade have supported revolutionary and nationalistic movements, guerilla wars, and terrorism (Westermeyer 1982). Generational change can influence the forms of psychoactive substance use within a given culture (Keaulana and Whitney 1990). Such change often involves the replacement of traditional cottage industry substances (e.g., locally grown tobacco, locally produced beer or wine) with industry-produced substances (e.g., manufactured cigarettes, imported beer or spirits). In some situations, young people have used substances unfamiliar to earlier generations. Secular use then replaces ritual or ceremonial use, individual choice replaces group decision making, and untried patterns replace patterns that evolved over centuries. Anomie, loss of a positive ethnic identity, is apt to occur among traditional peoples whose technological culture has been rapidly and extensively undermined by the sudden influx of foreign influences. Rapid and fundamental changes in technological bases of a culture can provoke tremendous changes in social organization, family relationships, cultural symbols, and other aspects of culture that affect psychoactive use patterns (Caetano et al. 1983). Conquest by a foreign power with dramatically different values and mores also can precipitate cultural tumult and subsequent substance abuse epidemics (Wallace 1970). Examples of substance abuse accompanying anomie include an amphetamine epidemic in postwar Japan (Tamura 1989) and abuse of alcohol and inhalants by aboriginal peoples of the Americas, Australia, and Oceania (Kahn et al. 1991; Walker et al. 1996). Genomic research has suggested differences in underlying biological mechanisms for addictive disorders among ethnic groups. For example, in one American Indian group, chromosome 5 was found to be associated with craving for alcohol (Ehlers and Wilhelmsen 2005). In another American Indian group, alcohol dependence was linked to chromosomes 4 and 11 (Long et al. 1998). Variability in alcohol dehydrogenase-2 among some African American persons with alcoholism has been shown to affect the susceptibility of developing cirrhosis and alcohol-related fetal damage (Yin and Agarwal 2001). Among Asian groups, up to 50% manifest a deficiency of the aldehyde dehydrogenase (ALDH2) isoenzyme, which is responsible for metabolizing acetaldehyde. A deficiency in this enzyme may protect against excessive drinking behavior by causing an alcohol flush and dysphoric reaction after consumption of alcoholic beverages (Wall et al. 1997). Although relatively new, human genetics data may increase our understanding of addictive diseases in these populations.

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Smuggled drugs, such as cocaine and heroin, tend to prevail in border, coastal, and commercial areas. By dint of geographical location, various ethnic groups become associated with the drug trade. Mafia members, Hispanic refugees and immigrants, and urban African Americans have been highly identified with the coastal, urban-centered heroin and cocaine drug trade in recent decades. Smuggling can thrive under the following community circumstances: A national boundary that lends itself to secret movement (e.g., a remote seacoast, mountains or deserts without roads, a crowded seaport) Occupation of the boundary region by a group that is economically disadvantaged relative to fellow citizens Occupation of the boundary by a distinct ethnic group that is sociopolitically disenfranchised Differing national laws or economics across the boundary, so that smuggling pays handsome profits For smuggling to be successful and stable, there must be social support. The local people must accept it morally—as a necessary evil if not as an honorable trade. Those who engage in smuggling as an occupation typically have other seasonal occupations, such as farming, fishing, trading, or crafting (Westermeyer 1982). Locally grown drugs, especially cannabis, hold much greater sway in the middle of the United States. Cannabis cash crops have become a key source of income in the Carolinas, Tennessee, Kentucky, Arkansas, Missouri, eastern Oklahoma, Kansas, and some of the western states. In these ecological niches, community leaders may be accepting—even supportive—of the drug trade, considering it a necessary evil that brings jobs and wealth into the community. Successful drug trade requires a shadow government, whose key members may share ethnic identity, kinship, and community affiliation. Security to conduct the trade, retribution in the event of nonpayment or theft, and allocation of retail franchises are key to a thriving drug trade. Status conflict may affect the decision to choose an occupation in the illicit drug trade. The distance between a person's aspired status and his or her actual status in the community constitutes the individual's status conflict. Status conflict can be a source of motivation, driving the individual to work or strive harder. An overwhelming degree of status conflict, with no possible resolution, may motivate an individual to accept the inherent risks of an illicit trade. Availability of, access to, and acceptance of illicit drugs are central features of an active drug trade within a small neighborhood or community. An illicit drug may be geographically available in a community, but all ethnic groups may not have equal access to the drug. Access involves factors such as knowing when and where drugs can be purchased, from whom they can be purchased, and how to complete a purchase. At the retail level, safety in conducting illicit sales lies in knowing one's clientele. Unfamiliar customers pose a risk. Selling only to identifiable members of one's own ethnic group may reduce this risk. Thus, for the customer to gain access to an illicit substance, the retailer must accept the potential buyer. This same analogy holds in gaining access to the wholesale trade. As one gains access to higher levels of wholesale trade, the profits mount, and the severity of the punishments (although not necessarily the risk of punishment) also may increase. In addition, the risk of theft, robbery, or violent takeover of a lucrative trade also exists. Trust can develop across cultures and ethnicities, but it is more difficult to achieve. In recent years, some communities have begun to coordinate both formal legal strictures and informal or cultural strictures (Table 45–3). Beauvais (1992) emphasized that without informal support, formal antisubstance laws are doomed to failure and may even worsen the problem of substance abuse (Thompson 1992). The pro-heroin effects of antiopium laws in several countries of Asia constitute an outstanding example (Westermeyer 1982).

EFFECTS OF ADDICTION ON ETHNIC AFFILIATION A decline in ethnic affiliation among addicted individuals accompanies reduced participation in activities

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that reinforce ethnic identity and support ethnic organizations. Examples include declining participation in extended family gatherings, religious rituals, ethnic celebrations, and other community activities. Disposable income goes to alcohol or drugs rather than to institutions representing community development. Addicted individuals who are parents contribute to anomie by not acculturating their children to the norms and values of their ethnic groups. Social role conflicts ensue when addicted individuals do not fulfill social expectations and responsibilities (e.g., parenting, working, otherwise meeting community obligations). Inability to discharge the responsibilities of a social role leads to social role conflict, with reduced social status. Alienation and isolation from an ethnic group can be either a cause or an effect of addiction. Some alienated or isolated people seek solace in substance abuse. Alternatively, an addicted individual may become alienated from his or her family, social network, and community (Holmgren et al. 1983). The effect of increasing social distance may be a reduction in the universal taboo against harming one's family or ethnic group. Thus, addicted individuals may steal from relatives and former friends, or they may use resources meant for the family to purchase drugs or alcohol. Alienation from the family produces a downward spiral into further substance abuse because of the diminished family support in dealing with loss or stress. During recovery, the regaining of trust among family and former friends always takes at least many months and may require years (Godlaski et al. 1997). As noted earlier, substance abuse may result in people losing a degree of their ethnic identity. Likewise, a renewed cultural identity may foster recovery. For example, many American Indian and Alaska Native substance abuse programs include an educational component emphasizing traditional beliefs and customs. Recovering African American patients have used the black church, a cornerstone in many African American communities, to sustain recovery (White and Sanders 2004). Findings thus far have suggested a potential benefit to positive ethnic associations.

MEDICAL COMORBIDITY AND CULTURE Rates of medical conditions known to be associated with addictive diseases have varied greatly across ethnic groups in the United States. For example, although African American and white people have relatively similar smoking rates (20.2% vs. 22.2%) (American Lung Association 2006), African American persons have disproportionately higher lung cancer mortality rates than do white persons. African American patients also manifest a shorter median survival and a lower 5-year survival after diagnosis of lung cancer (Flenaugh and Henriques-Forsythe 2006). Hispanic individuals have the highest cirrhosis rates at 13 per 100,000 compared with 8.7 for African American individuals and 6.8 for white individuals (Stinson et al. 2001). These highly variable rates probably reflect ethnic differences in health practices, health care–related disparities, and possibly genomic differences among ethnic groups. Historically, in the United States, HIV was highly prevalent among homosexual white males. However, over the past two decades, the HIV epidemic has shifted into racial and ethnic minority communities, increasing from fewer than half of the AIDS cases in 1985 to more than 70% of the total AIDS cases in 2002 (Cargill and Stone 2005). HIV epidemics associated with drug and alcohol use also have appeared in other parts of the world. In China, since 1990, for example, increased injection drug use and unsafe sexual practices have contributed to an HIV epidemic (Yang et al. 2006). In recent years, Malaysia has experienced a significant increase in HIV cases associated with heroin and methamphetamine use (Chawarski et al. 2006).

ETHNICITY AND TREATMENT Providing effective substance abuse treatment to ethnic minority populations requires an understanding of the significant health disparities that these groups have historically experienced. Despite recent progress, many ethnic minority groups continue to experience significant disparities related to addictive disease (Schmidt et al. 2006; Smedley et al. 2002). Ethnic minority groups have experienced more adverse health and social consequences from drinking than white persons have (Schmidt et al. 2006).

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These differences may be a result of limited financial resources, decreased access to treatment, and limited substance abuse research conducted in minority populations. An important component of providing effective substance abuse treatment to ethnic minority groups is the delivery of culturally competent services. The U.S. population has been growing more ethnically and culturally diverse. According to the 2000 U.S. census, individuals belonging to a racial or ethnic minority group represented approximately 30% of the population and this figure is expected to rise to approximately 50% by 2050 (U.S. Census Bureau 2004). Belonging to a particular ethnic minority group is associated with various sets of values, health beliefs, and expectations of patients that can differ from Euro-American norms (Lim 2006). Cultural differences between providers and patients may potentially decrease the ability of providers to provide effective care. Thus, in recognition of the growing diversity of the U.S. population, in 2001, the U.S. Department of Health and Human Services, Office of Minority Health, issued National Standards for Culturally and Linguistically Appropriate Services in Health Care. Acquiring an understanding of an individual's substance use disorder within the context of his or her cultural beliefs and attitudes within himself or herself, his or her family, and his or her community may assist providers in delivering care that will be acceptable and potentially more successful for their ethnic minority patients. Also, providing a treatment environment that acknowledges the needs and diversity of their minority patients may assist in ensuring culturally competent care. For example, providing ethnic minority patients with culturally tailored resources and materials, a treatment environment with culturally relevant décor, and treatment by culturally competent staff may assist in ensuring overall delivery of culturally competent care. These efforts may improve patient attendance, retention, and treatment outcomes, helping to decrease substance use treatment disparities in ethnic populations. Treatment access, like access to drugs, requires more than availability in the community. Kane (1981) found that a particular ethnic group did not seek alcohol or drug treatment from a local program because the program staff did not include any members of the ethnic group. Because of this lack in staffing, the program was not sensitive to the social aspects of addiction in that ethnic group. An element of acceptance lies in a staff's appreciating and perhaps using the models of healing and changing preferred by a particular ethnic group (Keene and Raynor 1993). Many examples of ethnicsensitive or ethnic-specific programs have been described in the literature (Argeriou 1978; Johnson and Westermeyer 2000; Red Horse 1982; Shore and Von Fumetti 1972). Perceived barriers to care can impede treatment seeking among minorities. In a community survey, the investigators asked 543 Native American veterans about perceived barriers to mental health care in Department of Veterans Affairs (VA) settings (Westermeyer et al. 2002b). An item analysis found 24 barriers that were all-inclusive and mutually exclusive. A parallel study of 100 VA staff members reported identical barriers (Westermeyer et al. 2002a). These 24 barriers fell into four general categories: 1. VA system barriers. Problems using or accessing VA services; absence of VA outreach or services in Native American communities (2.0 barriers per veteran ± 1.4). 2. Veteran barriers. Mistrust of VA, lack of knowledge of or familiarity with VA, inadequate resources to access VA (e.g., telephone, address, car, public transportation) (1.3 barriers per veteran ± 1.2). 3. VA staff member barriers. Staff's lack of familiarity or skill in providing care for Native American veterans (0.5 barriers per veteran ± 0.8). 4. Family-community barriers. Shame, stigma, not supporting veterans with mental health problems (0.04 barriers per veteran ± 0). On secondary analyses, the number of barriers reported was associated with the following: increased posttraumatic and depressive symptoms at the current time, higher lifetime rates of mood disorder, and increased use of complementary-alternative treatment during the last year. These findings suggest that perceived barriers may reduce treatment seeking in VA settings among those in need of care but favor complementary-alternative care.

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Cultural recovery involves regaining a viable ethnic identity; acquiring a functional social network committed to the person's recovery; making a religious, spiritual, or moral recommitment; reengaging in recreational or avocational activities; and gaining a social role in the recovering community, society at large, or both (Westermeyer 1992). Individuals who fail to make a satisfactory cultural recovery are at risk for readdiction. Most recovering people return to their culture of origin (or ethnic group of origin). Old conflicts, aversions, and rejections related to the culture of origin may make recovery in that culture impossible. Some people are able to recover in another cultural, ethnic, or religious group besides their own (Porter 2002). Recovering as an adult in a foreign culture or ethnic group is not a simple or brief task because individuals are best acculturated into a culture during infancy, childhood, or adolescence. Some persons who recover outside their ethnic group later provide support to their ethnic peers by helping others get treatment, by serving as a sponsor, or by hiring a recovering person. Recovery subcultures are substitute social groups and networks that can foster early recovery (Lieberman and Borman 1976). Such subcultures may have their own jargon, values, customs, symbols, status markers, and social organizations. A subculture of therapists, therapy groups, and self-help groups can guide the individual toward health and stability. These recovery subcultures can provide support as needed, can confront or challenge the recovering person according to the situation, and can help the person avoid dangerous situations that might precipitate relapse. The recovering person's family and friends may not be able to do this. In some cases, the recovery group may attempt to dominate the recovering person and keep him or her away from outside influences, even when the person is ready to cope with such influences. Likewise, people who begin recovery in religious cults may find their further progress stifled by isolation in the group. Some individuals may not be able to recover sufficiently to cope with the world as it is; consequently, some recovering people remain tied to the recovery group. Cultural reentry occurs when the recovering person reaches a point at which further progress involves branching out from the recovery subculture. Reentry may grow out of a desire for additional education, a new occupation, or a new avocation. This movement into new groups involves risks (e.g., exposure to alcohol or drugs, failure at a new enterprise, rejection by those biased against former alcoholic or addicted individuals). If the recovery subculture has done its work well, the recovering person should be prepared for this step (Westermeyer 1989).

SPECIFIC POPULATIONS Ethnic Minority Patients Recovery among ethnic minority patients may require dealing with identity issues. For these patients, substance abuse may have been a means of coping psychologically and socially with their feelings about minority status or the majority society (Lampkin 1971). During recovery, such people may find themselves consumed with ethnic issues (Westermeyer 1990). One type of problem is a negative ethnic self-identity. Another problem is an overwhelming hostility toward the majority society. Ideally, early attempts at resolving these ethnic issues should take place with a therapist or peers from the same ethnic group as the recovering person. After recovery is well under way, work with therapists or peers of other ethnic groups may not be a problem; it may even provide a means for working on cross-ethnic issues involving trust, projection, demonizing the other, and so forth. Work at a legitimate occupation can enhance the individual's self-esteem and increase his or her chances of recovery (Stead et al. 1990).

Travelers, Foreign Students, Immigrants, and Refugees Going geographic, long recognized in substance abuse subcultures, consists of an addicted person's use of travel or relocation to cope with a problem, when alcohol or drugs no longer facilitate such coping. This tactic is generally seen as a symptom of substance abuse rather than as a means of dealing with it (Kimura et al. 1975). In some cases, however, relocation may be used to promote early recovery

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efforts. Maddux and Desmond (1981) first described the utility of this method among individuals whose repeated returns to the same family, friends, work, or neighborhood precipitated relapses into substance abuse. Relocation to a different school, neighborhood, or even town can have a salutary effect, especially if accompanied by treatment, including family counseling. When returning home, the recovering person should plan carefully by considering alternatives and support systems, reentry into treatment, and other protective measures.

Victimized Persons Refugees, combat veterans, and individuals who have been raped may find that substance abuse temporarily stifles posttraumatic stress symptoms. In some cases, the symptoms may progress to posttraumatic stress disorder, which can complicate recovery. Substance abuse at the time of victimization or loss also may predispose individuals to posttraumatic stress disorder, by compromising their ability to adapt to victimization, integrate the experience, and recover from it (Green et al. 1992). Krupinski et al. (1973) studied refugees in Australia and noted a window in time—several years to a decade after relocation—when refugees are at greatest risk for developing substance abuse.

PREVENTION Prevention of substance abuse lies in creating communities safe from licit and illicit drugs. Creating such a community is a difficult, lengthy, expensive task if substance abuse is already established. The community must be able to assume responsibility for itself and to develop leadership that can establish and ensure responsible use of licit substances and eradicate illicit substances. This complex task involves close and active collaboration among public and private leaders, including those responsible for the public's health, education, and security. An approach that relies on outside agencies (e.g., the state or national government), on members of any one profession (e.g., clinicians, police, teachers), or any one sector of the population (e.g., parents, youths, workers) is doomed to failure. Moreover, once members of a community have been made safe from substance abuse, relapse to widespread substance abuse remains a risk if vigilance is suspended. Local eradication of highly prevalent substance abuse has occurred in Asian villages (Kato 1990), Native American communities (Red Horse 1982), and elsewhere (Smart et al. 1988). National prevention is also feasible but is not easily, rapidly, or cheaply accomplished (Smart et al. 1988). Passing antiaddiction legislation without undertaking intensive and extensive health, education, law enforcement, and social programs can exacerbate rather than reduce substance-related problems (Westermeyer 1974b).

KEY POINTS Knowledge about the evolution of alcohol and drug use among various cultures and ethnic groups can contribute to an understanding of substance-related problems among minorities today. The substances used and their routes of administration changed slowly and regionally until around 1500 A.D., when rapid changes resulted in the first substance-related epidemics. These changes have affected all minority groups, although in differing ways and to varying degrees. Evolving patterns of alcohol and drug use and medical comorbidities have affected cultural and ethnic groups in both similar and divergent ways. Awareness of historical and cultural factors can prove crucial in preventing or ameliorating such problems. For minority ethnic groups, the relationship with the majority society as well as internal dynamics within the group can affect how substances and their use and abuse are perceived and how related problems are addressed. Prevention and treatment involve not only medical and public health measures but also possible changes in minority community attitudes and mores, laws and law enforcement, education, the mass media, technology, and other aspects of our current ever-changing culture and its ethnic groups. Perceived barriers to care within a minority group can impede treatment seeking, even when services are available. These barriers may involve the type of service provided but also may involve the clinicians providing these services, the potential patients themselves, and the patients' families and communities.

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SUGGESTED READING National Institute on Alcohol Abuse and Alcoholism: A Call to Action: Changing the Culture of Drinking at U.S. Colleges. Bethesda, MD, National Institute on Alcohol Abuse and Alcoholism, 2002 Ruiz P: Ethnicity and Pharmacology. Washington, DC, American Psychiatric Press, 2000 Satcher D: Mental Health: Culture, Race, and Ethnicity; A Supplement to Mental Health: A Report to the Surgeon General. Washington, DC, U.S. Public Health Service, 2001, p 169 Tseng WS: Clinician's Guide to Cultural Psychiatry. San Diego, CA, Elsevier, 2003 Tseng WS, Streltzer J: Culture and Psychotherapy: A Guide to Clinical Practice. Washington, DC, American Psychiatric Press, 2001 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 46. Testing to Identify Recent Drug Use

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Robert L. DuPont, Carl M. Selavka: Chapter 46. Testing to Identify Recent Drug Use, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.358399. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Testing to Identify Recent Drug Use Robert L. DuPont, M.D. Carl M. Selavka, Ph.D.

TESTING TO IDENTIFY RECENT DRUG USE: INTRODUCTION The diagnosis of substance use disorder, like most other medical diagnoses, is primarily clinical, with the patient's history and the mental status examination playing central roles in the diagnostic process. Nevertheless, laboratory testing to identify recent drug use is increasingly important in clinical settings, ranging from the initial diagnosis to treatment management and from research and epidemiology to health care assessment. Drug testing identifies the recent use of specific abused substances and in some settings can help to differentiate chronic or repetitive ingestions from single or low-frequency uses. Laboratory testing is especially helpful in medical settings as part of the screening process to identify patients for evaluation for substance use disorder. In this chapter, we review the uses of drug testing. We describe the tests that are now in common use, including the science on which they rely, the information that these tests can provide to clinicians, and information about some potential strategic considerations when choosing from among the wide range of drug tests now available. Drug testing in addiction medicine can identify the recent, repetitive, or even the prospective use of particular drugs of abuse. Drug tests cannot detect or measure drug-caused impairment, physical dependence, or addiction to alcohol or other drugs (DuPont 2000). Those clinically important assessments rely, like the diagnosis of addictive illness itself, primarily on clinical assessments, with the laboratory findings often providing complementary supportive data. Drug tests are particularly useful because they identify recent drug use in settings where that information is of diagnostic significance (e.g., in emergency department and other medical care settings) and where the information has value in reinforcing a drug-free standard (e.g., in drug treatment, the criminal justice system, the workplace, and schools).

BIOLOGY OF DRUG TESTS Two of the hallmarks of addictive disorders are continued use despite problems caused by that use and dishonesty (DuPont 2000). Addicted people characteristically deny to themselves and to others the negative consequences of their alcohol and other drug use, and they characteristically lie about their alcohol and other drug use to anyone who might interfere with their continued substance use (DuPont 1998). Users of illegal drugs may not know what drugs they are taking, so that even if they wanted to tell their doctors their current drug use history, they may not be able to do so. Many people who have positive test results for recent drug use claim that the use leading to the positive test was isolated—or even the first time they used; this is exceedingly unlikely. Rare or occasional use of drugs is unlikely to be detected by drug testing. In fact, the vast majority of positive drug test results reflect repeated, continuous drug use (DuPont 1996; DuPont et al. 1995). Users of alcohol and other drugs consume their substances of choice for the specific effects these substances have on the reward centers of their brains (DuPont and Gold 1995; Volkow et al. 2002, 2004). To achieve this brain-rewarding effect, users consume the drugs by many routes of administration, including oral, intranasal, smoking, and injecting. The common preference of many experienced drug users involves the routes of administration that produce the most rapid increase in

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blood levels because these are most intensely rewarding (Wise 2003). Once consumed, the abused drugs are distributed so widely that they can be identified in virtually all parts of the body and in all body fluids and tissues. The drugs are typically metabolized by the liver and in the blood, each drug producing characteristic metabolites that are often longer-lasting and detectable at higher levels than the parent drug. Although the pharmacokinetics of this process are complex and substance-specific, the general pattern is universal. This common pattern makes testing for all drugs of abuse similar and relatively easily understood. On the other hand, the pharmacokinetics of each drug are important in the linkage of laboratory results to specific patterns of recent drug use. Although a wide range of techniques can be used to identify drugs and their metabolites, modern testing for drugs of abuse has settled into a sequence that usually begins with a relatively inexpensive immunoassay screening test, which has high sensitivity but not necessarily high specificity. This means the immunoassay screen can detect very low levels of drugs and drug metabolites in the tested specimen, but the results occasionally can be confounded by cross-reactivity with nondrug substances. Immunoassay drug tests depend on patented monoclonal antibodies that are developed to be highly specific to individual drugs or drug metabolites. For this reason, cross-reactivity with current immunoassay drug tests is seldom a problem. The immunoassay screening tests are widely used because they can be automated for laboratory testing and can be used to produce on-site test kits. In the workplace and other settings where drug test results must be forensically defensible, presumptive positive results from screening drug tests are confirmed with a highly specific confirmation test, such as a gas chromatography/mass spectrometry (GC/MS) test. This test is not subject to cross-reactivity and is specific to a single drug or drug metabolite. Screening tests can be performed on-site and do not require a clinical laboratory, although confirmation tests are performed only in a laboratory. This picture of a presumptive immunoassay screening test followed by a more sophisticated and expensive confirmation test can be used to produce optimal reliability for all tested specimens from urine and blood to sweat, saliva (now called oral fluid for biological accuracy), and hair. In many settings where this forensic standard is unnecessary, including most routine, frequently repeated drug testing in addiction treatment and the criminal justice system, an immunoassay test may be sufficient without confirmation (DuPont and Selavka 2003). The one exception to this general testing regimen involves the determination of the presence of ethanol. For this volatile substance, breath testing using relatively automated methods and oral fluid tests provide generally reliable results without the need for a separate confirming test to meet forensic standards. Over-the-counter drug kits are now available for home use, for example, for parents who use drug tests to deter or detect drug use by children. In this setting it is useful to have education about what drug tests do and do not do and to help manage positive test results (DuPont and Bucher 2005). One common misunderstanding about drug testing relates to the drugs being identified. Virtually all drugs of abuse can be identified with immunoassay screens that are specific to individual drugs. Each targeted drug requires a separate antibody test, which involves separate costs (Selavka 1997). Most laboratories and on-site drug test kits use limited screens for a small number of drugs in panels that are bundled to keep costs relatively low. When a test subject is thought to be using drugs outside of the narrow list of commonly used drugs, special order and more comprehensive laboratory tests are needed. In other words, drug tests do not identify "drug use" in a global sense. They do identify the recent use of the specific drugs that are targeted on the test sample. Therefore, when interpreting drug test results, it is important to know which specific drugs were targeted in specific test samples. Drugs of abuse other than those on the list of drugs targeted in the particular sample will not be identified, even if their use is recent and has had major behavioral or health effects.

SAMPLE SELECTION: URINE, HAIR, ORAL FLUIDS, OR SWEAT Two decades ago, when drug-testing technology was relatively primitive, the only commonly used sample for drug testing was urine, in which drugs and drug metabolites are relatively concentrated and easily identified without the need for complex extraction techniques. In earlier years, these initial drug

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tests were always done at large clinical chemistry laboratories. The exception was breath and blood testing for alcohol, which has been common for several decades. In more recent years, as drug-testing technology has improved and as more reliable procedures for collection and sample handling have been developed, it has become more practical to test sweat, oral fluid, and hair to identify recent drug use. Regardless of the sample selected, the drug tests themselves use the same highly reliable science in the same pattern of screening tests, followed, when indicated, by a confirming test. The sample selected for alcohol and other drug testing reflects many factors, including ease of access, cost of the test, and the most appropriate detection window (i.e., the period of time that is sampled to identify drug use). Breath, oral fluid, and hair samples are the most easily collected, whereas urine can present logistical and reliability issues, and blood and organ samples (such as liver biopsies) are the most difficult to obtain. When considered as a part of a total patient assessment, costs of analysis are similar, although hair, oral fluid, sweat, and blood testing are somewhat more expensive than urine testing. Sweat, oral fluid, and hair testing are done only at a limited number of specialized laboratories at present, but urine testing is done at most clinical laboratories and dozens of federally accredited specialized urine drug-testing laboratories. Urine testing kits are commonly used for on-site screening, providing results within a few minutes of collection. Oral fluid tests also can be performed on-site. If alcohol and other drug testing takes place in the workplace, then legal regulations are important considerations, including secure collection with forensic standards of specimen handling and laboratory confirmation (U.S. Department of Health and Human Services 1988, 1994). Because the level of drug or drug metabolite in urine is strongly influenced by recent fluid consumption, urine levels do not equate with blood levels. For this reason, and because blood and urine levels change rapidly over even short periods of time, urine results are read as either positive or negative at specific cutoff levels. Because both sweat patches and hair tests are not subject to the effects of fluid consumption and because they sample long time periods, both sweat patch tests and hair tests permit rough quantitation of drug use over the time periods sampled. Blood has the shortest window of detection because most drugs are cleared from the blood at measurable levels in 12 hours or less. Urine has a detection window of about 1–3 days because most drugs are cleared within this time after the most recent use of the drug (Jufer et al. 2000). This is true even for marijuana, unless the tested individual has been a chronic heavy smoker of marijuana, in which case the urine results may remain positive for up to a month after use stops. Even with the availability of today's more potent marijuana, after smoking one or two marijuana cigarettes (in the absence of prior heavy chronic marijuana use), urine testing results are negative in many subjects within 24 hours, and all results will be negative at the 100-ng/mL cutoff within 3 days. After smoking one or two marijuana cigarettes, urine test results will be negative in most subjects at the more sensitive 20-ng/mL cutoff within 5 days of last marijuana use (Schwartz 1998). Head hair grows at the rate of about 0.5 inches (or a bit more than 1 cm) per month. With each day of drug use, newly created hair cells incorporate drug from the bloodstream on that day, creating a virtual day-by-day "tape recording" of drug use. If a tested person has only a single day of drug use, the incorporation of drug into hair is predominantly localized to the tiny 0.3-mm length of hair representing that one day. When surrounded by the "ocean of abstinence" represented by hair growing on days without drug use, this single ingestion cannot be detected with conventional hair drug tests. Positive hair-testing results are generally expected only when a person has used a drug at least four to six times (at typical nonmedical doses) per month when conventional hair-test reporting thresholds (cutoffs) are used. For many hair drug-testing laboratories, even greater frequency of marijuana use is required before a tested person's routine recreational marijuana smoking becomes detectable at or above common testing cutoffs. For this reason, hair-testing positive results are generally interpreted as reliable indicators of chronic or at least frequently repeated and recent drug ingestion (Morrison et al. 1998). This longer detection window for testing hair, coupled with the ability to distinguish between

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light, moderate, and heavy use during the prior 90 days, makes it especially useful as part of the evaluation for admission to addiction treatment (Charles et al. 2003). It takes about a week for the hair to grow long enough from the base of the hair follicle in the scalp to the external skin surface. Thus, a standard 1.5-in sample of head hair contains drug residuals from the prior 90 days, minus the week immediately before sample collection. Hair testing is particularly useful and superior to urine testing in various situations in which the longer detection window is important (DuPont and Baumgartner 1995). Because preemployment urine drug testing is a scheduled test, a drug user has to refrain from nonmedical drug use for only 3–5 days before submitting a urine sample to pass a urine test for abused drugs. It is much harder for most dedicated drug abusers to refrain from drug use for 90 days before preemployment testing, the period covered by a standard hair sample. Longer hair, and therefore longer time periods, also can be tested as special order tests. If such longer time periods become important, or if a specific time between known periods of abstinence in a longer length of hair is critical, the testing laboratory can work with the clinician to properly segment and/or interpret results to maximize the probative information produced by such examinations. Hair is always collected by a third party under direct observation, not by the tested person in the absence of observation. Therefore, in contrast to urine samples, hair samples do not pose problems with sample substitution, adulteration, or dilution. However, hair treatments, such as perming, bleaching, and straightening, may reduce drug levels in hair in a way that can convert borderline positive results to negative results. Conventional hygienic hair treatments have little effect on the detection of drug use with hair tests. Hair is also less offensive to collect than urine and easier to store and transport. This higher threshold for a positive hair-test result means that eating poppy seeds will not produce a positive hair laboratory test result for opiates, as it commonly does in urine tests that do not include specific, sensitive testing for unique metabolites of heroin. Positive laboratory results for opiates on urine tests are routinely reversed by medical review officers, making testing of urine samples for opiates in the workplace all but worthless because of the poppy seed problem. More importantly, high cutoffs for urine opiate detection now in widespread use make it nearly impossible to detect abusers of heroin—a substance for which hair testing is particularly well suited. In recent years, there has been concern about possible racial bias in hair testing because of the potential for different drug levels to be retained in hair of different colors. This issue came up as a result of a study of drug levels in the hair of different colors on the same laboratory mouse (Uematsu et al. 1990). This concern about hair color has sometimes been conflated into an issue of racial differences in hair-test results. The claim is not that one race has inherently positive hair test results but that if people of different races use the same amount of drug (and in this debate, it usually has related to black individuals and cocaine), one race will have higher levels in the hair than the other race, leading to more positive hair-test results even if the levels of drug use are the same in the two racial groups. No data from large samples show racial bias in hair testing in human subjects. However, to test the hypothesis that hair tests are biased, both urine and hair tests were used in a large sample of police applicants. The results for cocaine are shown in Table 46–1. This study found that among black males, urine tests showed that 11 had positive test results for cocaine and 473 had negative test results; for white males, urine tests showed that 5 had positive test results for cocaine and 857 had negative test results. For hair tests in this same study, black males had 41 positive test results for cocaine and 443 had negative test results; for white males, hair tests showed that 20 had positive test results and 842 had negative test results. The odds ratio for hair tests compared with urine tests for cocaine for black males was 3.99 and for white males it was 3.90, virtually identical. If hair tests were biased compared with urine tests for cocaine, the odds ratio would have been significantly higher for hair than for urine. In fact, in this large real-life study, the odds of positive urine test results for black compared with white individuals were slightly higher than the odds ratio for hair test results (Mieczkowski and Lersch 2002; Mieczkowski and Newel 2000). The take-home message is that all modern drug tests use the same basic testing science—the

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immunoassay screen and the GC/MS (or equivalent) confirming test. Drug tests use this science to identify individual drugs and drug metabolites reliably and specifically in tested samples. This is true for urine, hair, sweat, and oral fluid testing. If this two-step process identifies the drug, then it is present. A person who has not consumed the drug of abuse being tested for will have a negative test result whether the test matrix is urine, hair, sweat, or oral fluids. However, it is possible for innocent exposure to produce a positive test result (as we describe later in this chapter, poppy seeds can produce a positive result for morphine on urine tests, and hand sanitizers can cause a positive alcohol result with ethyl-glucuronide [EtG] testing). These are not false positive results because morphine is present in urine after poppy seed consumption, and EtG is in the urine after intense use of an alcohol-containing hand sanitizer. Also, biological variations in the probability of a positive drug test result occur despite similar consumption of all drugs. For example, a small woman will have a higher blood alcohol concentration (BAC) for a given amount of alcohol consumed than will a large man. Of course, neither the small woman nor the large man will have positive test results if they have not consumed (or recently been exposed to) alcohol. Decades of experience with alcohol and other drug tests have shown that there is no reason to normalize drug test results so that the same dose of the drug produces the same result across large biological differences, including gender, age, and weight. Workplace drug testing conducted under federal guidelines is limited to a small number of drugs (codeine/morphine, amphetamine/methamphetamine, phencyclidine [PCP], marijuana, and cocaine) with laboratory-based urine tests. This means that the use of any other drug, many of which are commonly abused, is not detected under federal guidelines, including lysergic acid diethylamide (LSD), methylenedioxymethamphetamine (MDMA; "ecstasy") and other stimulants, and synthetic opioids (e.g., hydromorphone, oxycodone, and methylphenidate). These federal guidelines apply only to federally mandated drug testing (for federal workers and for Department of Transportation–mandated tests). All other drug testing, including testing in drug treatment programs, is not limited by the currently antiquated federal drug-testing standards. Nevertheless, many organizations that use drug tests in nonworkplace settings are unaware of the wider options available. Unfortunately, they often limit testing to these five drugs in urine tested at federally certified laboratories. Because preemployment drug testing dominates the drug-testing industry, most laboratory offerings and test kits focus on this narrow range of abused drugs. Urine tests, when used under nonregulated standards, can target a widely expanded list of controlled substances, offering important diagnostic information as is currently recognized and established by the comprehensive random drug testing routinely used by the U.S. military. The military test scheme includes testing all samples for the most commonly abused drugs, such as marijuana, cocaine, methamphetamine, and heroin, but then adding a rotation of other drugs to the panel in a random fashion so that the tested person does not know which other drugs are being tested for. This approach preserves the deterrent value of the test but limits the cost of testing. It also permits the military to keep track of the positive rates for many drugs over time so that if a new drug emerges as commonly abused, it can be added to the panel of drugs used to test all service personnel. This sophisticated approach to drug testing can be used in other settings, including drug treatment (DuPont and Graves 2005). Even a single dose of the most commonly abused substances—including inhalants (such as nitrous oxide), solvents (involved in "huffing"), and myriad drugs available to medical professionals (e.g., meperidine, fentanyl)—can be detected in urine in the 1–3 days after ingestion. But the clinician will need to use a reference toxicology laboratory to provide these specialty urine-testing services, often at substantially higher costs. Cheating, facilitated by the Internet and by determined opponents of drug testing, is the Achilles' heel of urine drug tests. Cheating can be reduced by direct observation of collection, but cheating is an inherent problem with urine tests. This limitation of the urine test is offset to some extent by several other important factors. Testing urine is generally less expensive than testing hair, oral fluids, or sweat, and it is far more widely available. When a wider list of drugs is needed in the screen, urine is usually the best

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choice because so many laboratories do urine tests, and most laboratories doing hair and oral fluid testing are limited in the range of drugs they can identify. Sweat patch testing is a relatively new matrix for drug testing, compared with urine, blood, and hair. The person wears a patch, similar to a nicotine patch worn by people attempting to quit smoking. Once removed, the patch cannot be replaced without noticeable puckering of the edges of the sweat test collection device. This feature provides reasonable integrity in the sweat patch collection process. Sweat is continuously absorbed into the pad component of the patch, with the water in the sweat evaporating through the outer patch membrane while the drugs of abuse and their metabolites accumulate on the absorbent pad. Because skin continuously desquamates, drug detection sweat patches can be worn for periods from a few hours to a few weeks, after which they fall off. During that time, they prospectively collect evidence of drug use rather than the retrospective "historical" data provided by drug tests performed on all other common matrices. Once removed under direct observation, the patches are sent to a laboratory for testing. Patches are commercially tested for the detection of cocaine, opiates, marijuana, PCP, and amphetamine/methamphetamine. Sweat patch testing is especially useful for treatment follow-up testing and in return-to-work settings when daily urine testing for drug use is impractical. Sweat patches are not routinely marketed for the detection of alcohol use, but alcohol detection patches may find greater application now that EtG has become a useful target metabolite for alcohol use in the prior 3–5 days (see discussion of EtG testing in the "Alcohol Testing in Urine" section later in this chapter). Hair testing and sweat patches offer important advantages over urine testing for abused drugs in many settings, including during treatment. Both are far more resistant to cheating, both offer rough quantitation (enabling the separation of heavy users from light users), and both more reliably produce positive test results for opiates after heroin ingestion. Oral-fluid testing for drugs of abuse is now commonly used by the insurance industry to detect nicotine (as its metabolite cotinine), cocaine, and other drug use. Oral fluid testing for abused drugs has gained popularity in the workplace and other settings (Barnes et al. 2003). For example, oral-fluid tests of impaired drivers can significantly improve the overall detection of ingested drugs in drivers regardless of whether these impaired drivers also drank alcohol. Oral fluid is in equilibrium with blood. For this reason, oral-fluid testing can detect drug use only within the prior 6–12 hours. Oral-fluid testing for alcohol is also available. Because oral fluid is easily obtained (unlike urine and blood) and can be screened on site (unlike hair samples), it is especially useful in postaccident and highway testing and in other settings in which immediate results and easy collection are important. The one limitation of oral fluid testing is that currently available on-site oral fluid test kits are much less effective than urine testing and laboratory-based oral fluid testing in detecting recent marijuana use. Oral fluid and urine tests have similar positive rates for other commonly used drugs of abuse in side-by-side testing (Yacoubian et al. 2001). In general, when hair testing and oral fluid testing are done at the same time on the same individuals as urine testing, more positive results are found with hair testing and fewer are found with oral-fluid testing, as can be seen comparing the positive rates of urine and hair testing on the same subjects in Table 46–1. These different positive drug test rates are primarily the result of the longer detection window of hair and the shorter detection window of oral fluids compared with urine, the drug test matrix most commonly used today. When testing is done repeatedly on the same individuals, as is typical in drug treatment and the criminal justice system, one way to maximize the benefits of the range of matrices now available is to rotate the testing matrix so the person being tested does not know whether a particular test will use urine, hair, or oral fluids. This strategy dramatically reduces the risk of cheating. It also allows the testing organization to compare the rates of positive test results with these three methods in ways that help to tailor the testing to be most cost-effective (DuPont and Graves 2005). Table 46–2 lists the commonly used matrices for drug testing and provides a summary of the typical applications of each, including their strengths and limitations.

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ON-SITE VERSUS LABORATORY DRUG TESTS About two decades ago, drug tests were virtually all done in large clinical chemistry laboratories, but today, with improved technology, drug tests can be done on-site with the use of test kits developed by many manufacturers. The major advantage of on-site testing is that the results are available within minutes. On-site drug tests have been developed for urine and oral fluids, neither of which requires extraction before testing. The on-site tests are immunoassays and, therefore, should be used as presumptive screening tests. In settings where forensic standards need to be met (e.g., when major consequences follow a single positive test result, such as in workplace drug tests), it is important to conduct a confirmation test requiring sophisticated equipment, usually available only at a laboratory. Because the vast majority of drug tests have negative results, use of on-site kits for the screening has tremendous practical advantages. For example, in drug treatment or probation and parole settings, on-site tests permit rapid assessment while the sample donor is at the testing site. However, two limitations need to be considered when using on-site screening drug tests rather than sending samples to a laboratory for the initial screening test. First, in settings where forensic standards must be met, a screening positive result must be considered a "presumptive positive." Therefore, implementation of the consequences for a positive test must be withheld until a confirmation test result is returned from the laboratory, which can take an additional day or longer. Second, on-site tests may be less sensitive (Walsh et al. 2003). This means that it is common to get presumptively negative results from on-site samples that laboratories would identify as a positive result. Because a test sample screened as negative is not routinely sent for a confirmation test, this false- negative problem is serious and is not corrected by the second, confirmation test. Far less often is the on-site test positive and the confirming test negative, but this outcome does occur. That is the reason that the confirmation test is critical in forensic settings. Nevertheless, despite these problems, on-site testing is a valuable option in many testing settings, including drug treatment. The problem of false negative results from on-site test kits can be assessed in programs by sending a significant percentage of test samples to the laboratory whether they screen negative or positive on the on-site test (Cone et al. 2003). With these data, it is possible to determine the probability of a false negative result on the on-site screen for each specific drug. Usually, marijuana, which is present in lower concentrations in urine and oral fluids, is the drug most likely to produce false negative results in on-site testing. The testing program can then balance that problem against the obvious benefits of the on-site screen and determine the best course of action.

DEALING WITH DIFFICULT RESULTS Most drug test results are easy to interpret, but in some instances, drug test results can be difficult to interpret, particularly if the tested individual disputes the positive result. Typically, the tested person admits to the recent drug use when confronted with a positive drug test result. If the result is difficult to interpret, it is wise to get help in interpreting the drug test result. Help can be found in two ways. The first is to contact the laboratory that did the test or, for on-site tests, the manufacturer of the test kits. They have access to forensic toxicologists who are usually able to provide expert advice on the interpretation of puzzling drug test results. The second strategy when confronted by a difficult drug test result is to contact a local medical review officer, a trained and certified physician who has expertise in interpreting drug test results. Lists of medical review officers can be accessed through the American Society of Addiction Medicine List of Medical Review Officers or the American Association of Medical Review Officers Registry (http://www.aamro.com /registry_search.html). In addition, local drug-testing laboratories have lists of medical review officers who can be contacted. Because drug tests are not always easily understood or well used, larger treatment and other programs doing drug tests should designate a specific staff member to learn how to interpret complex or confusing drug test results, so that the program has in-house expertise. The textbook of the American Society of Addiction Medicine, Principles of Addiction Medicine (Graham et al. 2003), is a reliable source with good

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and up-to-date information about drug tests. The American Society of Addiction Medicine and American Association of Medical Review Officers also offer courses for medical review officer certification, which can be helpful for physicians who want to learn more about drug tests and their interpretation. For help in developing and managing drug testing in specific settings, see three handbooks recently published by Hazelden covering drug tests in drug treatment, the criminal justice system, and schools (DuPont and Brady 2005; DuPont et al. 2005a, 2005b).

ALCOHOL TESTING IN URINE Although breath and blood testing is common and well understood (having been commonly applied in clinical settings for decades), alcohol also can be detected in urine along with other drugs of abuse. However, because urine in the bladder has been produced by the kidneys since the prior micturition and because urine concentration of alcohol and other drugs is largely determined by fluid consumption, the alcohol level in the urine sample is not correlated with the blood alcohol level. Alcohol is eliminated from the blood (and therefore from urine and breath) within a few hours of consumption, so urine test results are likely to be negative for alcohol a few hours after drinking stops. This short detection window for alcohol in the urine contrasts with the 1- to 3-day window during which urine is positive for most drugs of abuse following the last nonmedical drug dose. Because alcohol is rapidly eliminated from the body, testing of the breath, urine, or oral fluids will detect only alcohol use within the previous few hours. This biology makes alcohol testing useful in detecting recent and potentially impairing alcohol use (because both breath and oral fluid results permit quantification of the current BAC). However, standard alcohol tests are of very limited value when the standard is no use of alcohol, as is typical in substance abuse treatment. Within the last few years, a urine test has been developed for one of the common and relatively stable metabolites of alcohol, EtG (Skipper et al. 2004a, 2004b). EtG generally can be identified in the urine 3–5 days following drinking. This test is not useful unless drinking itself (as opposed to heavy drinking or impaired driving) is important to identify. This is the case in alcohol and other drug treatment programs when abstinence from alcohol consumption is a program requirement. It is also the case for people younger than the legal drinking age and for people under supervision of the criminal justice system when alcohol consumption is prohibited. EtG testing in urine is now widely available from drug-testing laboratories. The interpretation of EtG results can be difficult, however, because exposure to nonbeverage alcohol is widespread in the community (e.g., in mouthwashes and hand-sanitizing gels). Thus, a negative EtG test result reliably confirms that no alcohol consumption has occurred during the prior 3–5 days, a finding of great importance in many settings. Conversely, a positive EtG test result may or may not indicate recent consumption of beverage alcohol. One way to handle this confounding problem is to educate the tested person about the environmental exposure to alcohol so that these exposures can be avoided. This is similar to educating the heroin-addicted person in treatment about the possibility that poppy seeds may produce a positive result for morphine in urine. For this reason, it is important for the person being tested to avoid eating poppy seeds. When EtG testing is used, clinicians must heed the recommendations of the testing laboratory on the interpretation of results because this is a new test, and the applications of the test are rapidly evolving. Recently, studies of EtG levels in hair have been initiated both to differentiate social alcohol drinkers from problem-generating heavy drinkers and to distinguish beverage consumption from nonbeverage exposure to alcohol in the same way that hair testing separates poppy seed consumption from heroin use, a separation that urine tests cannot achieve. Studies are also under way with the unique cocaine metabolite found when alcohol is also consumed, cocaethylene (Politi et al. 2006, 2007; Wurst et al. 2003a, 2003b). Cocaethylene is routinely applied in drug-testing applications to identify polydrug abusers who consume both cocaine and alcohol. EtG testing, now commercially available for urine testing, may become more commonly available not only in hair testing but also in sweat patch and oral-fluid testing in the future.

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CONCLUSION Today drug testing makes use of the highest levels of modern biotechnology to detect reliably the presence of specific abused drugs and their unique metabolites in a growing number of matrices. Drug tests provide valuable information about the recent use of alcohol and other abused drugs. Drug testing is essential in both the diagnosis of substance use disorders and the evaluation and treatment of these disorders. During drug abuse treatment, drug testing encourages treatment adherence and abstinence from alcohol and other drug use. Drug testing also permits the early detection of relapse to substance use, thus enabling timely and appropriate intervention. Understanding the science of drug testing and the practical aspects of how drug tests work and how to interpret the results of drug tests have become essential skills for everyone involved in modern drug abuse treatment.

KEY POINTS Because drugs of abuse are distributed to virtually every part of the user's body, they can be detected in all fluids and tissues. Urine is the most commonly used matrix for drug testing, but hair, oral fluid (saliva), and sweat patches are increasingly used. No one matrix is best; they each have their strengths and weaknesses. Drug tests detect recent drug use. They do not detect dependence, intoxication, impairment, or addiction. Most drug test results are confirmed by the sample donor's admission of recent drug use. Difficult and disputed cases benefit from additional help in interpretation, including assistance from the laboratory that conducted the test or the kit manufacturer for on-site tests and a certified medical review officer. Smarter drug testing requires the use of all four common test matrices (urine, hair, oral fluid, and sweat patches) so the donor does not know which matrix will be used. It is desirable to vary the drugs tested for. This approach reduces cheating, improves the deterrent effect of testing, and permits comparison over time of the rates of positive results for the various matrices.

REFERENCES Barnes AJ, Kim I, Schepers R, et al: Sensitivity, specificity, and efficiency in detecting opiates in oral fluid with the Cozart Opiate Miroplate EIA and GC-MS following controlled codeine administration. J Anal Toxicol 27:402–407, 2003 [PubMed] Charles BK, Day JE, Rollins DE, et al: Opiate recidivism in a drug-treatment program: comparison of hair and urine data. J Anal Toxicol 27:412–428, 2003 [PubMed] Cone EJ, Sampson-Cone AH, Darwin WD, et al: Urine testing for cocaine abuse: metabolic and excretion patterns following different routes of administration and methods for detection of false-negative results. J Anal Toxicol 27:386–401, 2003 [PubMed] DuPont RL: Do random workplace drug tests primarily identify casual or regular drug users? MRO Update July/August:5–7, 1996 DuPont RL: Addiction: a new paradigm. Bull Menninger Clin 62:231–242, 1998 [PubMed] DuPont RL: The Selfish Brain: Learning From Addiction. Washington, DC, American Psychiatric Press, 2000 DuPont RL, Baumgartner WA: Drug testing by urine and hair analysis: complementary features and scientific issues. Forensic Sci Int 70:63–76, 1995 [PubMed] DuPont RL, Brady LA: Drug Testing in Schools: Guidelines for Effective Use. Center City, MN, Hazelden, 2005 DuPont RL, Bucher RH: Guide to responsible family drug testing and alcohol testing. Rockville, MD, Institute for Behavior and Health, Inc., 2005

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DuPont RL, Gold MS: Withdrawal and reward: implications for detoxification and relapse prevention. Psychiatr Ann 25:663–668, 1995 DuPont RL, Graves H: Smarter student drug testing. Rockville, MD, Institute for Behavior and Health, Inc., 2005 DuPont RL, Selavka CM: Drug testing addiction treatment and criminal justice settings, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 1001–1008 DuPont RL, Griffin DW, Siskin BR, et al: Random drug tests at work: the probability of identifying frequent and infrequent users of illicit drugs. J Addict Dis 14:1–17, 1995 [PubMed] DuPont RL, Mieczkowski T, Newel R: Drug Testing in the Criminal Justice System. Center City, MN, Hazelden, 2005a DuPont RL, Newel R, Brethen P: Drug Testing in Drug Abuse Treatment. Center City, MN, Hazelden, 2005b Graham AW, Schultz TK, Mayo-Smith MF, et al. (eds): Principles of Addiction Medicine, 3rd Edition. Chevy Chase, MD, American Society of Addiction Medicine, 2003 Jufer R, Wstadik A, Walsh S, et al: Elimination of cocaine and metabolites in plasma, saliva, and urine following repeated oral administration to human volunteers. J Anal Toxicol 24:467–477, 2000 [PubMed] Mieczkowski T, Lersch K: Drug testing police officers and police recruits: the outcome of hair analysis and urinalysis compared. Policing: An International Journal of Police Strategies and Management 25:581–601, 2002 Mieczkowski T, Newel R: Statistical examination of hair color as a potential biasing factor in hair analysis. Forensic Sci Int 107:13–38, 2000 [PubMed] Morrison JF, Chesler SN, Yoo WJ, et al: Matrix and modifier effects in the supercritical fluid extraction of cocaine and benzoylecgonine from human hair. Anal Chem 70:163–172, 1998 [PubMed] Politi L, Morini L, Leone F, et al: Ethyl glucuronide in hair: is it a reliable marker of chronic high levels of alcohol consumption? Addiction 101:1408–1412, 2006 [PubMed] Politi L, Zucchella A, Morini L, et al: Markers of chronic alcohol use in hair: comparison of ethyl glucuronide and cocaethylene in cocaine users. Forensic Sci Int 172:23–27, 2007 [PubMed] Schwartz H: Urine testing in the detection of drugs of abuse. Arch Intern Med 148:2407–2412, 1998 Selavka C: Testing for drugs in hair. The Prosecutor 31:38–44, 1997 Skipper GE, Weinmann W, Theirauf A, et al: Ethyl glucuronide: a biomarker to identify alcohol use by health professionals recovering from substance use disorders. Alcohol 39:445–449, 2004a Skipper GE, Weinmann W, Wurst FM: Ethylglucuronide (EtG): a new marker to detect alcohol use in recovering physicians. Journal of Medical Licensure and Discipline 90(2):14–17, 2004b Uematsu T, Sato R, Fujimori O, et al: Human scalp hair as evidence of individual dosage history of haloperidol: a possible linkage of haloperidol excretion into hair with hair pigment. Arch Dermatol Res 282:120–125, 1990 [PubMed] U.S. Department of Health and Human Services: Mandatory guidelines for federal workplace drug testing programs. 53 Federal Register 11979 (1988) U.S. Department of Health and Human Services: Proposed revisions to mandatory guidelines for federal workplace drug testing programs. 59 Federal Register 29908 (1994) Volkow ND, Wang G, Fowler JS, et al: Brain DA D2 receptors predict reinforcing effects of stimulants in

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humans; replication study. Synapse 46:79–82, 2002 [PubMed] Volkow ND, Fowler JS, Wang G: The addicted human brain viewed in the light of image studies: brain circuits and treatment strategies. Neuropharmacology 47 (suppl 1):3–13, 2004 Walsh JM, Flegel R, Crouch D, et al: An evaluation of rapid point-of-collection oral fluid drug-testing devices. J Anal Toxicol 27:429–439, 2003 [PubMed] Wise R: Brain reward circuitry: insights from unsensed incentives, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 57–71 Wurst FM, Skipper GE, Weinmann W: Ethyl glucuronide—the direct ethanol metabolite on the threshold from science to routine use. Addiction 98 (suppl 2):51–61, 2003a Wurst FM, Vogel R, Jachau K, et al: Ethyl glucuronide detects recent alcohol use in forensic psychiatric inpatients. Alcohol Clin Exp Res 27:471–476, 2003b Yacoubian GS, Wish ED, Perez DM: A comparison of saliva testing to urinalysis in an arrestee population. J Psychoactive Drugs 33:289–294, 2001 [PubMed]

SUGGESTED READING DuPont RL, Selavka CM: Drug testing addiction treatment and criminal justice settings, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 1001–1008 DuPont RL, Newel R, Brethen P: Drug Testing in Drug Abuse Treatment. Center City, MN, Hazelden, 2005 Willette R: Drug testing in the workplace, in Principles of Addiction Medicine, 3rd Edition. Edited by Graham AW, Schultz TK, Mayo-Smith MF, et al. Chevy Chase, MD, American Society of Addiction Medicine, 2003, pp 993–1000 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 47. Medical Education

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Erik W. Gunderson, Frances R. Levin, Petros Levounis: Chapter 47. Medical Education, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.978158 5623440.358830. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Medical Education Erik W. Gunderson, M.D. Frances R. Levin, M.D. Petros Levounis, M.D.

MEDICAL EDUCATION: INTRODUCTION During the past five decades, there has been an increasing awareness of the need for improvement in substance abuse education for medical students, residents, and practicing physicians. In 1956, the annual report of the American Medical Association emphasized that alcoholism is an illness and should be regarded within the purview of medical practice. This set the stage for a series of "milestones" outlined by Lewis (1990) that included a federally funded Career Teacher Program in 1971, the establishment of several specialty organizations (e.g., the American Society of Addiction Medicine [ASAM], initially known as the American Medical Society on Alcoholism; the Association for Medical Education and Research in Substance Abuse; and the American Academy of Addiction Psychiatry [AAAP]), and the development of fellowships in alcoholism and substance abuse (Galanter and Burns 1993). Perhaps because of these milestones, there has been increased addiction training in both medical school and residencies throughout the United States. Although the number of teaching units in medical schools increased substantially during a 16-year period (1976–1992) (Fleming et al. 1994), training in the management of alcohol, tobacco, and other substance use disorders remains disproportionately low in medical school and residency programs compared with other chronic disorders, such as diabetes or hypertension (Isaacson et al. 2000; Klamen 1999; Powers et al. 2004; Prochaska et al. 2006; Spangler et al. 2002). Part of the problem might stem from a lack of faculty members with expertise to teach about substance use (Fleming et al. 1994). The Career Teacher Program, founded in 1971 by the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and the National Institute on Drug Abuse (NIDA), funded 59 teachers in medical schools throughout the United States and provided a major impetus to improving addiction training in medical schools (Ewan and Whaite 1982). This funding mechanism lasted 10 years and was subsequently replaced by Faculty Fellow Training grants. Initially, these grants were designed to support three to five members from primary care departments and psychiatry, but they were subsequently expanded to include nursing, social work, and psychology school. As Chappel and Lewis (1997) noted, this program provided modest part-time support, and its scope was dramatically diminished over time. The lack of experienced faculty remains a barrier for residency program directors to expand substance use curricula (Isaacson et al. 2000; Prochaska et al. 2006). A critical need exists to train faculty in the area of substance abuse so that they may be able to help expand curricula for physicians in training and practicing physicians. In this chapter, we provide an overview of the knowledge, attitudes, and skills of physicians in various stages of their training and what information should be conveyed. We also describe some of the educational initiatives that have been developed to address physicians' deficits in these areas, and we review studies that have evaluated the effect of these educational initiatives.

KNOWLEDGE, ATTITUDES, AND PRACTICE HABITS Despite increased awareness of the importance of substance abuse training in medical education,

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deficits in knowledge and clinical skills remain that are compounded by negative attitudes toward substance abusers. A comprehensive survey conducted by G. Geller et al. (1989) assessed the knowledge, beliefs about role responsibility, perceived skills regarding substance use disorders, and attitudes among medical students and house staff at Johns Hopkins School of Medicine and Hospital. Whereas level of knowledge was relatively high across all years of medical school and residency training, attitudes became increasingly more negative as individuals progressed in their training. After the third year of medical school, the percentage of individuals who thought that they had a major responsibility for screening, referral, and follow-up decreased dramatically. Furthermore, perceived skills in screening showed no improvement as medical students progressed in their residencies, and perceived skills at follow-up diminished. A more recent survey from a single medical center found more negative attitudes and decreased satisfaction caring for alcohol- and drug-abusing patients as training progressed from medical school through residency (Lindberg et al. 2006). A longitudinal survey study at four medical schools in New Zealand found worsened perceptions of self-efficacy regarding the effectiveness of the management of illicit drug users over time (Cape et al. 2006). G. Geller et al. (1989) hypothesized that the lack of adequate curriculum, exposure to end-stage addiction, and lack of faculty expertise all may contribute to these changes in attitudes. A lack of knowledge and/or responsibility by physicians for the detection of and intervention in substance use disorders was reflected by the practice habits of house staff and physicians within the same hospital setting (Moore et al. 1989). All patients newly admitted to the adult inpatient services were screened for alcoholism. However, detection rates by house staff and faculty physicians were lower than 50% for all specialties, except for psychiatry. For those patients with nonrecovered alcoholism diagnoses, the rates of initiating treatment ranged from low (less than 50%) to high (100%), depending on the specialty. Numerous studies at other institutions also have consistently indicated a need for improvement in resident practice habits, finding that residents often fail to appropriately screen for or diagnose alcoholism and other substance use disorders in their clinic and hospitalized patients (Buchsbaum et al. 1992; Bush et al. 1987; Cleary et al. 1988; Coulehan et al. 1987; Dawson et al. 1992). Although such studies have prompted medical educators to address this problematic practicing behavior, more recent studies show that sufficient improvements in knowledge, perceived skills, and practices of physicians in training have not been attained regarding management of alcohol, tobacco, and other substance use disorders (Cerise et al. 1998; Conigliaro et al. 1998; Kahan et al. 2006; Park et al. 2005; Prochaska et al. 2005; Stein et al. 1996). Hence it is not surprising that practicing physicians also inadequately address substance use by their patients, according to findings based on physician self-reporting (Bradley et al. 1995; Friedmann et al. 2000, 2001), medical record charting (Graves et al. 1992; McGlynn et al. 2003), and patient reporting (National Center on Addiction and Substance Abuse at Columbia University 2000). In the results of a survey conducted by the National Center on Addiction and Substance Abuse at Columbia University (2000), of 648 primary care physicians and 510 adults receiving treatment for substance use in 10 treatment programs throughout the United States, some troubling findings were highlighted. These included the following: More than 50% of the patients reported that their primary care physician did nothing about their substance abuse, with fewer than half of the physicians making the diagnosis. Ten percent of the patients reported that physicians knew about the substance abuse but did nothing to address the problem. Fewer than 20% of the primary care physicians considered themselves "very prepared to identify alcohol or drug dependence"; in contrast, 80% felt very comfortable in diagnosing hypertension and diabetes. Approximately 75% of the patients reported that their primary care physicians were not involved in their decision to seek treatment. These findings suggest that there remains a great need for improved substance abuse education in medical school and residency curricula.

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Research attempting to determine correlates of optimal practices with regard to substance users has found conflicting results. Studies of medical students and primary care residents suggest that self-efficacy and positive attitudes, such as greater confidence, are associated with favorable self-reported practices (G. Geller et al. 1989; Gunderson et al. 2005; Schorling et al. 1994). However, another study of medical residents found no relation to attitudes but rather that having had a supervised clinical experience on alcohol abuse was associated with better practices (Warburg et al. 1987). In a large national survey of primary care residents graduating from family practice, internal medicine, and obstetrics/gynecology programs, 62% felt highly prepared to counsel about smoking compared with 36% for substance abuse (Park et al. 2005). Family practice residents felt more prepared than obstetrics/gynecology residents to provide tobacco counseling. Regarding substance abuse counseling, females felt more prepared than males, but no difference by specialty or percentage of training was seen in an ambulatory setting (Park et al. 2005). The survey did not include items on prior substance use training. A survey study of third-year medical students rotating on their pediatric clerkship found that students were less likely to assess the use of tobacco by parents and their children than to complete developmental assessments and injury prevention counseling (A. C. Geller et al. 2005a). More optimal self-perceived performance was associated with feedback and role modeling of the supervising primary care pediatrician, indicating an important influence of faculty members on the practices of physicians in training. Surveys attempting to find practice correlates of practicing physicians have tended to focus on self-assessment and attitudes rather than examining potential correlates with prior training. A survey of primary care physicians in Texas found that self-efficacy and outcome expectations were positively related to screening and counseling for alcohol, tobacco, and other drug problems but were negatively related to outside referral (Gottlieb et al. 1987). In a national survey of 2,000 physicians practicing in several specialties, more optimal alcohol abuse screening and intervention practices were associated with greater confidence in alcohol history taking, familiarity with expert guidelines, and less concern that patients would object (Friedmann et al. 2000). In another national survey of board-certified internists, preventive alcohol practices were associated with belief in the effectiveness of alcohol consumption counseling (Bradley et al. 1995). More optimal practices with regard to illicit drug abuse have been associated with psychiatry specialty, confidence in drug use history taking, optimism about treatment efficacy, and less concern that patients would object (Friedmann et al. 2001).

TRAINING INITIATIVES ON SUBSTANCE USE DISORDERS IN MEDICAL SCHOOL Initially, the major focus in substance abuse education in medical schools was to change the negative course of students' attitudes during medical school with the hope that this might improve clinical practice. Pursch (1978) emphasized that the direct patient contact in substance abuse treatment programs and attendance at Alcoholics Anonymous (AA) meetings were the key ingredients to changing negative attitudes of physicians rather than didactic training. Unfortunately, this advice has often gone unheeded (Hanlon 1985).

Information That Needs to Be Covered Burger and Spickard (1991) noted that despite efforts made to train faculty and develop curricula to train medical students, the students still lacked adequate skills in diagnosing and treating substance abuse. These authors emphasized that substance abuse education must be integrated within the medical school curriculum to stress the importance of the material and to bring substance abuse training into the mainstream of medical education. This sentiment has been echoed by Miller et al. (2001, p. 416), who eloquently stated that substance abuse teaching should be like the "insertion of beads...into an overall necklace of medical school education." Recently, Dartmouth Medical School has taken a comprehensive and methodological approach to addiction medicine curriculum development by sorting content according to six competency domains established by the Liaison Committee on Medical Education

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(2007), the nationally recognized accrediting authority for medical education programs leading to the M.D. degree in U.S. and Canadian medical schools (Seddon Savage, M.S., M.D., personal communication, May 23, 2007). The six domains include 1) knowledge, 2) skills for patient care, 3) interpersonal skills and communication, 4) professionalism, 5) practice-based learning and improvement, and 6) systems-based practice (Table 47–1). Specifically regarding tobacco education, a consortium of medical schools recently developed specific core competencies and learning objectives for medical student tobacco education (A. C. Geller et al. 2005b). Objectives were broken down into affective, cognitive, and skills-based components, analogous to the knowledge, attitude, and practice-based approaches of many substance use training initiatives. Miller et al. (2001) described a substantial number of barriers that impede implementation of a substance abuse curriculum or additional training in substance use disorders into medical education. These include lack of curricular time, lack of coordination of efforts among departments, shortage of treatment sites in which to provide relevant clinical experiences, lack of interested or qualified faculty, and lack of time for faculty to develop an integrated curriculum. Berger and Spickard (1991) provide an approach to overcoming some of these barriers to improve substance abuse medical education (Table 47–2). It is not surprising that one of their greatest difficulties was identifying expert faculty, particularly during the medical students' clinical training. Without supportive faculty and a "champion" to help initiate change, enhancements in existing medical school substance abuse curricula are particularly problematic.

Description of Medical School Substance Abuse Training Initiatives A series of papers published throughout the 1980s described substance use training initiatives (usually of less than 15 hours total) that consisted of lectures alone (Whitfield 1980) or a combination of didactic and experiential training, often within an ongoing clerkship (Coggan et al. 1981; Confusione et al. 1982; Nocks 1980). Siegal and Rudisill (1983) described an intensive experience at a weekend intervention program that targeted persons involved in alcohol-related vehicular legal offenses. Under the supervision of professional substance abuse counselors, students were exposed to group counseling sessions and to counseling and education sessions with patients' families; they were also required to attend AA meetings. Korcok (1984) also described a comprehensive training experience that consisted of a 4-week-long elective that incorporated lectures, participation in group therapy, half-day visits to treatment programs such as halfway houses, attendance at AA meetings, and also direct clinical experiences with patients and families. Student satisfaction with these programs was high. Although attitudinal changes or practice behaviors were not formally assessed, these types of integrative programs are potentially of great consequence. Exposure of medical students to patients in substance abuse treatment settings is a striking departure from what they normally see in medical settings (i.e., individuals with end-stage addictive disease who are not interested in treatment or have frequently failed treatment). Experiential training with substance-abusing patients in recovery may decrease the therapeutic nihilism that medical students develop throughout their medical training. In fact, on the basis of the results of annual medical student surveys administered while a comprehensive substance use curriculum was being developed, Gopalan et al. (1992) suggested that experiential training and electives during the clinical years of medical school are an important aspect of training to encourage the development of positive attitudes toward managing substance abuse.

Evaluation of Substance Abuse Curricula in Medical School Studies assessing the effect of medical student training programs on substance use have often focused on assessment of changes in student knowledge and attitudes (el-Guebaly et al. 2000). For example, Chappel and Veach (1987) found that incorporating a course on substance use in the curriculum of second-year medical students can lead to improved attitudes across several areas (e.g., treatment intervention, treatment optimism, nonmoralism). Their 28-hour course included lectures, small group

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discussions, clinical problems, and visits to treatment programs and AA meetings. Given the evidence that brief interventions by primary care physicians can lead to reduction in alcohol consumption among problem drinkers (Bien et al. 1993; Fleming et al. 1997), it is not surprising that new training initiatives have focused on teaching these skills to medical students and that subsequent studies have examined the effect of such training on skills and practices. Roche et al. (1997) and Walsh et al. (1999) reported improvement in alcohol interventions during videotaped interviews with simulated patients by medical students who had participated in a brief (1- to 3-hour) didactic training session, regardless of whether the session included an additional interactive component that included feedback. More recently, medical students who participated in a 3-hour training improved their knowledge, attitudes, and practices regarding screening and brief intervention for patients with risky alcohol consumption patterns (Babor et al. 2004). This improvement was also noted in a smaller number of trained practicing physicians, and the self-reported practice improvement correlated with patient report on exit interviews (Babor et al. 2004). In an innovative randomized controlled educational trial in Canada, 76 medical students participated in a 3-hour skills-based workshop on management of alcohol use disorders or depression, the latter of which served as a control (Kahan et al. 2003). Those who participated in the alcohol training showed better skills as assessed by simulated patients regarding management of problem drinking and alcohol dependence, and they had greater self-efficacy and knowledge about alcohol reduction strategies on follow-up survey (Kahan et al. 2003). In a study from Australia, Gaughwin et al. (2000) examined the effect of medical student training on history taking and management of alcohol dependence in the emergency department and on the medical wards by assessing charting practices after the medical students became interns. In this retrospective study, charts were examined from interns exposed as medical students to a new 30-hour substance use curriculum and an inpatient drug and alcohol unit. These charts were compared with those of interns who were not exposed to the new training initiative during medical school. They found that interns who participated in the curriculum and rotated on the inpatient unit were more likely to take an alcohol history (although no difference was found in documentation that they quantified consumption) and appropriately manage alcohol dependency (Gaughwin et al. 2000). In a comprehensive review of tobacco intervention training in U. S. medical schools, Spangler et al. (2002) found that enhanced, interactive instructional methods such as the use of standardized patients or role-playing were more effective than traditional didactic methods. They also found that these approaches could be integrated feasibly into medical school curricula. Interactive Web-based smoking cessation curricula are promising to expand training, particularly when time constraints and lack of access to materials and experienced faculty are barriers to integration (Pederson et al. 2006). Medical students from two schools who participated in such a Web-based training had improved knowledge and perceived skills on pre- and posttest surveys (Pederson et al. 2006).

TRAINING INITIATIVES ON SUBSTANCE USE DISORDERS IN RESIDENCY Information That Needs to Be Covered With the increased recognition that graduating residents should have certain core competencies in managing substance use disorders, guidelines have been developed to help guide training of primary care house staff and other physicians (Table 47–3). These competencies are simply meant to provide a basic framework and may need to be modified according to the type of residency program. For example, pediatric residency programs should include competency in the recognition of possible risk factors and assessment of adolescents for alcohol and drug abuse. Although most child and adolescent psychiatry residency program directors in the United States report having a diverse substance abuse training experience for their house staff (Waldbaum et al. 2005), calls for improvement in addiction training among psychiatrists continue, particularly regarding the need to improve long-term management skills and treatment of comorbid substance use and psychiatric disorders (Renner et al.

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2005).

Description and Evaluation of Residency Training Initiatives Most of the recent literature that has focused on substance abuse training initiatives has provided an evaluation component to determine whether the training led to changes in knowledge or practices. Although innovative, comprehensive substance abuse training has been described for psychiatric residents (Renner 2004), most research examining the effect of substance use education during residency typically has been conducted in primary care programs. Many curricula studied have focused on alcohol misuse and attempted to improve screening and intervention skills, although some also have addressed knowledge and attitudes. In a study of primary care residents, attending physicians, and nurse practitioners, Ockene et al. (1997) found that a 3-hour training program to teach a counseling intervention for high-risk and problem drinkers resulted in improved knowledge, attitudes, and skills as assessed by pre- and posttest survey and performance evaluation with simulated patients. The training program had a small group and individual tutorial session that used role-play with simulated patients who provided feedback to the provider (Ockene et al. 1997). In recent studies of similarly brief curricula, internal medicine residents showed improvement in knowledge, attitudes about AA (Rose et al. 2006), and perceived ability to manage substance use disorders (Nigwekar and Morse 2006). Other studies have used medical record review to assess the effect of curricula. A retrospective study of family practice resident charting after a 3- to 4-week rotation on a chemical dependency unit found a significant increase in diagnoses of alcoholism and chemical dependency during the year after the rotation (Mulry et al. 1987). Another study of family practice resident charting practices examined the effect of 1) attending physician feedback on house staff charting and 2) incorporation of the CAGE Questionnaire on a standard patient evaluation form (Lawner et al. 1997). During the 6 months after the intervention, residents were more likely to record CAGE screening questions and to document the quantity and frequency of alcohol consumption. Although documentation of interventions did not change for patients with positive CAGE screens, this could have resulted because the educational effort focused on screening rather than on how to intervene. In a study that used simulated patients, Levin et al. (1999) reported an increase in internal medicine and pediatric resident interviewing and intervention skills after participation in a 5-day experiential and didactic training program at Hazelden Residential Program of New York City. Self-reported ratings also improved after program participation. A similar training program that combined experiential and didactic training during 4 half-day sessions for family medicine residents also found improvement in self-reported knowledge and attitudes (Confusione et al. 1988), although there was no statistical comparison, and the study lacked a behavioral outcome. Wilk and Jensen (2002) tested the effect of a 1-hour intervention in which internal medicine residents interviewed, examined, and then intervened with a known simulated patient who used tobacco and reported excessive alcohol use. After the intervention, the resident received feedback and instruction on guidelines on alcohol screening and brief intervention. The intervention was viewed positively by the residents, and a comparison of residents' performances with an unannounced simulated patient before the intervention and 1–2 months after the intervention showed a dramatic two- to threefold improvement in alcohol screening and intervention (Wilk and Jensen 2002). In a recent study, the Objective Structured Clinical Exam was used to teach addiction medicine competencies to internal and family medicine residents (Parish et al. 2006). House staff assessment and management skills regarding alcohol and illicit drug abuse improved between the first and final Objective Structured Clinical Exam sessions, which confirmed the utility of providing performance-based assessment and immediate feedback to trainees. It is of note that performance was not associated with self-assessed interest or competence. Several studies have evaluated curricula for psychiatry and emergency medicine residents. A 1-day educational conference on knowledge, diagnosis, and management of alcohol, tobacco, and opiate

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addiction was offered to all psychiatry residents in Michigan. The conference, led by several addiction specialists, was found to enhance the belief that physicians can motivate their patients to seek treatment and to increase residents' interest in pursuing an addiction psychiatry fellowship (Karam-Hage et al. 2001). However, the follow-up survey administered at the end of the training did not assess the effect on skills or practices, and those who completed the survey were highly self-selected. A nonrandomized controlled educational trial was conducted at two similar emergency medicine residency programs to examine whether a 4-hour training program that included a didactic session, demonstration video, and skills-based workshop would improve house staff knowledge, attitudes, and practices as reflected by a survey and medical record charting (D'Onofrio et al. 2002). House staff from control and intervention institutions completed surveys on knowledge, attitudes, and practices at baseline and 1 year after the intervention, and their charts were reviewed at baseline and 6 months after the intervention. Compared with residents in the control program, who received no formal didactic or skills-based training related to addressing alcohol problems, residents in the intervention program had significant improvement in knowledge scores and in screening and intervention practices based on chart review (D'Onofrio et al. 2002). In a similarly designed nonrandomized controlled trial at two pediatric residency programs, Kokotailo et al. (1995) examined the effect of an experiential curriculum on alcohol and other drugs, in which the intervention group participated in an adolescent assessment program, interactive didactic sessions, role-play, and a session on interviewing skills. Pre- and posttest assessment was performed with written examination, self-assessment, and simulated patients. Compared with control subjects, house staff in the intervention group showed significantly greater improvement in their knowledge, confidence, and screening and interviewing skills (Kokotailo et al. 1995). In a review of tobacco training initiatives for pediatric residents, most studies assessed educational interventions that combined active and passive methods and were delivered in the residents' primary care continuity clinics (Hymowitz 2006). Overall, most of the relatively brief and focused training initiatives led to improvement in resident knowledge, attitudes, and practices regarding tobacco intervention. Several studies used standardized patients or exit interviews at the clinic to corroborate self-reported improvement. Active approaches, as well as faculty role modeling in continuity clinics, were thought to have contributed to positive changes in practices (Hymowitz 2006). Further support for active training methods has been documented in other residency programs, such as family medicine, internal medicine, and surgery (Cornuz et al. 2002; Steinemann et al. 2005; Strecher et al. 1991).

POSTRESIDENCY TRAINING INITIATIVES ON SUBSTANCE USE DISORDERS Addiction Psychiatry Fellowships and Certification Physicians who have completed a residency program in general psychiatry can pursue further training in addiction psychiatry through a fellowship program (also sometimes called a residency program in addiction psychiatry). As of May 2005, 41 such postresidency training programs that were accredited by the Accreditation Council for Graduate Medical Education (ACGME; 2007) existed in the United States. On average, the fellows spend about half of their time in direct clinical care and the other half in academic activities (Galanter et al. 2002). Some of these programs accept physicians who have completed residency in other fields (e.g., internal medicine, neurology). However, unlike psychiatrists, these fellows would not be eligible for the addiction psychiatry boards. The addiction psychiatry boards are administered by the American Board of Psychiatry and Neurology (ABPN; 2007a), which lists core competencies on its Web site. The first subspecialty certification examination (for what was then called Added Qualifications in Addiction Psychiatry) was given in 1993. As of December 2006, 1,959 psychiatrists were certified in addiction psychiatry (American Board of Psychiatry and Neurology 2007b). Today, psychiatrists who complete an ACGME-accredited fellowship and are certified in general psychiatry by the ABPN are eligible to sit for a subspecialty certification examination given by ABPN once every 2 years. This 4-hour, multiple-choice, computer examination

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covers addiction psychiatry topics such as evaluation and consultation, pharmacotherapy, pharmacology of drugs, psychosocial treatment, and the biological and behavioral basis of practice. The ABPN certification in the subspecialty of addiction psychiatry is valid for 10 years. To maintain certification beyond 10 years, the addiction psychiatrist must take a recertification examination that is similar to the certification examination in content and format. The American Board of Medical Specialties now mandates that medical specialties and subspecialties, including addiction psychiatry, adhere to the concept of maintenance of certification, which is broader than the concept of recertification. Maintenance of certification involves not only examinations but also documentation of commitment to lifelong learning and assessment of practice-based performance (Burke 2002).

Certification in Addiction Medicine The ASAM offers a certification examination to physicians who have completed residency training in any medical specialty and have an additional year of clinical experience in treating substance abuse. The ASAM examination, like the ABPN examination, is offered every 2 years, with recertification required every 10 years (American Society of Addiction Medicine 2007b). Both ASAM and ABPN certifications are widely recognized and accepted as evidence of expertise in substance abuse. For example, physicians who are certified by either ASAM or ABPN are exempt from taking a special training course before being approved by the U. S. Drug Enforcement Administration (DEA) to prescribe buprenorphine to their patients (Substance Abuse and Mental Health Services Administration 2007). In addition to being eligible to sit for the ASAM boards through having a year of clinical experience, several formal fellowship programs in addiction medicine are now available across the United States (American Society of Addiction Medicine 2007a). The American Osteopathic Association (AOA) offers a Certification of Added Qualifications in Addiction Medicine. The certification examination is available to osteopathic physicians who are certified in anesthesiology, internal medicine, or psychiatry and neurology and who have either 1) completed 1 year of AOA training in addiction psychiatry or 2) fulfilled extensive work and continuing medical education (CME) requirements in addiction psychiatry or addiction medicine (American Osteopathic Association 2007).

Description of Programs Targeting Medical School Faculty Despite the availability of specialty training and certification through these medical societies, a need to train faculty about substance use remains. Following the success of the Physicians in Residence program that is primarily targeted toward house staff from all specialties (Levin et al. 1999), the Hazelden Foundation (2007) introduced the Faculty Training Program on Addiction for Primary Care Physicians. Up to eight faculty members from primary medical specialties such as internal medicine, pediatrics, psychiatry, and primary care undergo an intensive 5-day, 30-hour program on site at a Hazelden residential program. Like the Physicians in Residence program, the faculty program provides a lecture series and a strong experiential component. The participants fully engage in the activities of the residence, join the group exercises, and assume a participant-observer role in daily treatment. In addition, the faculty members train in motivational interviewing techniques and in planning for integration of their training into the academic training of medical students, residents, and fellows at their home institutions. The program is jointly sponsored by the University of Wisconsin Medical School, and the participants receive CME credits. Bigby and Barnes (1993) described an experiential training program targeting general medicine faculty. A 3-day course sponsored by five medical centers covered various addiction topics, with less than 20% of the program being didactic. The experiential components included role-playing, case discussions, the use of simulated patients, and attendance at self-help groups. The participants described substantial improvements in their attitudes toward substance abusers, described greater confidence in their clinical skills, and noted increased teaching about substance abuse management. Other faculty programs have been more limited in scope, with on-site lectures or skills-based training (Fleming et al. 1994, 1997). Project MAINSTREAM (the Multi-Agency INitiative on Substance abuse TRaining and Education for

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AMerica) is a program that funds teams of three faculty fellows from different disciplines (e.g., medicine, social work, nursing) to work on faculty development and community projects (Stuart et al. 2002). Project MAINSTREAM (2007), administered by the Association for Medical Education and Research in Substance Abuse, is the first systematic effort to bring together and train substance abuse educators from different professions. Fellows work together for 2 years in interdisciplinary faculty learning groups, which consist of three academic faculty members from different disciplines. The groups develop and implement community-based, service-learning, and curricular-enhancement substance abuse field projects (Straussner et al. 2006). To date, Project MAINSTREAM has trained 39 fellows and 13 interdisciplinary faculty learning groups in the United States. Faculty fellows of Project MAINSTREAM have rated the interdisciplinary faculty learning group model positively, and they found the interdisciplinary collaborations both feasible and valued at their home institutions (Madden et al. 2006). Another program that trains junior faculty as substance use educators is the Alcohol Medical Scholars Program (2007), which was established to promote optimal education in medical schools regarding the identification and care of people with alcohol use disorders and other substance-related problems. In addition to supporting the development of faculty skills as educators, the program has disseminated lectures online since 2000. The National Institute on Drug Abuse and Boston University have sponsored creation of a 4-day training program for incoming chief residents and chief resident–faculty mentor pairs called the Chief Resident Immersion Training Program (2007). Chief Resident Immersion Training aims to train future chief residents through various skills-based and experiential training methods so that they may develop a substance use training initiative to be implemented within the first 3 months of their chief residency year. The program is a promising way to train faculty and disseminate effective substance abuse curricula (Nigwekar and Morse 2006).

Description and Evaluation of Programs Targeting Physicians in Practice Apart from these postresidency initiatives to train specialists and teaching faculty, most practicing physicians who want to further their education and training in substance use disorders attend CME programs (Sandlow and Dos Santos 1997). CME activities are a major means by which practicing physicians stay up to date with medical information to improve practices and optimize patient outcome (Davis et al. 1999). El-Guebaly et al. (2000) reviewed 11 studies that assessed the outcome of CME programs devoted to teaching physicians about substance use disorders. Most programs tended to use a combination of didactic and interactive interventions to enhance screening, early intervention, and referral by primary care physicians, although a few included psychiatrists and obstetricians (el-Guebaly et al. 2000). Many studies found it difficult to recruit physicians for CME programs on substance use. The results of the studies examining the effect of these programs were often equivocal, but they suggested a need for educational reinforcement of training to improve CME influence (el-Guebaly et al. 2000). These conclusions were supported by a meta-analysis of randomized controlled trials of formal CME programs not specifically related to substance abuse (although one study assessed CME training on tobacco), which found that multiple longitudinal CME interventions improved physician performance (Davis et al. 1999). This study also concluded that interactive sessions (i.e., role-play or discussion groups), but not didactic sessions, can affect change in physician practices (Davis et al. 1999).

Coupling Educational Interventions With Physician Prompts Studies assessing the effect of brief, skills-based curricula have reported improvement in physician confidence in detecting and intervening for hazardous alcohol consumption (Proude et al. 2006), whereas others have reported an effect on actual practice (Babor et al. 2004; D'Onofrio et al. 2005). Most promising, however, is a growing body of literature on the benefit of coupling brief educational training with a clinic system intervention, such as a physician prompt. Prompts, including chart-based reminders and computer-generated reports, may improve primary care tobacco counseling as well as increase cessation rates (Strecher et al. 1991; Unrod et al. 2007). Prompting primary care faculty and

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house staff with alcohol screening results and specific recommendations for intervention improves physician counseling and may improve patient outcome (Adams et al. 1998; Bradley et al. 2002; Saitz et al. 2003; Seale et al. 2006). Educational interventions and system-based prompts may improve primary care physician ability to provide maintenance care for patients with alcohol use disorders in remission (Friedmann et al. 2006).

Physician Training on the Use of Buprenorphine for Treatment of Opioid Dependence Most substance abuse educational interventions and research have focused on tobacco and alcohol, and less emphasis has been placed on training physicians about management of opioid abuse. With the passage of the Drug Addiction Treatment Act (DATA) in 2000 and subsequent U. S. Food and Drug Administration approval of buprenorphine for treatment of opioid dependence, it became possible for physicians to provide office-based buprenorphine treatment (Clark 2003). Under DATA, physicians without specialty substance abuse certification can qualify to prescribe buprenorphine by participating in 8 hours of CME training sponsored by designated medical societies, such as the ASAM, American Psychiatric Association (APA), and AAAP. Training is available through in-person, online, and CD-ROM courses, which include materials and content outlined in national practice guidelines from the Center for Substance Abuse Treatment (2004). In addition, specific training approaches have been described for Australia (Lintzeris et al. 2002). Barriers to physician implementation of buprenorphine treatment in their practices include logistical and economic concerns (Stanton et al. 2005), as well as concerns among HIV treatment providers about medication interactions (Sullivan et al. 2006). Among newly trained physicians surveyed after completion of combined online and in-person training, other important barriers included lack of experience and concerns about starting buprenorphine in patients (Gunderson et al. 2006). Although this study found that physicians preferred the in-person training component that included an experiential session with patients receiving buprenorphine maintenance treatment, future studies should directly compare online and in-person training methods. Physicians who are interested in further support can access the Physician Clinical Support System (2007), a national mentoring network of experienced buprenorphine treatment providers. Although expansion of buprenorphine treatment may decrease the national treatment gap in opioid dependence treatment, curricular development is needed to help prepare physicians to recognize the growing national problem with prescription opioids (Colliver et al. 2006).

OBSERVATIONS ABOUT EFFECTIVE EDUCATIONAL STRATEGIES On the basis of the findings of the studies described earlier that assessed the effects of various educational strategies, several observations may be made that could help optimize substance use curriculum development for training physicians (Table 47–4). Brief skills-based curricula can improve physician knowledge, attitudes, and practices. Curricula should incorporate interactive sessions that are skills-based, such as small-group discussions or role-play, rather than solely using standard didactic programs. Attempts should be made to incorporate an experiential component if possible. Although experiential training ideally should take place in a substance use treatment setting, simulated patients also are an effective way to educate medical personnel about substance use, and the use of simulated patients has been rated favorably compared with prerecorded videotaped interview and even real patients in one study teaching medical students about alcohol misuse (Eagles et al. 2001). Because selection and duration of strategies to train medical personnel depend on available resources (el-Guebaly et al. 2000), simulated patients or substance use treatment settings may not be available for medical training. In these instances, attempts should be made to incorporate an interactive component into the training. Also, the curriculum should incorporate feedback to help reinforce optimal skills and practices; this has been shown to be effective in several studies (Lawner et al. 1997; Ockene et al. 1997; Parish et al. 2006; Wilk and Jensen 2002). Clinic system interventions, such as physician prompting with screening results or intervention recommendations, may complement brief, skills-based training. Finally, curricula should be implemented for broad groups of medical personnel, not only self-selected individuals with a high interest in the field, given that the greatest influence of an

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educational intervention is likely on those with the most negative areas at pretest (el-Guebaly et al. 2000).

PERSISTENT BARRIERS TO THE DIAGNOSIS AND REFERRAL OF SUBSTANCE-ABUSING PATIENTS Although the emphasis has been on improving knowledge, attitudes and skills, other factors explain why physicians often do not adequately address substance use problems with their patients. The National Center on Addiction and Substance Abuse at Columbia University (2000) identified several factors that contribute to this problem, including patient resistance, time constraints, fear that discussing substance abuse may encourage patients to see other physicians, and the fact that insurance does not reimburse physicians' time. Managed care has placed even greater time constraints on physicians, and addiction treatment benefits have decreased substantially over the past decade (Hay Group 1999). This lack of insurance "may discourage physicians from discussing substance abuse with patients and referring them for treatment" (National Center on Addiction and Substance Abuse at Columbia University 2000). Both patient and physician advocates will be needed to reverse this troubling trend, and support should be given to current legislative initiatives supporting insurance parity for substance use disorders (Join Together 2007).

CONCLUSION Although training guidelines have been developed and progress has been made in improving medical school, residency, and postresidency substance abuse education, these directives have not been uniformly applied. Repeatedly, the literature stresses the importance of developing physician role models who have expertise in substance abuse education. These individuals can help implement curricula change, provide supervised experiences to medical students and residents, and help reduce the stigmatization experienced by alcohol- and drug-dependent patients, a phenomenon that remains common in medical settings. Clearly, barriers exist that make change difficult. However, these obstacles are not insurmountable. Many innovative approaches to substance abuse training are being implemented and evaluated for their success in producing behavior change. Providing physicians with interactive and clinically relevant training experiences, exposure to patients who have benefited from treatment, adequate reimbursement for time spent assessing patients for substance use disorders, and a supportive administrative environment will almost certainly lead to substantial improvement in the treatment of substance abuse.

KEY POINTS There is a tremendous need to expand medical education about substance use. Competency domains are available to help guide curriculum development. A growing literature supports various training approaches, which may facilitate integration into different educational settings. Even brief, skills-based curricula can improve physician knowledge, attitudes, and practices regarding substance use management. Efforts to train medical practitioners should be implemented broadly throughout all levels of training, from student to practicing physician.

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Chapter 48. Prevention of Substance Abuse

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Richard R. Clayton, Melissa J. H. Segress, Crystal A. Caudill: Chapter 48. Prevention of Substance Abuse, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.359197. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Prevention of Substance Abuse Richard R. Clayton, Ph.D. Melissa J. H. Segress, M.S. Crystal A. Caudill, M.P.H.

PREVENTION OF SUBSTANCE ABUSE: INTRODUCTION Prevention is usually thought of as relevant primarily for children and youths, not adults. For every drug, several potential targets exist in trajectories of drug use for prevention activities. These include 1) initiation; 2) continuation; 3) progression within a drug class to more extensive, intensive use patterns; 4) progression across drug classes; 5) progression to dependence; 6) regression to cessation; and 7) lapse and relapse. The preponderance of research on substance abuse prevention to date has focused on two targets: 1) attempts to reduce the likelihood of initiation (or at least delay onset) and prevalence of use among youths and 2) reducing the likelihood of relapse among adult drug abusers. In this chapter, we concentrate on primarily youth-focused prevention. The strategies that have been used to attempt to reduce the likelihood of initiation or delay onset are based on at least two assumptions: 1) catch youths before they start using drugs and 2) find youths where they are, and deliver prevention to them. The best place to find youths is in school or in front of a television set, where they spend a disproportionate amount of time. Therefore, a great deal of what we know about prevention (its efficacy and effectiveness) comes from school-based, curriculum-driven programming and from media-based prevention initiatives. Some efforts have been made to deliver substance abuse prevention to families, workplaces, and communities, but these efforts have been minimal in comparison to school and the media as vectors for prevention. Because of the disproportionate focus on youths and initiation among youths, a significant amount of attention has been devoted to the so-called gateway drugs: tobacco, alcohol, and marijuana. One aspect of the concept of gateway is the time order, or sequence of occurrence, of initiation. It is therefore interesting that most efforts to prevent use of gateway drugs do not involve use of inhalants, steroids, or nonmedical use of prescription medications that are often prescribed for youths (e.g., medications for treatment of attention-deficit/hyperactivity disorder [ADHD]). Use of inhalants and ADHD medications often precede use of some or all of the three gateway drugs that get the most attention. Some drug-specific prevention initiatives have been developed for inhalants and steroids, but these are usually stand-alone efforts largely independent of prevention efforts targeting the gateway drugs. Almost no prevention efforts have specifically targeted use of cocaine, heroin, methamphetamine, lysergic acid diethylamide (LSD), methylenedioxymethamphetamine (MDMA; "ecstasy"), and prescription drugs in general. Use of multiple drugs is seldom the focus of substance abuse prevention activities, even though multiple drug use is the norm rather than the exception. From an etiological perspective, the dominant approach to substance abuse prevention has been to identify the predominant risk and protective factors for substance abuse (Clayton 1992; Hawkins et al. 1992). These risk and protective factors are usually grouped into several domains: genetic, biological, social, psychological, contextual, economic, and cultural. The first two of these domains are clearly specific for individuals rather than population groups and cannot be changed. This is important because the essence of prevention is attempting to modify changeable and malleable risk and protective factors. If a factor is not amenable to change, then it is not a legitimate target of preventive intervention efforts.

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Thus, most substance abuse prevention initiatives are focused primarily on changing the social, psychological, contextual, economic, and cultural risk and protective factors that are predictive of drug use.

TAXONOMIES OF PREVENTION There are three broad-based taxonomies of prevention. The first taxonomy and one that is most familiar to clinicians is the traditional medical and public health model. Primary prevention is preemptive in nature and involves reduced incidence of a disorder (i.e., occurrence of new cases). Secondary prevention is focused on reducing prevalence (i.e., the total number of new and old cases). Tertiary prevention is focused on reducing the sequelae and complications arising from the problem or disorder once it is manifest. The second taxonomy is the one most widely used in the substance abuse prevention arena: A universal preventive measure is desirable for everybody in the eligible population. A selective preventive measure is desirable only when the individual is a member of a subgroup of the population whose risk of becoming ill is above average. An indicated preventive measure applies to persons who, on examination, are found to manifest a risk factor, condition, or abnormality that identifies them, individually, as being at high risk for the future development of a disease. (Mrazek and Haggerty 1994, pp. 20–21) The third taxonomy of prevention is less widely used but clearly anchored in population-based public health. It involves downstream interventions, in which the focus is on the individual and his or her lifestyle or behavior; midstream interventions, in which the focus is on the community and institutions within communities; and upstream interventions, in which policies that support prevention are made (McKinlay and Marceau 2000). The field of substance abuse prevention has, for the most part, adopted the universal, selective, and indicated constructs to guide its work.

SCHOOL-BASED, CURRICULUM-DRIVEN PREVENTION The scientific roadmap (see Flay et al. 2005) for school-based, curriculum-driven prevention involves clinical trials testing for efficacy (the beneficial effects of a program or policy under optimal conditions of delivery), effectiveness (effects of a program or policy under more real-world conditions), and dissemination (taking a program to scale with widespread reach and penetration). In this section, we review selected efficacy and effectiveness trials. Clinicians should note that research on the prevention of substance abuse is subject to the same scientific process and principles applicable to evaluation of treatment protocols. We have found an extensive literature on randomized trials of the efficacy of "social influences" or "social competency" school-based curricula that usually attempt to change the following types of mediators: 1) normative beliefs among adolescents, 2) perceptions of consequences of substance use or abuse for adolescents, and 3) social problem-solving skills (e.g., communication skills, decision-making skills, resistance and assertiveness skills).

Life Skills Training Perhaps the most widely cited study of a school-based prevention program with efficacy is Life Skills Training. This social influences and competency program involves 15 sessions during the sixth grade, 10 booster sessions in the seventh grade, and 5 booster sessions in the eighth grade. Botvin et al. (1995) randomly assigned 56 schools to a control condition or two experimental conditions. The first experimental condition involved teachers personally trained by Botvin and his colleagues who also received technical assistance as needed. In the second condition, teachers received training from Botvin and his colleagues via videotape but no technical assistance. Botvin also divided his sample into those students who were exposed to 60% or more of the lessons (labeled by Botvin as "high fidelity") and those who received fewer than 60% of the lessons ("low fidelity"). The emphasis was on gateway drugs

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(i.e., tobacco, alcohol, marijuana), and youths were followed up on for 6 years. No statistically significant differences were found between teachers who were personally trained and those who received training via videotape. Statistically significant effects on drug use were noted when the control condition was compared with the two experimental conditions "for students in the high-fidelity condition." However, note that between 1 in 4 and 1 in 3 students were classified as low fidelity. These low-fidelity students were probably more likely to be high-risk youths. Separate analyses by these authors determined that no statistically significant effects were seen between low-fidelity students and the students in the control condition. Simply put, Life Skills Training seems to work for those with good attendance (present for 60% or more of the lessons), not for those with higher absenteeism.

Hutchinson Smoking Prevention Program Whereas the Life Skills Training study focused on prevention of use of a few gateway drugs, the Hutchinson Smoking Prevention Program (HSPP) focused only on smoking. The study was conducted in 40 school districts, 20 of which received the intervention, and 20 of which served as the control districts (Peterson et al. 2000). The 40 districts were selected at least partially because they contained only one high school, so experimental and control participants would never be mixed. The theory-driven social influences intervention began in the third grade and continued through the tenth grade, with content developmentally tailored to grade level. The total number of potential prevention exposure units was 46.75 hours. Implementation fidelity was high, with 80% of the teachers effectively communicating the key concepts of the lessons. None of the control districts violated their commitment to remain free of interventions during the 15-year trial. Overall, the HSPP study retained 93% of the participants at 2 years beyond high school. To lose only 7% of the sample over this period of time is impressive. The principal results examined daily smoking among males and females in the twelfth grade. The results were disappointing. Less than 1 percentage point difference was found between experimental and control students (males and females were examined separately) in daily smoking in the twelfth grade. HSPP and the Life Skills Training interventions were driven by a social influences framework, there were considerably more exposure units in the HSPP than in Life Skills Training, the focus was on one instead of a few drugs, and the design in the HSPP was rigorous (Clayton et al. 2000).

Project ALERT Project ALERT, a universal prevention program, now involves 11 lessons in the seventh grade and 3 booster sessions in the eighth grade, but its initial version included 8 lessons in the seventh grade and 3 lessons in the eighth grade. The first evaluation occurred between 1984 and 1986 in 30 schools: the lessons were taught by adult health educators in 10 schools, the curriculum was delivered by adult teachers assisted by teenage peer leaders in 10 schools, and 10 schools served as controls. The results were promising—those who received the intervention were 30%–50% less likely to start using or to be currently using marijuana. Among students who were experimenting with cigarettes at the beginning of the seventh grade, those in the intervention group were 33%–55% less likely to become regular or current smokers. Only modest reductions were found for alcohol use. There were no significant differences by who delivered the intervention (see Ellickson and Bell 1990). These youths were followed up on through the ninth, tenth, and twelfth grades (see Ellickson et al. 1993). As has been true for many such prevention efforts, the significantly different effects observed earlier had decayed by the last follow-up. Project ALERT is particularly interesting because the early research was used to change some aspects of the curriculum (new sessions on inhalants, smoking cessation, and alcohol as well as home learning activities to get parents involved), new research was conducted to test efficacy and effectiveness (Ellickson et al. 2003; Ghosh-Dastidar et al. 2004), and an independent evaluation was conducted (St. Pierre et al. 2005). In the large randomized trial, Ellickson et al. (2003) found effects for the revised curriculum on initiation of cigarette and marijuana use, current and regular cigarette use, and alcohol misuse. The reported reductions ranged from 19% to 39%. Effects were not observed for initial and current drinking or for current and regular marijuana use. Ghosh-Dastidar et al. (2004) found a

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moderate effect on targeted risk factor mediators associated with cigarette and marijuana use and more modest gains with the pro-alcohol risk factors. St. Pierre et al. (2005) conducted an effectiveness trial that involved agricultural extension agents to deliver the curriculum. They found no positive effects on substance use or the mediators and risk factors addressed by the curriculum. In addition, they engaged in a substantial effort to explain why no effects were found and were not able to offer a feasible and defensible explanation for the differences in their evaluation and those conducted by the individuals who developed and tested the curriculum for efficacy and early effectiveness. From our selective review of the vast scientific literature on substance abuse prevention programming that is school-based and curriculum-driven, several points emerge: Efficacy designs often do not resemble reality (Hallfors et al. 2006). Most efficacy trials collect baseline data, and some get the intervention and others do not. A follow-up usually occurs 1 year or more after the intervention. Drawing a line from baseline to follow-up for experimental and control participants and asserting that the difference between the lines exists because of exposure to a school-based, curriculum-driven intervention is audacious and ignores the thousands of experiences individuals have in the interim that could influence scores at follow-up. Influences on substance abuse exist at multiple levels. The curricula used in social influences and competency interventions assume that the most critical predictors of drug use lie "inside" the individual in his or her ability to make good decisions and use resistance skills. These approaches largely ignore the fact that every child receiving a prevention lesson has a family, regardless of what that consists of; lives in a neighborhood and a community; and may be embedded in a variety of peer and social organizational groups (e.g., boy and girl scouts, soccer teams). These "outside the individual" environmental influences may have an equal or even stronger effect on substance abuse than do intraindividual factors. Substantial differences exist across schools and across classes and cohorts within schools. This heterogeneity is often missed or ignored in evaluation research. Some schools are at "higher" risk for having greater incidence and prevalence of drug use than are other schools. Classification of entire schools according to risk has been largely ignored (Cameron et al. 1999). Almost all prevention programming has focused on substance abuse patterns as the targeted outcomes. Considerably less attention has been paid to the outcomes of most importance to school administrators and teachers: academic performance indicators such as grades, achievement test scores, and attendance, retention, and school order or disorder. Teachers delivering the curriculum in a school are critical. Little research has been done on the differential effectiveness of teachers to deliver these curricula, and almost no attention has been paid to the conglomeration of ineffective teachers in chaotic schools with students from high-risk familial and neighborhood environments. Even with these caveats, prevention science shows that school-based, curriculum-driven prevention programming has produced statistically significant effects under controlled conditions. Societal, community, and parental concerns about drug use among children have led to widespread dissemination in schools of prevention programming that has passed muster on efficacy criteria (albeit usually not via independent evaluation). In other words, evidence indicates that prevention in schools works, but the most appropriate questions may be Whom does prevention work for? Where does prevention work? When does prevention work? Why does prevention work? How does prevention work?

MEDIA-BASED PREVENTION A substantial amount of research has been conducted on media as a vector for prevention of substance

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abuse. In this section, we selectively review some of the more prominent efforts. When mass media mechanisms, particularly public service announcements (PSAs), are used as a strategy to help prevent substance abuse, the goal is to have viewers be aware of the media message, encode it, decode it, be able to recall the message and where one encountered it, and then apply the essence of the message to decisions about drug abuse.

Partnership for a Drug-Free America Recall is, of course, one of the most important measures of effectiveness. When this one criterion is used, the "This is your brain; this is your brain on drugs" PSA created by the Partnership for a Drug-Free America scores very high. However, the ultimate goal of media campaigns is to raise awareness and draw attention to an issue and change knowledge, attitudes, and behavior about that issue or phenomenon. Although the "This is your brain on drugs" campaign is widely remembered, the actual effects of the campaign were not evaluated.

American Legacy Truth Campaign The "Truth" tobacco countermarketing campaign has been extensively and rigorously evaluated. It was initially delivered in Florida with significant positive effects (Niederdeppe et al. 2004; Sly et al. 2001) and later used as part of a national campaign directed by the American Legacy Foundation. Farrelly et al. (2005) found a dose-response relation between exposure to the Truth antismoking advertisements and the prevalence of smoking among youths. In fact, they estimated that the campaign accounted for about 22% of the 18%–25.3% decline in smoking prevalence that occurred nationally among youths between 1999 and 2002 (Thrasher et al. 2004). Wakefield et al. (2006) used the Monitoring the Future surveys to examine the effect of the tobacco industry–sponsored smoking prevention advertising. They found no beneficial effects and the possibility of some harmful effects on youths in grades 10 and 12.

Office of National Drug Control Policy's National Youth Antidrug Media Campaign The Office of National Drug Control Policy's National Youth Antidrug media campaign has three goals: 1) educate and enable America's youths to reject illegal drugs; 2) prevent youths from initiating use of drugs, especially marijuana and inhalants; and 3) convince occasional users of these and other drugs to stop using drugs. Research evaluating the Office of National Drug Control Policy's antidrug campaign covering the period 1999 through June 2004 (Orwin et al. 2006) found that more than 7 of 10 parents and youths reported exposure to one or more of the media messages weekly. The recall of the advertisements increased substantially over the years of the campaign. Brand recognition of the campaign's theme was high. The campaign had favorable effects on 3 of 4 parent beliefs and behavior outcome measures (i.e., talking with children about drugs, doing fun activities, beliefs about monitoring). However, no evidence of effects on parental monitoring behavior was found until the last data collection of the campaign. Parental monitoring is considered a major protective factor for prevention of adolescent drug use. Furthermore, no evidence indicated effects on marijuana, the early interventions, or the campaign as a whole. However, unfavorable effects did occur. Higher exposure led to weaker antidrug norms, and there may have been a significant unfavorable effect of exposure to the marijuana initiative on when use of marijuana began. Health communications researchers at the University of Kentucky have been conducting efficacy trials on a different approach to constructing PSAs. The traditional approach to targeting or segmenting audiences for any kind of message, including antidrug messages, is by demographics (age, gender, race/ethnicity, socioeconomic status, special interests). Some communications researchers have used so-called psychographic characteristics (in particular, sensation seeking) to target or segment audiences for antidrug messages. The assumption is that those high in sensation seeking will pay attention only to messages high in sensation value and will be especially attracted to messages embedded in high-sensation value programming. Palmgreen et al. (2001) evaluated three televised antimarijuana

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campaigns in two matched communities over several months and found a reversal in the upward developmental trend in 30-day marijuana use among high-sensation seekers. Low-sensation seekers had low levels of marijuana use, and no campaign effects were noted for them. Use of various forms of mass media illustrates the universal, primary, and upstream types of prevention programming. Some campaigns have been clearly efficacious and effective but others less so, as described earlier. Substance abuse is a complex phenomenon. Major differences are seen between substances and the etiological factors that account for abuse of the various substances. Capturing the essence of a message that is persuasive and compelling in 30-second PSAs is extremely difficult. Confirming that these short bursts of prevention programming have measurable effects on patterns of substance abuse (e.g., initiation, continuation, progression) is a formidable task. The success rates with tobacco use in the Truth campaign and in the community trial that used sensation seeking as a targeting variable are evidence of the value of media-based prevention and the need for further work on media-based prevention programming.

COMMUNITY-BASED COALITIONS A huge effort has been expended to prevent substance abuse where the proverbial "rubber meets the road"—in communities—primarily through the vehicle of community antidrug coalitions and community mobilization. One of the first broad-based community coalition efforts involved the so-called Fighting Back initiative in communities. Fourteen middle-sized (population between 100,000 and 250,000) communities participated. Community leaders chose, developed, and implemented prevention strategies that included, at a minimum, public awareness, prevention targeted specifically at youths, early identification and intervention, treatment and relapse prevention, and, later in the program, environmental strategies. The Fighting Back initiative was essentially about community empowerment and mobilization. Hallfors et al. (2002) conducted a rigorous evaluation of the effects of 12 of the Fighting Back community efforts. The results are counterintuitive but instructive: Strategies aimed at either youth or community prevention outcomes showed no effects, while strategies to improve adult-focused outcomes showed significant negative effects over time, compared to matched controls. Coalitions with a more comprehensive array of strategies did not show any superior benefits, and increasing the number of high-dose strategies showed a significant negative effect on overall outcomes. (Hallfors et al. 2002, p. 237) These findings are disappointing because the assumption of community-organized, community-driven, and community-focused prevention is intuitive and because large amounts of funding were invested in the Fighting Back initiative. Before the evidence of efficacy was available, the federal government invested an even larger amount of funding toward antidrug community coalitions in a much larger number of communities (i.e., effectiveness before evidence of efficacy). Although the evidence from the initiative described earlier is not compelling, evidence does show that community coalitions focused on high-risk drinking and alcohol-related injuries have been effective. Holder et al. (2000) combined several mutually reinforcing strategies (i.e., media attention to alcohol problems, changes in alcohol serving practices in local bars and restaurants, reductions in retail sale of alcohol to young people, increased enforcement of drinking and driving laws, and reductions in the concentration of alcohol retail outlets) to produce significant reductions in high-risk alcohol behaviors and consequences. Most of the strategies described by Holder and his colleagues are environmentally and policy oriented rather than attempts to change risk factors "under the skin." Substance abuse is a complex bundle of issues necessarily embedded in communities that are themselves extremely complex. Given the heterogeneity within and across communities, it is not surprising that marshalling "research" evidence of the efficacy and effectiveness of community coalitions to prevent substance abuse would be difficult. From a more clinical perspective, the efficacy of specific community coalitions may require a "perfect storm" mixture of 1) a problem that is particularly salient

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at the time, 2) leadership with the persuasive skills and charisma to focus the community on the malleable aspects of the problem, 3) a willingness of the existing organizations and coalitions to put this problem above the problem to which they are devoted, 4) the readiness of the community at large to tackle this problem, and 5) a willingness to change leadership in different phases of response to the problem. Some leaders are great at galvanizing energy around an issue but not good at maintaining and sustaining that energy.

CONCLUSION Prevention is often offered as the answer to just about everything. Prevention covers the breadth of public health activity from head lice and dog bites to substance abuse and bioterrorism. Prevention is relevant across the developmental age range from prenatal through infancy; childhood; adolescence; young, mid, and older adulthood; to death. Unfortunately, the construct is used so widely in every arena of public discourse that its essential elements and the evidence base for preventive interventions are often not clear and sometimes not known. Prevention can take place at many levels—from the individual to interpersonal to local to state, national, and international levels. Prevention and treatment are often thought of as ends of a continuum. An alternative approach is to see treatment as another kind of prevention. Prevention is often focused on attempting to change specific behavioral patterns but requires that we start with the consequences of behavior to understand better what must be prevented. For example, supply reduction efforts (usually law enforcement activities) can be seen as primary prevention for the consequences of drug abuse (crime, burden on the treatment system, premature mortality, and excessive morbidity associated with substance abuse). Prevention requires an understanding of health disparities to determine which strategies will provide the most reach and penetration to populations most at risk. Efficacious and effective prevention strategies and programs are necessarily designed to influence known malleable risk and protective factors that, if changed, may lead to a reduction in the consequences of substance abuse. Prevention is often thought of as the bailiwick of health behavior specialists, but it cannot succeed without a comprehensive and integrated understanding of a variety of disciplines that contribute to our knowledge of the epidemiology, etiology, and treatment of substance abuse.

KEY POINTS Prevention science is still a relatively new area of scientific investigation. Even so, tremendous progress has been made in conducting rigorous research on efficacy and effectiveness, and research on dissemination has ramped up in recent years. Prevention requires a focus on malleable risk and protective factors that exist at numerous levels. If something cannot be changed, it is not a legitimate target of prevention. To date, more attention has been paid to intraindividual factors that may be malleable than to environmental factors that could be changed and, if changed, could affect many individuals. Prevention has focused largely on children and youths rather than adults; on initiation of drug use rather than other transition points (continuation, progression within and across drug classes, regression to cessation, and relapse); and on school-based prevention that is curriculum-driven, televised media messages, and the formation and sustenance of community-based coalitions. Little has been done to make prevention more comprehensive and integrated and to parse out the effects of various prevention strategies considered together rather than independently. Substance abuse is complex. Large individual differences in substance abuse patterns exist, but the biggest return on investment in prevention will focus on covering large segments of the population and accepting a relatively small percentage change rather than having a large effect on a small number of individuals. Prevention as it currently exists does not lend itself well to individual tailoring. Accumulating evidence indicates that school-based, curriculum-driven prevention programming can be efficacious, but a host of substantive and research issues remain to be solved.

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Evidence indicates that media-based prevention strategies can be efficacious, but the knowledge base is suggesting that there are many issues and problems that need to be examined rigorously. Evidence suggests that community coalitions can have an efficacious effect on substance abuse at the community level, but significantly more work is needed to have an algorithm that seems to work across communities. Documentation that a prevention effort is efficacious in a controlled setting does not in any way guarantee that it will be effective when disseminated. Studies of effectiveness and dissemination are needed to show compellingly how to take a prevention program to scale. Those involved in substance abuse prevention are often hard on themselves for not reporting large effects from interventions. A lesson may be learned from the prevention of cardiovascular disease. As many as 20% of the people who receive prescriptions do not even get them filled, and about 50% of the people taking routine medicines take them inconsistently (Miller 1997). After a major national push on hypertension, fewer than 60% of those receiving treatment had the condition "controlled" (Hajjar and Kotchen 2003). The question that has driven the substance abuse prevention field to date is "Does prevention work?" In the coming decades, the question driving the field will be "Prevention works, but for whom, when, where, under what circumstances, why, and how?"

REFERENCES Botvin GJ, Baker E, Dusenbury L, et al: Long-term follow-up results of a randomized drug abuse prevention trial in a white middle-class population. JAMA 273:1106–1112, 1995 [PubMed] Cameron R, Brown KS, Best JA, et al: Effectiveness of a social influences smoking prevention program as a function of provider type, training method, and school risk. Am J Public Health 89:1827–1831, 1999 [PubMed] Clayton RR: Transitions in drug use: risk and protective factors, in Vulnerabilities to Drug Abuse: Conceptual and Methodological Issues. Edited by Glantz M, Pickins R. Washington, DC, American Psychological Association, 1992, pp 15–52 Clayton RR, Scutchfield FD, Wyatt SW: Hutchinson Smoking Prevention Project: a new gold standard in prevention science requires new transdisciplinary thinking. J Natl Cancer Inst 92:1964–1965, 2000 [PubMed] Ellickson PL, Bell RM: Drug prevention in junior high: a multi-site longitudinal test. Science 247:1299–1305, 1990 [PubMed] Ellickson PL, Bell RM, McGuigan K: Preventing adolescent drug use: long-term results of a junior high program. Am J Public Health 83:856–861, 1993 [PubMed] Ellickson PL, McCaffrey DF, Ghosh-Dastidar G, et al: New inroads in preventing adolescent drug use: results from a large-scale trial of project ALERT in middle schools. Am J Public Health 93:1830–1836, 2003 [PubMed] Farrelly MC, Davis KC, Haviland ML, et al: Evidence of a dose-response relationship between "truth" antismoking ads and youth smoking prevalence. Am J Public Health 95:425–431, 2005 [PubMed] Flay BR, Biglan A, Boruch RF, et al: Standards of evidence: criteria for efficacy, effectiveness and dissemination. Prev Sci 6:151–175, 2005 [PubMed] Ghosh-Dastidar B, Longshore D, Ellickson PL, et al: Modifying pro-drug risk factors in adolescents: results from project ALERT. Health Educ Behav 31:318–334, 2004 [PubMed] Hajjar I, Kotchen TA: Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988–2000. JAMA 290:199–206, 2003 [PubMed]

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Hallfors D, Cho H, Livert D, et al: Fighting back against substance abuse: are community coalitions winning? Am J Prev Med 23:237–245, 2002 [PubMed] Hallfors D, Cho H, Sanchez V, et al: Efficacy vs effectiveness trial results of an indicated "model" substance abuse program: implications for public health. Am J Public Health 96:2254–2259, 2006 [PubMed] Hawkins JD, Catalano RF, Miller JY: Risk and protective factors for alcohol and other drug problems in adolescence and early adulthood. Psychol Bull 112:64–105, 1992 [PubMed] Holder HD, Gruenewald PJ, Ponicki WR, et al: Effect of community-based interventions on high-risk drinking and alcohol-related injuries. JAMA 284:2341–2347, 2000 [PubMed] McKinlay JB, Marceau LD: To boldly go. . . . Am J Public Health 90:25–33, 2000 [PubMed] Miller NH: Compliance with treatment regimens in chronic asymptomatic diseases. Am J Med 102:43–49, 1997 [PubMed] Mrazek PJ, Haggerty RJ: Reducing Risks for Mental Disorders: Frontiers for Prevention. Washington, DC, Academy Press, 1994 Niederdeppe J, Farrelly MC, Haviland ML: Confirming "truth": more evidence of a successful tobacco countermarketing campaign in Florida. Am J Public Health 94:255–257, 2004 [PubMed] Orwin R, Cadell D, Chu A, et al: Evaluation of the National Youth Anti-Drug Media Campaign: 2004 report of findings [NIDA Web site]. June 2006. Available at: http://www.nida.nih.gov.ezproxy2.library.usyd.edu.au/DESPR/Westat/ Palmgreen P, Donohew L, Lorch EP, et al: Televised campaigns and adolescent marijuana use: tests of sensation seeking targeting. Am J Public Health 91:292–296, 2001 [PubMed] Peterson AV, Kealey KA, Mann SL, et al: Hutchinson Smoking Prevention Project: long-term randomized trial in school-based tobacco use prevention: results on smoking. J Natl Cancer Inst 92:1979–1991, 2000 [PubMed] Sly DF, Hopkins RS, Trapido E, et al: Influence of a counteradvertising media campaign on initiation of smoking: the Florida "truth" campaign. Am J Public Health 91:233–238, 2001 [PubMed] St. Pierre TL, Osgood DW, Mincemoyer CC, et al: Results of an independent evaluation of project ALERT delivered in schools by cooperative extension. Prev Sci 6:305–317, 2005 Thrasher JF, Niederdeppe J, Farrelly MC, et al: The impact of anti-tobacco industry prevention messages in tobacco producing regions: evidence from the US truth campaign. Tob Control 13:283–288, 2004 [PubMed] Wakefield M, Terry-McElrath Y, Emery S, et al: Effect of televised, tobacco company-funded smoking prevention advertising on youth smoking-related beliefs, intentions, and behavior. Am J Public Health 96:2154–2160, 2006 [PubMed]

SUGGESTED READING Botvin GJ, Baker E, Dusenbury L, et al: Long-term follow-up results of a randomized drug abuse prevention trial in a white middle-class population. JAMA 273:1106–1112, 1995 Farley T, Cohen DA: Prescription for a Healthy Nation: A New Approach to Improving Our Lives by Fixing Our Everyday World. Boston, MA, Beacon Press, 2005 Farrelly MC, Davis KC, Haviland ML, et al: Evidence of a dose-response relationship between "truth" antismoking ads and youth smoking prevalence. Am J Public Health 95:425–431, 2005 Hallfors D, Cho H, Livert D, et al: Fighting back against substance abuse: are community coalitions winning? Am J Prev Med 23:237–245, 2002

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Peterson AV, Kealey KA, Mann SL, et al: Hutchinson Smoking Prevention Project: long-term randomized trial in school-based tobacco use prevention: results on smoking. J Natl Cancer Inst 92:1979–1991, 2000 Wakefield M, Terry-McElrath Y, Emery S, et al: Effect of televised, tobacco company-funded smoking prevention advertising on youth smoking-related beliefs, intentions, and behavior. Am J Public Health 96:2154–2160, 2006 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Chapter 49. Forensic Addiction Psychiatry

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Avram H. Mack, Monica Barros: Chapter 49. Forensic Addiction Psychiatry, in The American Psychiatric Publishing Textbook of Substance Abuse Treatment. Edited by Marc Galanter, Herbert D. Kleber. Copyright ©2011 American Psychiatric Publishing, Inc. DOI: 10.1176/appi.books.9781585623440.35 9350. Printed 10/7/2011 from www.psychiatryonline.com Textbook of Substance Abuse Treatment >

Forensic Addiction Psychiatry Avram H. Mack, M.D. Monica Barros, M.D.

FORENSIC ADDICTION PSYCHIATRY: INTRODUCTION There is an increasing probability that the addiction clinician will, willingly or not, come into contact with legal issues in the course of practice. This reflects many trends, including the widespread use of substances of abuse, increases in the prison population, increase in litigation, and professional interest in forensic psychiatry. After all, violence, suicide, interpersonal conflicts, lawsuits, psychiatric commitment, and even crimes (and sentences) are often a part of the lives of those who misuse substances. Traditionally, such involvement has been divided into the realm of either the expert forensic consultant or the clinician. With the growth of systems for mandated treatment as "diversion" from judicial interventions (e.g., drug courts; see Chapter 33 in this volume, "Community-Based Treatment"), this dichotomy has been blurred further, and many more addiction psychiatrists may be formally engaged in forensic psychiatry. At a minimum, such work requires solid clinical skills, but it also requires an adequate familiarity with one's role in the legal system. Clinicians who deal with addiction need a grasp of forensic issues in order to practice with skill and to communicate effectively in legal settings. This chapter is geared toward the general or addiction psychiatrist who needs guidance in the intersection of substances and the law. We cannot comment on every conceivable forensic role of the addiction psychiatrist. Instead, we provide a basic approach to forensic addiction psychiatry, and then we discuss key points to a variety of settings in which clinicians may be asked to provide an opinion. For legal issues that come up in clinical care (such as confidentiality, Tarasoff duties, or liability reduction), rather than in judicial settings, the reader is directed to Lifson and Simon (1998) or Gutheil and Appelbaum (2000).

FORENSIC PSYCHIATRY: PROCESS In any situation in which a clinician has been asked to respond specifically to the question(s) of an authority, the process by which that answer is created is as important as the content of the answer itself. The pieces of the process that are most important include those that ensure that the communication is consistent with the ideals of the American Academy of Psychiatry and the Law (2005): honesty and objectivity. Considerations of this process are discussed below.

Communicating Psychiatric Information to Legal Bodies "Forensic" (adj.) Used in or suitable to courts of law or public debate —Garner 2003 Consideration of the practice of forensic psychiatry depends on an understanding of the fundamental differences between it and clinical work. Although clinical psychiatry and forensic psychiatry are both based on solid knowledge of current medical information and, when appropriate, careful assessment of the individual and his or her mental state, they differ in their goals. Forensic psychiatry is the provision of objective statements regarding psychiatric conditions for certain audiences that seek responses to specific questions. The forensic psychiatrist's need to eschew bias and to "strive for objectivity" is disparate from the clinician's interest in altruistic clinical intervention and the clinician's method of communication with other clinicians. These differences dictate the need for clinical and forensic practice

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to be separate and unique approaches to the individuals, organizations, or institutions with which the forensic practitioner has contact. Engaging in forensic practice requires an understanding of how to create, communicate, and protect one's findings and opinions in manners suitable to courts or other such institutions.

Basic legal settings To communicate effectively with the legal world, the clinician must be acquainted with basic rules and features of American law as well as the particular features of the local jurisdiction (Group for the Advancement of Psychiatry 1991; Gutheil 1998; Rosner 2003). Whether either party is the government, a person, an insurance company, or a regulatory body, nearly any case with which a psychiatrist may become involved is set in an adversarial framework, in which opposing sides are pitted against each other. More than any other area, it is essential for the forensic expert to understand his or her limited, yet thoughtful, role: the production of an opinion that is as unbiased and objective as possible. The opinion or finding should be malleable in the face of further pertinent information to which the practitioner is exposed, but more than advocating for any party's overall position, the expert's duty is to protect his or her own opinion from intentional or unintentional distortions, obfuscations, or other misuse by any of the parties.

Fact versus expert witness Professionals who testify in a deposition, hearing, or trial may do so as witnesses of facts or as experts. It is important to maintain the distinction between these roles, and one must think ahead about which role he or she is being asked to perform. A clinician who is asked to describe his or her patient or who is asked (perhaps via subpoena) to produce his or her records on the patient is serving as a fact witness. This is very different from the expert, who, in cases of crime or litigation, has been asked to give an independent opinion related to the legal questions at hand. In judicial settings, any duly trained clinician is called an expert vis-à-vis the expertise he or she brings to the setting—one does not need to be an academic superstar to receive this appellation. Clinicians should be very careful about offering to serve as experts in cases involving their own patients—to do so almost certainly will affect the treatment, and it may be impossible for the clinician to maintain the objectivity required of the expert witness. Occasionally, individuals seeking a short cut to a physician's legal testimony pose as bona fide patients and attempt to use the medical record (which is a legal document) to their benefit. It is not uncommon for one parent in a custody battle to request the clinician to testify on his or her behalf—to do so would inject transference and countertransference into the therapeutic relationship with both the patient and his or her parents. Crossing this line is ethically prohibited by the American Psychiatric Association and American Association of Psychiatry and the Law guidelines. The reader is referred to Gutheil (1998) for further details on this question of "wearing two hats."

Distinctions between medical diagnoses and legal definitions What does the legal system need from a forensic opinion? Attorneys, juries, and judges need an explanation regarding an area of expertise. Certain clinical terms that are spoken naturally among other clinicians may tend to be misunderstood in the adversarial setting. The forensic psychiatrist should be able to discuss his or her opinion in language that can be understood by a lay audience while retaining clinical utility. Some terms are easily misused in adversarial settings or even in laws and regulations. For example, unlike the medical usage of narcotic to refer to an opioid, a standard law dictionary defines narcotic as "An addictive drug. . .A drug that is controlled or prohibited by law" (Garner 2003). The clinician communicating with nonmedical bodies must work to ensure that relevant, yet correct, language is used. The potential for misuse of language is particularly important in diagnosis. In forensic situations, it is essential to use diagnostic terms that are accepted by all parties. Addiction is a word that carries biological, behavioral, and social connotations. It should not be misused in a legal context. Among physicians, it has been interchangeable with substance dependence, and this has been linked to

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demonstrable alterations in neural activity. Some experts also use addiction to distinguish dependence on illicit substances from chemically induced dependence by medications. However, the medical community also has come to consider food, gambling, and sexual intercourse as addictions. Attorneys, clients, and some doctors may apply the suffix -ism to any behavior they wish to portray as compulsive or uncontrollable. Caution is necessary when addiction is used to discuss behaviors beyond substances of abuse because there has been a backlash to the expanding application of this word. In most jurisdictions, the standard is the current classification of mental disorders, the American Psychiatric Association's (2000a) DSM-IV-TR. Courts and attorneys frequently misunderstand DSM-IV-TR substance use disorder diagnoses and need the expert to provide clarification. DSM-IV-TR has an imperfect fit with the needs of courts: for example, the court often asks the expert for predictions on the future, or degree of dangerousness, neither of which has a DSM category. This awkward fit reflects a problem for the psychiatrist in the courtroom—remember that although one may feel pressured to, one should refrain from making predictions that one cannot quantify or validate. Courts also should be reminded that an abnormal finding on a test or an instrument does not imply a diagnosis. Chemical dependency is another term that is used in legal arenas, frequently in probate or mental health courts, which may commit individuals to emergency or long-term care. The law defines chemical dependency in terms of deleterious effects of alcohol or drug use, but it is typically not specifically tied to DSM criteria. Physicians asked to comment on alleged chemical dependency must know the legal rather than simply the clinical criteria for this status.

Clinical Assessments for Legal Bodies Although courts or attorneys may ask for it, there is no such thing as a "complete psychiatric assessment." The expert psychiatrist must help the attorney or the court pose a specific question to be answered in his or her report and testimony. Every forensic psychiatry assessment must be done with a particular focus and a specific question in mind. The forensic assessment of a subject who abuses substances must include a thorough review of all history, including medical, psychiatric, and social function. Collateral sources of historical information are essential. Sinha and Easton (1999) have provided a useful guide for the Forensic Substance Abuse Evaluation. In addition, standardized instruments and laboratory tests may be presented as past medical records, or they may be obtained by the expert. Use of standardized instruments, such as the Michigan Alcoholism Screening Test, is acceptable because these may provide normalized data with which to make comparisons. Laboratory studies may be important, depending on the time frame and setting, but it is essential to know what tests are being ordered and their significance. For example, a urine drug screen for alcohol gives different information than does a serum carbohydrate-deficient transferrin (CDT) test. In addition, sensitivity, specificity, and the potential for false-positive or false-negative results vary in each case; some addiction clinicians and many forensic psychiatrists are unaware of the qualities of each laboratory study and of the potential for false-positive results on a test such as the CDT (Fleming et al. 2004). Even the presence of an abnormal CDT, liver enzyme, or macrocytic anemia level, and any other pathophysiological effects of exposure to alcohol, does not necessarily imply addiction or dependence, and such claims seem necessarily incomplete (Baron et al. 2005). To ignore such possibilities serves neither the individual, the profession, nor justice.

FORENSIC PSYCHIATRIC CONTENT: AREAS OF FORENSIC ADDICTION EXPERTISE Violence and Crime and Substances The connections between violence, crime, and substances have been recognized to some extent for most substances of abuse, but these links continue to be elucidated. In this chapter, we discuss violence toward others, but the various associations between substances of abuse and suicide have been studied as well (for a review, see Mack and Lightdale 2005).

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Violence and aggression Aggression is defined as overt behavior with the intent to inflict noxious stimulation or to behave destructively toward another organism. Violence is aggression among humans. Hostility is defined as unfriendly human attitudes, including tantrums, irritability, refusal to cooperate, and suspicion. All of these behaviors can cause significant short- and long-term problems for the actor, and it is important to consider the ways in which substances of abuse may promote these behaviors. Substances of abuse may promote aggression, hostility, or violence by heightening physiological or psychological states, including anxiety, paranoia, confusion, agitation, irritability, grandiosity, sensation, motor reactivity, or vigilance. The effects of substances on such behaviors are independent of major mental disorder (Steadman et al. 1998). Substances may effect aggression, hostility, or violence during intoxication or withdrawal, during a substance-induced psychiatric or neurological state, or as a result of the comorbidity that comes with use. These effects vary according to the particular substance: intoxication may be associated with irritability, grandiosity, poor judgment, confusion, or psychosis, all of which may lead to aggression. Withdrawal also might include agitation, delirium (which often includes violence, albeit disorganized), or anxiety. Substance-induced psychiatric states (mental disorders caused by ongoing use of a substance) might create conditions with some increased violence risk, including reversible or irreversible cognitive deficits, mood disorders, psychosis, or seizures. Finally, comorbid conditions add to violence risk (Steadman et al. 1998; Swanson 1994), especially when the patient is nonadherent to treatment or has a personality disorder as a comorbid condition. Crime is distinct from violence in that it is a social construct. Crime is also linked to substance use, although a causal relationship cannot be as well defined as in the case of violence. Of the people arrested for violent offenses, 70% test positive for substances of abuse (Sinha and Easton 1999). Evidence suggests that alcohol use commonly precedes or accompanies violence between sexes, especially among male perpetrators (Leonard and Quigley 1999), and that the risk of child abuse and child neglect is increased when substances are used (Schuck and Widom 2003). In the United States, 34% of the risk for community violence is attributable to substance use (Swanson 1994). Forty percent of the risk for homicide by Finnish men was found to be attributable to alcohol use (Eronen et al. 1996).

Comorbid substance use and psychiatric disorders There is a significant difference in the dangerousness associated with severe mental disorders when substance abuse enters the picture. Investigation, particularly the MacArthur Violence Risk Assessment Study, has shown that persons with co-occurring substance use and psychiatric disorders are more frequently violent than are persons in the general population who do not have a psychiatric or substance use diagnosis or persons who have severe mental illness alone (Steadman et al. 1998; Swartz et al. 1998). The most important findings over the past decade have shown that violence is not usually associated with major mental disorders that occur in isolation: perhaps only 4% of reported violence is the result of mental disorders (Swanson 1994). However, when these mentally ill patients use substances, the risks of violence increase dramatically (Steadman et al. 1998). Added to this risk is the finding that treatment noncompliance increases the risk of violence (Torrey 1994) and that treatment noncompliance increases with substance use (Swartz et al. 1998). This line of research has shown that substances play an important role in violence among those with major mental disorders.

Alcohol The documented relationship between alcohol and aggression is based on epidemiological evidence (Murdoch et al. 1990) and "laboratory" evidence in which intoxication is effected in controlled environments (Bushman and Cooper 1990) followed by situations engendering anger toward others. Note that individuals with antisocial personality disorder are 21 times more likely to develop alcohol use disorder (Moeller and Dougherty 2001). Alcohol use can include physiological states that have risks of aggression.

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Intoxication causes behavioral dyscontrol and adrenergic reaction Withdrawal includes agitation, restlessness, or delirium in severe states Neurological injuries or disease caused directly or indirectly by alcohol Cognitive impairment following chronic use Given these scenarios and others, it is important to consider history and future risk of violence in those who use alcohol heavily.

Cannabis There is an increasing understanding that cannabis is not as benign as previously thought, and this includes literature on cannabis, violence, and crime. Cannabis, which remains the most widely used illicit substance worldwide (United Nations 1997), may affect the tendency to be violent or disruptive in heavy users who are experiencing withdrawal. A cannabis withdrawal syndrome with increased cortisolreleasing factor (Tanda et al. 1997) and aggression, restlessness, and irritability has been defined and recognized by some investigators (Budney et al. 2004). In addition, both youth and adult cannabis users frequently have comorbid psychiatric disorders. Cannabis use is frequently a part of the lives of those who commit crimes. Cannabis use is highly associated with crimes involving weapons and crimes such as reckless endangerment and attempted homicide (Friedman et al. 2001). Of all those convicted of homicide in New York State in 1984, marijuana was the "most commonly used illicit drug" (Spunt et al. 1994). Cannabis dependence is associated with increased violent crime (Arseneault et al. 2000). Finally, one study that compared the effect of drugs on the likelihood of violence between groups of youths of "high" and "low" delinquency found the only significant effect to be mediated by cannabis (Friedman et al. 2003).

Other substances Data support increased risk of violence when other substances are used, including opioids (especially during withdrawal); phencyclidine (PCP), in which the risk occurs during the agitation and confusion of intoxication; cocaine, which has risk of violence to others during the irritability or psychosis of intoxication and a risk of agitation during withdrawal; and nicotine, which has a risk of agitation during withdrawal.

Effect of Substance Use Disorders on the Criminal Process The criminal process is a stepwise pathway that jumps from the prohibited action (the actus reus) to prosecution of and the assignment of blame (conviction) for the action. Along the way, various events in law enforcement or judicial settings call for decisions on how to proceed: whether to report an incident, whether to prosecute, under what crime to prosecute, whether the defendant may stand trial, whether he or she can be held responsible, whether he or she had—or could have had—the requisite "evil mind" (mens rea) or intent for that crime, what the punishment should be, and so forth. The opinion of the addiction expert may be helpful with any of these decisions. The criminal defendant's addictive disorder is particularly important in terms of the mitigation of responsibility, when substance use treatment is mandated as an alternative to incarceration, or when the long-term medical or psychiatric effects of substances interfere with the defendant's ability to proceed in the criminal process. However, intoxication or addiction alone is almost never accepted as a complete defense in determining responsibility for a criminal act. Each state has laws that may relate to the potential for intoxication or addiction to be a mitigating factor for culpability in certain crimes. Potential experts should understand the nuances of these positions. In each state, laws define specific criteria that must be met as a part of any expert's opinion, and the expert must have a grasp of that legal language before engaging in any consultation.

Criminal defenses In a few special situations, responsibility cannot be assigned to a criminal offender. These situations include "insanity," involuntary intoxication, and being otherwise incompetent (such as being a minor).

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Over time, case law and statutes have almost completely eliminated voluntary intoxication as a defense against responsibility for any crime. However, involuntary intoxication may be exculpatory. This term reflects situations in which intoxication occurs via trickery, under duress, or as a result of a previously unknown vulnerability to an atypical reaction to a substance or side effect of medication (Myers and Vondruska 1998). Some jurisdictions have specific guidelines and limitations for an acceptable involuntary intoxication defense (Downs and Billick 2000). A possibly exculpatory condition is "settled insanity": a situation in which long-term use has led to a chronic brain injury that is different from an acute intoxication or toxic psychosis (Slovenko 1995). Although voluntary intoxication is not an excuse for criminal acts, it may alter the law under which the individual is prosecuted (Slovenko 1995). When "specific intent" is required to be convicted of a particular charge (e.g., murder rather than manslaughter for a homicide), voluntary intoxication has been successfully used as a defense against intent (that the perpetrator could not have had the specific intent required for a murder conviction). In some states, when accidents occur while a person is intoxicated, the forensic psychiatrist is asked to investigate the presence or absence of mens rea when the substance was first ingested (Wagenaar and Toomey 2002). The psychiatric expert must check with the attorney as to which charge is a specific intent crime and which rules apply in the relevant jurisdiction for that case. The concept that an intoxicated offender may not be able to recall or comment on an act because he or she was in a state of "blackout" is very controversial in legal context. This has been advanced as a defense for culpability and for mens rea. This condition is supported by little evidence-based medical information, but most addiction psychiatrists and lay people are familiar with the clinical phenomenon. Forensic psychiatrists, especially those without much experience in addiction psychiatry, may misuse, inappropriately downplay or identify, or otherwise misapply the term blackout. Concerns about malingering have fed doubt in the courtroom about whether and how the occurrence of a blackout can be clearly determined. One study found that blackouts can occur during criminally relevant behavior, but they rarely occurred at blood alcohol concentrations of less than 250 mg/100 mL. A good approach is to seek subjective data such as blood alcohol concentrations and to analyze the nature of the offense because blood alcohol concentrations high enough to produce blackouts also would likely impair fine motor control and make it difficult to perform acts such as firing at a target from a far distance (van Oorsouw et al. 2004). It is important to distinguish this effect of intoxication from amnesia: a blackout is a period for which memory is not ever recorded, whereas in amnesia, previously known information is forgotten. In some situations, intoxication alone may directly establish a defendant as guilty. Crimes such as driving while intoxicated or driving under the influence are called "strict liability crimes." For such charges, mens rea is not required for a conviction; the actus reus is simply the intoxication. All that is required is evidence that the legal standard for intoxication was met. Some states have mandated maximum sentences in cases in which death resulted from a driver who was driving while intoxicated or driving under the influence. These sentences are applied even if the influence by the substance is shown to have played a minimal role in the events leading to the death.

Sentencing recommendations Following a criminal conviction, a defendant enters the sentencing phase of the legal process. In various jurisdictions, psychiatric opinions may play an important role in the sentencing phase. The psychiatrist can wield great influence in identifying substance use disorders and in making clear recommendations for treatment both during a sentence and after the sentence would be completed. A recent case in the federal system, United States v. Booker (2005), provides leeway to U.S. district court judges to diverge from sentencing guidelines if the presence of psychiatric disorders (including substance use disorders) substantially affected some part of the criminal behavior.

Correctional addiction psychiatry

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A record proportion of the American population is currently under some sort of criminal justice supervision, and most of these individuals have active substance use disorders or dual diagnoses (Abram et al. 2003; Peters et al. 1998). Correctional tends to refer to the settings in which individuals in the criminal justice system are under some sort of supervision during the stepwise course through the judicial process: not only institutions of incarceration (jails or prisons) but also the periods in which the individual lives in the community under supervision either before a trial (pretrial release), as a part of punishment (probation), or as a manner of early release from incarceration (parole or supervised release). As a result, psychiatrists must be prepared to advise on screening, treatment, making recommendations for release conditions, and also being a part of the treatment for those reentering the community. Both the American Psychiatric Association (2000b) and the National Commission on Correctional Health Care (2003) have developed guidelines for correctional facilities, and the Office of Juvenile Justice and Delinquency Prevention (2005) has created guidelines for clinicians who come into contact with incarcerated youths. Incarceration is a setting in which the individual is removed from the community, and the attention that needs to be given by addiction specialists at the various stages of incarceration varies according to the setting and its purpose. Broadly speaking, the individual exist in three very different incarceration ecologies: 1) the lockup (on arrest); 2) jail (following arraignment, during trial, prior to sentencing, or in sentences of up to 1 year); and 3) prison (postsentencing for more than 1 year). Substance-related disorders may appear at any point in the incarceration process, and ongoing, focused surveillance should be a part of every correctional system. For example, appropriate short-term clinical attention may be needed to treat the aggression of intoxication, reducing the potential for morbidity and mortality associated with intoxication (e.g., cocaine) or withdrawal (e.g., alcohol). Proper recognition of substance use disorders can lead to long-term benefits for the institution and for society: when individuals receive treatment for addiction, research has shown that focused rehabilitation-oriented treatment can lead to favorable outcomes following incarceration, including decreasing drug use and criminal activity and improving overall functionality (Gendreau 1996; Mateyoke-Scrivner et al. 2004), and it is more so if aftercare is provided (Griffith et al. 1999). A recent study in England reported substantial decreases in criminality in individuals with substance use disorders following voluntary participation in either residential or outpatient treatment programs (Gossop et al. 2005). Unfortunately, in reality, the typical levels of available psychiatric and medical services differ greatly among these settings (Weinstein et al. 2005). Psychiatrists should be advocates for ensuring that appropriate services are available at these various stages.

Screening Any drug of abuse may be carried by an individual when he or she enters custody directly from the outside world, and many arrestees have been using just prior to arrest. This intake is a critical moment when the staff must carefully examine the individual for intoxication, overdose, or active withdrawal from any substance—especially alcohol, benzodiazepines, or other sedatives. Those who are surrendering often have a "last hit" before entering incarceration. Ironically, for long-term users who are not actively intoxicated or in withdrawal, the opportunity to be referred to rehabilitation programs can be missed at screening. The clinician should use all available data, including testing and medical history, to guide more detailed screening. Substance use disorder prompts further, specialized medical assessment for associated pathology such as infectious disease, cardiac injury, or thromboembolic events or potential (Baillargeon et al. 2003). Screening for substance use disorders also must be geared to detect comorbid psychiatric conditions, which are common among the addicted incarcerated population.

Treatment and rehabilitation The correctional setting provides the opportunity for abstinence, treatment, and possibly rehabilitation. Several studies have shown that residential treatment during incarceration followed by continued care in

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the community led to reduction in recidivism and relapse (Belenko and Peugh 2005). However, because of the lack of standardized and validated clinical assessment tools in correctional facilities, little information is available about the treatment needs of inmates. Substance use disorders in this population are often accompanied by a variety of other concerns, including mental health issues, unemployment, and lack of education, which make successful treatment and recovery more difficult; these issues typically are not addressed by currently available resources (Belenko and Peugh 2005). The available resources for long-term treatment of addictions vary greatly among the incarcerated. Unfortunately, most prison systems do not address addiction in long-term inmates, and when available, long-term residential programs fail to address treatment issues of inmates with shorter terms of incarceration (Belenko and Peugh 2005). In some systems, addiction is addressed only in the last months of incarceration. Other systems have ongoing Alcoholics Anonymous meetings, education, and group and even individual psychotherapies. The lack of access to adequate treatment for addicted and mentally ill people in the general population contributes to the large numbers who are arrested. Also, unfortunately, substances do make their way to prisoners, for whom short-term detoxification may be the appropriate first step.

Nonincarceration correctional settings For both those referred directly to probation and those released after some period of incarceration, the risks of ongoing use are tremendous. Yet, this represents an important period in which abstinence can be maintained while in the community. For those who are being released from incarceration, this risk is present regardless of whether the release is sudden, planned, or after a short time or a long time. In vast numbers of U.S. jurisdictions, the capacity for local justice systems to create a solid plan for care and monitoring is low. Upon discharge, both those with substance use disorders and those with substance use disorders comorbid with psychiatric conditions are at high risk for relapse, which may affect criminality as well. One Scottish study found that of the increased deaths after release, many had injection drug use, especially with HIV (Bird and Hutchinson 2003). Data suggest that psychosocial aspects of reentry are the most important in reducing relapse and recidivism (Rounds-Bryant et al. 2004). Addiction psychiatrists may work with parole boards, probation officers, or pretrial service agencies to mandate treatment following release. Depending on the prevailing law, parole, probation, or pretrial agencies may mandate treatment according to their own authority by referring the case to the court or by referring parolees to mandated treatment programs (see the section "Mandated Treatment: The 'In Between'" later in this chapter). When asked by a court to suggest a treatment plan for the parolee, the addiction psychiatrist should offer multiple modes of multidisciplinary treatment and surveillance. One should consider residential, group, or day treatment; medication management; and other treatments. The period of treatment should be for a minimum of 1 year. Random screens are best done twice weekly. Attendance at activities should be required. The clinician should reevaluate at regular intervals.

Civil Matters and Family Law Civil law is the part of the judicial system that addresses conduct and conflict among a wide range of noncriminal human interactions—from family issues such as divorce and custody to personal injury, negligence, wills, and estates. Individuals involved in such matters may be encumbered by addictions. As in criminal proceedings, the psychiatrist may be asked to play a role in civil cases as either a fact or an expert witness. The psychiatrist may be asked to place substance use in the context of past behavior or to make predictions about future behavior. We review several frequently visited topics in this section. For issues relating to the workplace, see Mack et al. (2005).

Family and matrimonial law In disputes over divorce, custody, guardianship, adoption, or child safety, the substance use of any involved party is commonly at issue. The fiercely adversarial nature of these proceedings often impedes

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the formation of a valid picture. In such situations, the evaluating psychiatrist functions best when appointed by the court rather than being retained by either opposing side. It is crucial to evaluate all involved parties. Appropriate consent must be obtained before the examination of a minor. The psychiatrist is often asked to comment on the substance use of parents and its effects on the child. Although the presence of a substance use disorder does not necessarily mean lack of parental fitness, it certainly is a factor that should be considered. Recommendations for custody and visitation may be made with substance abuse treatment as a condition.

Personal injury Substance abuse issues often arise when one party that alleges injuries sues another party for damages. Either side may allege that the other was intoxicated at the time of the injury and may seek the help of a psychiatrist to establish or to negate such claims. The effect of long-term addiction also may be raised. Injured parties may blame the party that provided the substance of abuse. Many cases have exposed the liability of bars, bartenders, and parents of minors (Mack et al. 2005). For example, parents who allow a minor to serve alcohol or to use alcohol on their premises may be breaking the law and are exposing themselves to civil liability. Sexual harassment cases may be brought in either criminal or civil settings, and addictions may be raised as an issue in such cases as well.

Disability Claims of disability based on addictions may be made to private insurance companies or to the federal government. Addiction psychiatrists are naturally the experts of choice for such cases. They may be retained by the individual claiming disability or by the insurance company for an "independent medical examination." If the case goes to court, expert testimony will be included. Any physician who completes paperwork certifying disability should consider the possibility that he or she may be called to testify about his or her findings in court. Management of addictions in patients with chronic pain complaints is clinically complex; this complexity translates into the expert question of whether returning to work is possible. The treating psychiatrist might do well to refer a patient for consultation with an addiction psychiatrist or pain expert when faced with such a question.

Other areas An addiction psychiatrist may have special expertise in other areas of civil law. In malpractice cases, a patient may allege that a physician caused him or her to become addicted to substances, or a patient may claim that his or her physician was impaired by substances. Of the impaired physicians in state health and recovery programs, 50%–70% are there because of substance use disorders. Because workplace actions frequently lead to legal consequences, the addiction psychiatrist is frequently involved in consultation regarding the workplace (Wagenaar 2001). The presence of substance use is frequently a part of retrospective challenges to testamentary capacity (Shulman et al. 2005; Spar and Garb 1992).

Addiction and Administrative Law Administrative law refers to the expectations, due process procedures, and practices of various regulatory bodies that have oversight over the status of individuals involved in professions, athletics, the military, and other areas of social activity (sometimes including driver's licenses). For example, when a state medical board investigates a physician, it adheres to its own regulations and requirements, also known as administrative law. In some cases, military or other administrative law proceedings require psychiatric input about addiction. These include noncivil and noncriminal institutions such as athletic, security, licensing, or ethics bodies. The English Civil Aviation Authority or the American Federal Aviation Administration may hold hearings on pilots licenses, and entry into sensitive government employment may be barred by a history of substance use alone. Driver's license questions are usually handled in general criminal courts, but decisions on noncriminal aspects of driving may be decided by administrative bodies in some states. Each institution or organization has different interests when considering substance use. Administrative

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bodies may seek evidence about a licensee's degree of substance use and its effect on ability to perform, or other bodies may be attempting to determine whether the individual should be offered employment. The key tool for the expert is the language of the regulations or statutes under which the individual is being scrutinized. This ranges from the person being "alcoholic" to having been intoxicated with a blood alcohol level greater than 0.04% (above which airplane flying is impaired; Dave 2004). In some cases, the forensic expert is asked by an employer to perform a "fitness for duty" evaluation; in other cases, an individual who is in the process of losing his or her status has the right to bring forth evidence (in the form of an expert's opinion) that he or she does not have problems with substances. When their opinions are in opposition to the interests of the individual, forensic experts often weather a great deal of scrutiny and criticism because the livelihood or other special aspects of the individual's life are at stake.

MANDATED TREATMENT: THE "IN BETWEEN" Between functioning as a clinician and as a forensic expert, physicians play a part in a growing number of settings in which treatment is mandated by a body of authority (usually a court). The cascade of names and laws for these systems might be confusing: these provisions may overlap in some jurisdictions, they may have different names despite similar procedures and goals, and motions for these systems occur in different types of courts (courts themselves may have different names in different jurisdictions). In some areas, individual judges have created such courts de novo without state legislation. Court-ordered treatment has two major avenues. Although they may lead to the same end, these systems represent different goals. First are the systems designed to move disordered criminal offenders out of the justice system into treatment. Second are the laws that provide for the involuntary commitment (inpatient or outpatient) of patients whose disorder has endangered themselves or others (Monahan et al. 2005). Many of these systems are exclusive for either substance use or psychiatric treatment, and many jurisdictions have systems for only one of these two realms of treatment. A central dilemma of all of these programs is whether treatment of addictions is possible when it is forced on the individual (given the success of these programs, however, this dilemma should spur important academic thought about addiction treatment generally). Psychiatrists with knowledge of addictions can play a major role in these proceedings, and judges are often welcoming of such advice.

Criminal Diversion Diversion refers to institutions, practices, and laws that divert criminal offenders who have a mental disorder or a substance use disorder out of the standard criminal justice system and into alternatives. This may occur at many different points in the criminal process, including prearrest, prearraignment, pretrial, in lieu of punishment, or after some punishment. A comprehensive review of the rationales for, and of the many types of, diversion programs can be found in a volume by the Council of State Governments (2002). The core feature of diversion is that an authority releases the offender from further blame or from punishment in return for engaging in treatment. Typically, the offender must express to the authority (police, prosecutor, or judge) a voluntary willingness to engage in treatment. It is unclear whether this willingness represents a wish for treatment or a simple avoidance of criminal proceedings. Drug courts are one type of diversion found in a limited number of jurisdictions. Drug courts mandate treatment and seem to have low recidivism rates and lead to education, cost savings, and drug-free infants. These programs are generally for nonviolent offenders with less serious charges (e.g., misdemeanors). These institutions may protect the patient or the public from violence or accidents, and they may reduce expenditure on incarceration or hospitalization, but some states require a mental disorder other than a substance use disorder to be present. However, being in a drug court may obscure the presence of a psychiatric disorder, and those involved should advocate for awareness and diagnosis in such cases (Hagedorn and Willenbring 2003). Some have called for the growth of co-occurring courts that deal with persons with both major mental disorders and substance use disorders.

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Involuntary Treatment Mandated treatment exists in some jurisdictions for those with serious and pervasive substance use disorders who have been or will likely become dangerous to themselves or others. Various states, counties, and the federal government have been developing ways in which to intervene (Gerbasi et al. 2000). Thomsen and Appelbaum (2002) have commented on the valid legal basis for this approach. The U.S. Supreme Court ruled in 1961 in Robinson v. California that "A state might establish a program of compulsory treatment for those addicted to narcotics. Such a program might require periods of involuntary confinement, and penal sanctions might be imposed for failure to comply with established treatment procedures" (Robinson v. California 1962). As of 1997, 31 states and the District of Columbia had statutes specifically allowing involuntary treatment or commitment for substance-dependent individuals. This treatment can be inpatient, outpatient, or partial hospitalization. The criteria and process for commitment vary by state, but usually they require a judicial hearing in which the individual's or the community's safety is believed to be endangered by the refusal of the patient to receive treatment. Even in states in which these statutes exists, we have found that many clinicians and families (and even judges or attorneys) are unaware of them and, as a result, fail to benefit from the legal avenues available to enhance patients' entry into or compliance with essential treatment and care.

LIABILITY FOR THE FORENSIC EXPERT Although the increased popularity of forensic psychiatry has been attributed in part to its insulation from the various liabilities inherent in clinical care, any professional who performs high-stakes evaluations and who must communicate them under great scrutiny (including legal requirements for honesty) faces many liabilities. It is difficult enough to speak in a courtroom or even in front of a stenographer, but it is even more difficult to do so under oath, in a cross-examination, under criticism, with media attention, under the threat of complaints to professional or ethical boards, or even with accusations of perjury (which is a criminal offense) (Binder 2002). The forensic expert is always well served to be in the position of "friend to the Court," as is the case in drug courts, in which case he or she is asked to be a neutral expert rather than appearing to be beholden to one of the parties, but even that position is not a complete shield from criticism or accusations of bias. Gutheil and Simon (2005) provide a review of the narcissistic vulnerabilities of the forensic expert that may impede one's work in this field. The threat of complaints or lawsuits may rise in forensic settings in which the practitioner appears to have a conflict of interest—a good example includes "fitness for duty" examinations, in which it is clear that the examiner, who may hold the "key" to the evaluee's livelihood, has been hired by the organization or institution. Avoiding real or apparent conflicts of interest is one important task that helps in the protection of a valid opinion or finding.

CONCLUSION Both the clinician and the expert may be confronted with legal situations in which substance use plays an important role. The professional's role may be very different in these various situations, and it is essential to enter this area with a clear understanding of one's responsibilities and obligations to one's patient, retaining attorney, profession, and own ethics and the law. One should never hesitate to clarify these issues through consultation with a peer, a local medical society, or an attorney. Involvement with the legal issues as they relate to addictive disorders is a complex, yet potentially rewarding role one can play as a clinician. In this manner, mental health knowledge can be suitably and effectively conveyed to social institutions that need it.

KEY POINTS Being engaged in forensics has risks and liabilities. Know your audience to communicate suitable information. Substances of abuse increase the risk of violence in individuals.

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Correctional settings vary in the status of the individual. Special types of mandated treatment and "diversion" may have effects on reducing recurrent criminal behavior.

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SUGGESTED READING American Academy of Psychiatry and the Law: Ethics guidelines for the practice of forensic psychiatry. Adopted May 2005. Available at: http://www.aapl.org/pdf/ETHICSGDLNS.pdf. Accessed April 13, 2007 American Psychiatric Association: Psychiatric Services in Jails and Prisons, 2nd Edition. Washington, DC, American Psychiatric Association, 2000 Binder RL: Liability for the psychiatrist expert witness. Am J Psychiatry 159:1819–1825, 2002 Group for the Advancement of Psychiatry, Committee on Psychiatry and Law: The mental health professional and the legal system. Rep Group Adv Psychiatry 131:1–192, 1991 Steadman HJ, Mulvey EP, Monahan J, et al: Violence by people discharged from acute psychiatric inpatient facilities and by others in the same neighborhoods. Arch Gen Psychiatry 55:393–401, 1998 Torrey EF: Violent behavior by individuals with serious mental illness. Hosp Community Psychiatry 45:653–662, 1994 Copyright © 2011 American Psychiatric Association. All Rights Reserved.

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Addiction. Hales Et Al (2011) American Psychiatric Publishing Textbook of Substance Abuse Management, 4th Ed

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