Selmar Q. Maribojo, Jr Chapter 31 Opioid Analgesics & Antagonists INTRODUCTION What are analgesics? Substances employed for their ability to reduce the perception of pain impulses impulses by the CNS Terminology: Opioid All compounds compounds related related to opium opium Opiates Drugs derived from opium Narcotic “Stupor”, substance with abuse or addictive potentials Opioid analgesics Natural and semisynthetic alkaloid derivatives from opium Synthetic surrogates Opiod like drugs whose actions are blocked by naloxone Endogenous peptides that interact with opioid receptors Morphine Prototypical opioid agonist Standard against which all drugs with strong analgesic action are compared Relieve severe pain with remarkable efficacy Pure alkaloid, naming it after Morpheus, the Greek god of dreams Opium poppy Source of crude opium from which isolated morphine Naloxone Nonselective antagonist Blocked the action opioid analgesic and other opioid-like drugs BASIC PHARMACOLOGY OF THE OPIOID ANALGESICS I Source of Morphine Opium is obtained from the poppy o Papaver somniferum and P album Crude opium o After incision, the poppy seed pod exudes a white substance that turns into a brown gum Opium contains many alkaloids, the principle one being morphine, which is present in a 10 % concentration is synthesized commercially from morphine Codeine is Codeine II Classification & Chemistry A. Spectrum of clinical use Analgesics Analgesi cs o Antitussives Antitussi ves o o Antidiarrheal Antidia rrheal B. Strength of analgesia o Strong Moderate o Weak o C. Ratio of agonist to antagonist Agonists o Antagonist Antagon ist o Mixed agonist-antagonis o
Opiod drugs
Agonist
Partial agonist
Antagonist
(Morphine)
(Codeine)
(Naloxone)
Certain opioid analgesics are modified in the liver, resulting in compounds with greater analgesic action Opioids derived from opium are phenanthrene derivatives and include four or more fused ring Most of the synthetic opioids are simpler molecules
Morphine Codeine Naloxone
Full agonist at the opioid receptor Simple substitution of an allyl group on the nitrogen Partial (or "weak") receptor agonist.
Strong antagonist at receptor Simple substitution of an allyl group on the nitrogen plus addition of a single OH group Nalbuphine Capable of producing an agonist (or partial agonist) effect at one opioid receptor subtype and an antagonist effect at another
III Endogenous Opioid Peptides Naturally occuring ligands for opioid receptors Three families of endogenous opioid peptides with their precursor proteins have been described in detail: Endorphins Prepro-opiomelanocortin (POMC) o Enkephalins Preproenkephalin (proenkephalin A) o methionine-enkephalin (met-enkephalin) leucine-enkephalin (leu-enkephalin) Dynorphins Preprodynorphin (proenkephalin B) o POMC
Contains the met-enkephalin sequence, β-endorphin, and several nonopioid peptides, including adrenocorticotropic hormone , β-lipotropin, and melanocyte-stimulating hormone (ACTH) ,
Preproenkephalin Contains six copies of met-enkephalin and one copy of leuenkephalin Leu- and met-enkephalin have slightly higher affinity for the (delta) than for the opioid receptor Preprodynorphin Yields several active opioid peptides that contain the leuenkephalin sequence: o Dynorphin A Dynorphin B o α and β neoendorphins o Additional family: Endomorphin-1 and endomorphin-2 Unknown mechanism Possess many of the properties of opioid peptides, notably analgesia and high-affinity binding to the receptor. Selectively activate central and peripheral -opioid receptors “Both the endogenous opioid precursor molecules and the endomorphins are present at CNS sites that have been implicated in pain modulation. “ Suggests that they can be released during stressful conditions such as pain or the anticipation of pain and diminish the sensation of noxious stimuli
Dynorphin A An analgesic analgesic action action through its binding to (kappa) opioid receptors receptors “controversial” Found in the dorsal horn of the spinal cord o Role in the sensitization of nociceptive neurotransmission. Increased levels can be found in the dorsal horn after o tissue injury and inflammation Proposed to increase pain and induce a state of long-lasting hyperalgesia. Appears to be independent of the opioid receptor system but dependent on the activation of the bradykinin receptor Can bind and activate the N -methyl-D-aspartate (NMDA) receptor complex
Receptores types I Classic Receptor All are members of the G protein-coupled family of receptors and show significant amino acid sequence homologies. Mu receptors Mediate supraspinal and spinal analgesia, sedation, respiratory depression and physical dependence, miosis, and reduced GI motility, modulation of hormone and neurotransmitter release Subtypes μ 1 , μ 2 o μ 1 – supraspinal and spinal analgesia o μ 2 – mediate respirator depression Enkephalins and endorphins are endogenous ligands Morphine is an exogenous ligand Endorphins > Enkephalins > Dynorphins Delta receptors Mediate supraspinal and spinal analgesia, dysphoria, psychotomimetic effects (eg hallucination), respirator and vasomotor stimulation caused by drugs with antagonist activity Subtypes δ 1 , δ 2 Enkephalins are endogenous ligands Morphine is an exogenous ligand Enkephalins>> Endorphins & Dynorphins Kappa receptors Mediate supraspinal and spinal analgesia, psychotomimetic effects (eg hallucination), slowed GI transits Subtypes κ 1 , κ 2 , and κ 3 κ 1 – mediates spinal analgesia o o κ 2 - unknown o κ 3- mediates supraspinal analgesia Dynorphins are endogenous ligands Morphine is an exogenous ligands Dynorphins >> Endorphins and Enkephalins Propsed to mediate a sedation analgesia with reduced addiction liability and respiratory depression Respiratory depression and miosis may be less severe o with κ agonists Summary Tables Receptor Functions Subtype Sedation (Mu) Inhibition of respiration Modulation of hormone Neurotransmitter release Modulation of hormone (Delta) Neurotransmitter release Psychotomimetic effects (Kappa)
Endogenous Opioid Peptide Affinity Endorphins > enkephalins > dynorphins
Opioid motif – Tyr-Gly-Glu-Phe-(Met or Leu) Selected Endogenous Opioid Peptides Leu-enkephalin Tyr-Gly-Glu-Phe-Leu Met-enkephalin Tyr-Gly-Glu-Phe-Met Dynorphin A Tyr-Gly-Glu-Phe-Leu-Arg-Arg-Ile…. Tyr-Gly-Glu-Phe-Leu-Arg-Arg-Gln…. Dynorphin B α neoendorphins Tyr-Gly-Glu-Phe-Leu-Arg-Lys-TryPro-Lys β neoendorphins Tyr-Gly-Glu-Phe-Leu-Arg-Lys-Try-Pro β3 endorphin Tyr-Gly-Glu-Phe-Met-Thr….. Novel Endogenous Opioid related Peptides Phe-Gly-Gly-Phe-Thr….. Orphanin FQ/Nociceptin PHARMACOKINETICS Absorption Most opioid are well absorbed when given by subcutaneous, intramuscular, and oral routes Considerable interpatient variability in the first pass o effect Unable to predict effective oral dose Oral dose of the opioid (eg, morphine) may need to be much higher than the parenteral dose to elicit a therapeutic effect due to first pass effect. Morphine, hydromorphone, oxymorphone undergo extensive first pass effect Certain analgesics such as codeine and oxycodone are effective orally because they have reduced first-pass metabolism Nasal insufflation of certain opioids can result in rapid therapeutic blood levels by avoiding first-pass metabolism. Other routes of opioid administration include oral mucosa via lozenges, and transdermal via transdermal patches Distribution All opioids bind to plasma proteins with varying affinity Rapidly leave the blood compartment and localize in o highest concentrations in tissues that highly perfused Brain, lungs, liver, kidneys, and spleen Drug concentrations in skeletal muscle may be much lower Serves as the main reservoir because of its greater o bulk. Blood flow to fatty tissue is much lower than to the highly perfused tissues very important of accumulation after frequent higho dose administration or continuous infusion of highly lipophilic opioids that are slowly metabolized, eg, fentanyl Cross the placental barrier
Enkephalins > endorphins and dynorphins
Dynorphins > > endorphins and enkephalins
All Receptor subtypes functions as supraspinal and spinal analgesia Mu & Kappa subtypes also functions as slowed gastrointestinal transit II Non Classic Receptors ORL1 (orphanin opiod like subtype 1), also known as NOP Orphanin FQ/Nociceptin Novel receptor-ligand system homologous to the opioid peptides Receptors: G protein-coupled orphanin opioid-receptoro like subtype 1 (ORL1) o Ligand: Nociceptin/Orphanin FQ Widely expressed in the CNS and Periphery Implicated in both pro- and anti-nociceptive activity as well as in the modulation of drug reward, learning, mood, anxiety, cough, and of parkisonism Nociceptin Structurally similar to dynorphin except for the absence of an Nterminal tyrosine Acts only at the ORL1 receptor, now known as NOP
Metabolism The opioids are converted in large part to polar metabolites (mostly glucuronides), which are then readily excreted by the kidneys A. Conjugation in the liver by UDP-glucuranosyltransfereases B. Hydrolysis by common tissue esterases C. Hepatic oxidative metabolis by CYP3A4, CYP2D6 Conjugation in the liver by UDP-glucuranosyltransfereases
Metabolism of morphine
Excretion Urinary tract/Enterohepatic circulation Polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine Small amounts of unchanged drug may also be found in the urine Glucuronide conjugates are found in the bile, but enterohepatic circulation represents only a small portion of the excretory process.
Conjugation of Morphine
~10%: morphine6-glucuronide (M6G)
Morphine-3glucuronide (M3G)
Common opioid analgesics Brand
Generic name Active metabolite with analgesic potency four to six times
Limited ability to cross the bloodbrain barrier
Produce unexpected adverse effects
Act as neuroexcitatory to GABA/glycinergic system
CNS uptake of M3G and, to a lesser extent, M6G can be enhanced by coadministration with probenecid or with drugs that inhibit the P-glycoprotein drug transporter.
Metabolism of Hydromorphone
Hydromorphone
Conjugation
Hydromorphone-3glucuronide(H3G)
CNS excitatory
However, hydromorphone has not been shown to form significant amounts of a 6-glucuronide metabolite The effects of the active metabolites should be considered in patients with renal impairment before the administration especially when given at high doses.
Metabolism of Heroin and Remifentanil “Esters” undergo hydrolysis by common tissue esterases Heroin Hydrolysis Monoacetylmorphine Morphine
Morphine
--
Hydromorphone
Dilaudid
Oxymorphone
Numorphan
Methadone
Dolophine
Meperidine
Demerol
Fentanyl
Sublimaze
Sufentanil
Sufenta
Alfentanil
Alfenta
Levorphanol
Levodromoran
Codeine
--
Hydrocodone
--
Oxycodone
Percodon
Propoxyphene
Darvon
Pentazocine
Talwin
Nalbuphine
Nubain
Buprenorphine
Buprenex
Butorphanol
Stradol
Approx equiv. dose (mg)
O:P Potency ratio
Duration of analgesia (hr)
Intrinsic activity
High High High High High high High High
10 1.5 1.5 10 60-100 0.1 0.02 Titrated
Low Low Low High Med Low IV only IV only
2-3 30-60 5-10 4-5 60-120
High High Med Med Oral only
4- 5 4-5 3-4 4-6 2-4 1-1.5 1-1.5 0.250.75 4-5 3-4 4-6 3-4 4-5
30-50 10 0.3 2
Medium IV only Low IV only
3-4 3- 6 4-8 3-4
High Low Med Med Very low Med High High High
PHARMADYNAMICS A Mechanism of Action Opioid agonists produce analgesia by binding to specific G proteincoupled receptors that are located in brain and spinal cord regions involved in the transmission and modulation of pain. Some effects may be mediated by opioid receptors on peripheral sensory nerve endings.
Conjugation of morphine "Glucoronidation: Glucuronic acid: M3G & M6G
Metabolism of Phenylpiperidine opiods Meperidine Fentanyl “no active metabolites ” Alfentanil Sufentanil Hepatic oxidative metabolism is the primary route of o degradation Leaves only small quantities of the parent compound o unchanged for excretion. Normeperidine Accumulation of a demethylated metabolite of meperidine May occur in patients with decreased renal function o and in those receiving multiple high doses of the drug. In high concentrations, may cause seizures. Fentanyl
Hepatic oxidative metabolism by the P450 isozyme CYP3A4 metabolizes by N-dealkylation in the liver. CYP3A4 is also present in the mucosa of the small o intestine and contributes to the first-pass metabolism when it is taken orally.
Metabolism of Codeine, oxycodone, and hydrocodone Undergo metabolism in the liver by P450 isozyme CYP2D6 , resulting in the production of metabolites of greater potency.
Potential receptor mechanisms of analgesic drugs. The primary afferent neuron (cell body not shown) originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it synapses via glutamate and neuropeptide transmitters with the secondary neuron. Pain stimuli can be attenuated in the periphery (under inflammatory conditions) by opioids acting at μ -opioid receptors (MOR) or blocked in the afferent axon by local anesthetics (not shown). Action potentials reaching the dorsal horn can be attenuated at the presynaptic ending by opioids and by calcium blockers (ziconotide), α 2 agonists, and possibly, by drugs that increase synaptic concentrations of norepinephrine by blocking reuptake (tapentadol). Opioids also inhibit the postsynaptic neuron, as do certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.
I Receptor types All are members of the G protein-coupled family of receptors and show significant amino acid sequence homologies. Multiple receptor subtypes have been proposed based on pharmacologic criteria μ1,μ2 o o δ1,δ2 κ 1 , κ 2 , and κ 3 o II Cellular actions The opioids have two well-established direct G protein-coupled actions on neurons: Close voltage-gated Ca 2+ channels on presynaptic o nerve terminals Reduce transmitter release o Hyperpolarize and thus inhibit postsynaptic neurons by opening K + channels. III Relation of physiologic effects to receptor type The majority of currently available opioid analgesics act primarily at the μ-opioid receptor Analgesia and the euphoriant, respiratory depressant, and physical dependence properties of morphine result principally from actions at μ receptors. Opioid analgesic effects are complex and include interaction with δ and κ receptors. Morphine does also act at κ and δ receptor sites κ opioid receptors have been developed for reduced incidence of respiratory depression or propensity for addiction and dependence Butorphanol and nalbuphine have shown some clinical success as analgesics Can cause dysphoric reactions and have limited o potency Butorphanol has also been shown to cause significantly greater analgesia in women than in men. IV Receptor Distribution and Neural Mechanisms of Analgesia All three major receptors are present in high concentrations in the dorsal horn of the spinal cord. Receptors are present both on spinal cord pain transmission neurons and on the primary afferents that relay the pain message to them (Figure below, sites A and B). Opioid agonists inhibit the release of excitatory transmitters and they directly inhibit the dorsal horn pain transmission neuron. o Thus, opioids exert a powerful analgesic effect directly on the spinal cord Site of Actions of opiod analgesics A Ascending Pain Sensory Pathway Nociceptive nerve endings Spinal Cord Thalamus B Descending Pain Modulation Pathway Midbrain Medulla “Part of the pain relieving action of exogenous pepides involves the release of endogenous peptides” Putative sites of action of opioid analgesics. Sites of action on the afferent pain transmission pathway from the periphery to the higher centers are shown. A: Direct action of opioids on inflamed or damaged peripheral tissues B: Inhibition also occurs in the spinal cord C: Possible sites of action in the thalamus.
Brainstem local circuitry underlying the modulatin effect of μ-opioid receptor (MOR) –mediated analgesia on descending pathways. The pain-inhibitory neuron is indirectly activated by opioids (exogenous or endogenous), which inhibit an inhibitory (GABAergic) interneuron. This results in enhanced inhibition of nociceptive processing in the dorsal horn of the spinal cord
Opioid analgesic action on the descending inhibitory pathway. Sites of action of opioids on painmodulating neurons in the midbrain and medulla including the midbrain periaqueductal gray area (A), rostral ventral medulla (B), and the locus caeruleus indirectly control pain transmission pathways by enhancing descending inhibition to the dorsal horn (C).
Organ System Effects CNS: Analgesia (Sensory & Affective) Euphoria; Drowsiness; Apathy; Mental confusion; alteration in Mood Sedation – little or no amnesia Dysphoria (restlessness & Malaise Respiratory depression secondary to inhibition of brainstem respiratory mechanism; dose related; decreased response to CO2 challenge Cough suppression Miosis Truncal rigidity Nausea and vomiting – caused by direct stimulation of the emetic chemoreceptors located in the medulla; ? vestibular component Peripheral Effects Cardiovascular Most have no significant direct effect on the heart and cardiac rhythm except bradycardia Medperidine tachycardia secondary to its antimuscarinic effects GIT Stomach Motility is decreased o Tone is increased o Decreased HCL secretion o Small intestines Increased resting tone with periodic spasm o o Decreased amplitude in nonpropulsoive contraction Large intestines o Decreased propulsive peristalsis Increase tone o Biliary tract o Contract biliary smooth muscles Renal function Depressed secondary to decrease renal plasma flow Mu opioids have antidiuretic effects Enhance renal tubular Na reabsorption Increas4e ureteral/bladder tone
Increase sphincter tone Uterus – prolong labor Neuroendocrine – stimulate the release of ADH, prolactin, somatotropin; inhibit the release of LH Pruritus
Benzomorphone Pentazocine – a kappa agonist with weak mu anagonist or partial agonist properties Dezocine – highest affinity for mu receptors and less interaction with kappa receptors
Effects of Drugs with both agonist and antagonis action Buprenorphine Agonist at mu receptor with high binding affinity but low intrinsic activity Antagonist at delta and kappa receptor Can antagonize the action of more potent mu agonist Bind to ORL1 Pentazocine Agonist at kappa, weak antagonist at mu and delta receptors Nalbuphine Similar to pentazocine but a potent antagonist at mu receptors “Psychotomimetic effects have been reported ff use of drugs mixed agonist antagonist actions
Tramadol
Classification
Strong agonist
Phenanthrenes
Morphine, all – morphone Methadone Meperidine, Fentanyl, all – fentanil Levophorphanol --
Phenylheptylamines Phenylpiperidines
Morphinans Benzomorphone
Mild to Moderate agonist Codeine, all – codone Proxyphene Diphenoxylaye, Difenoxin, Loperamide ---
Mixed Receptor actions Nalbuphine, Buprenorphine ---
Butorphanol Pentazocine, Dazocine
Phenanthrenes Morphine, Hydromorphone, Oxymorphone – strong agonist useful in treating severe pain Codeine, Oxycodone, Dihydrocodeine, Hydrocodone – Less efficacious than morphine; rarely used alone but are combined with ASA, acetaminophen, etc Nalbuphine – a strong kappa receptor agonist and a mu receptor antagonist; respiratory depression is relatively resistant to naloxone reversal Buprenorphine – potent and long acting partial mu receptor agonist; resistant to naloxone reversal, effective in the detoxification and maintenance of heroin abusers Phenylheptylamines Methadone – can be administered PO, IV, SQ, rectal routes; potent mu receptor agonist; D and I isomers can block both NMDA receptor and monoaminergic re uptake; can relieve difficult to treat pain; use in the treatment of opioid abuse for detox and maintenance Propoxyphene – low analgesic activity, low abuse liability but increase incidence of death association with misuse Phenylpiperidines Meperidine – antimuscarinic effects; negative inotropic effect; potential for producing seizures secondary to normoperidine Sulfentanil>>>Fentanyl>Alfentanil Diphenoxylate/Difenoxin – used for diarrhea; used in combination with atropine Loperamide – limited access to the brain Morphinans Levorphanol – synthetic opioid analgesis resembling morphine Butorphanol – produce analgesia equivalent to nalbuphine & Buprenorphin but produce more sedation; predominantly a kappa agonist but may act as a partial agonist or antagonist at the mu receptor
Central acting analgesic Block serotonin reuptake and inhibit NET function Weak mu receptor Associated with seizures, nausea and dizziness Serotonin syndrome May be used as an adjunct with pure opioid agonist in the treatment of chronic neuropathic pain
Tapentadol Has a modest mu opioid receptor affinity and a significant norepinephrine reuptake inhibiting action In animal models, its analgesic effects were only moderately reduced by naloxone but strongly reduced by an alpha 2 adrenoreceptor antagonist Binding to NET > tramadol but binding to SERT < tramadol As effective as oxycodone in treating mod to severe pain Risk for seizure and serotonin syndrome Antitussives Dextromethorphan – stereoisomer of levorphanol; free addictive properties, produces less constipation than codeine; enhance the analgesic action of morphine Levoprpoxyphene – stereoisomer of dextropropoxyphene, devoid of opioid effects, sedation as side effect Opioid Antagonist Relatively high affinity for mu receptors; lower affinity for other receptors and can reverse agonists at delta and kappa sites Completely reverses opioid effects in 1-3 mins No tolerance to antagonistic action Naloxone
Short duration of action IV Poor efficacy PO Undergoes glucoronide conjugation Treatment of acute opioid overdose, adverse effect assoc with IV and Epidural opioids and opioid induced ileus or constipation Naltrexone Well absorbed PO st May undergo rapid 1 pass effect Maintenance for addicts Nalmefene Available only IV Longer half life Treatment of acute opioid overdose New Antagonists Methylnatrexone and Almivopan o Do not cross the BBB o Block adverse effects of strong opioids on peripheral mu receptors o With minimal effect on analgesic action Without precipitating an abstinence syndrome o Methylnatrexone Tx of constipation in patients with late stage advanced o illness Almivopan Tx of post operative ileus following bowel resection o surgery Clinical Use of Opioid analgesic Analgesia Acute pulmonary edema Cough Diarrhea
Shivering Premedications and adjuncts in anesthesia
Adverse Effects Behavioral restlessness, tremuolousness, hyperactivity Respiratory depression Nausea and vomiting Increased intracranial pressure Postural hypotension accentuated by hypovolemia Constipation Urinary retention Urticaria, Itching around the nose Tolerance and Physical Dependence Endogenous ligands
Endocytosis Resensitization Recycling of receptor in the plasma membrane Mu receptor
Tolerance Begins with the first dose, clinically manifests after 2-3 wks of frequent exposure; develops rapidly with large doses at short interval No tolerance develops to the miotic, convulsant and constipating actions The mechanism of development of tolerance and physical dependence is poorly understood Receptor recycling o Failure of morphine to induce endocytosis is an important component of tolerance and dependence o Receptor uncoupling Tolerance is due to dysfunctional of structural interactions between the mu nd receptor and G proteins, 2 messenger systems and their target ion channels o NMDA receptor complex NMDA receptor antagonist can block the development of tolerance Delta opioid receptor function as an independent o component in the maintenance of tolerance Cross Tolerance May develop such as patient tolerant to morphine show reduction in analgesic response to other agonist opioid but it is usually partial or incomplete Opioid rotation o o Recoupling Use of delta antagonist with mu receptor agonist o Physical dependence Results in a characteristic withdrawal or abstinence syndrome S/Sx – rhinorrhea, lacrimation, yawning, chills, piloerection, hyperventilation, hyperthermia, mydriasis, muscular aches, vomiting, diarrhea, anxiety and hostility The time of onset, intensity and duration of abstinence syndrome depend on the drug used and its biologic half life Psychologic dependence Primary reasons for opioid abuse liability o Euphoria, indifference to stimuli, sedation Abdominal effects o Physical dependence o
Contraindications and Cautions in Therapy Use of pure agonists with weak partial agonist – risk of diminishing analgesia or inducing a state of withdrawal Use in patient with head injuries Increase CO2 secondary to respiratory depression = o cerebral vasodilation Opioid Drug Interactions Drug Groups Sedative-Hypnotics Antipyschotic tranquilizers MAO inhibitors
Interaction with Opioid Increased CNS depression Increased sedation; variable effect on respiratory depression; accentuation of antimuscarinic and alpha blocking actions High incidence of Hyperpyrexic coma; hypertension
Factors to consider Route of administration Duration of Drug action Ceiling effect Duration of therapy Potential for adverse effects Patient’s past experience with opioids
