Opioid lecture

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Opioid lecture

  1. 1. Opioids Joshua H. Pozner, M.D. Mount Sinai School of Medicine Department of Anesthesiology Division of Pain Medicine
  2. 2. Drug Scheduling <ul><li>Controlled Substances Act – 1970 </li></ul><ul><ul><li>Regulates prescribing and dispensing of psychoactive drugs </li></ul></ul><ul><ul><li>5 Schedules </li></ul></ul><ul><ul><li>Grouped according to: </li></ul></ul><ul><ul><ul><li>Potential for being harmful </li></ul></ul></ul><ul><ul><ul><li>Value for medical purposes </li></ul></ul></ul><ul><ul><ul><li>Potential for abuse, dependence, or addiction </li></ul></ul></ul>
  3. 3. Drug Scheduling <ul><li>Schedule I: No accepted medical use </li></ul><ul><ul><li>Heroin, LSD, MDMA, GHB </li></ul></ul><ul><li>Schedule II: </li></ul><ul><ul><li>Fentanyl, oxycodone, morphine, amphetamine, methylphenidate, cocaine </li></ul></ul><ul><li>Schedule III: </li></ul><ul><ul><li>Combination products (hydrocodone + APAP), buprenorphine, butalbital </li></ul></ul><ul><li>Schedule IV: </li></ul><ul><ul><li>Benzodiazepines </li></ul></ul><ul><li>Schedule V: Least dangerous </li></ul><ul><ul><li>Codeine cough syrup, diphenoxylate </li></ul></ul>
  4. 4. Opioids <ul><li>Opioid: Agent whose action is mediated by binding to opioid receptors </li></ul><ul><li>Opiate: Alkaloid derived from the resin of the opium poppy </li></ul>
  5. 5. Endogenous Opioids <ul><li>β -Endorphins (µ receptor) </li></ul><ul><li>Enkephalins (δ receptor) </li></ul><ul><li>Dynorphins ( κ receptor) </li></ul>
  6. 6. Opioid Receptors <ul><li>Mu, Kappa, Delta </li></ul><ul><ul><li>G-protein coupled receptors </li></ul></ul><ul><li>Produce analgesia by inhibiting excitatory neurotransmission </li></ul><ul><li>Act both pre- and post-synaptically </li></ul><ul><li>Block voltage-dependent calcium channels </li></ul><ul><li>Location </li></ul><ul><ul><li>Periaqueductal gray region </li></ul></ul><ul><ul><li>Nucleus accumbens </li></ul></ul><ul><ul><li>Cerebral cortex </li></ul></ul><ul><ul><li>Amygdala </li></ul></ul><ul><ul><li>Nucleus of the solitary tract </li></ul></ul><ul><ul><li>Dorsal horn of spinal cord – substantia gelatinosa </li></ul></ul><ul><ul><li>Dorsal root ganglia </li></ul></ul><ul><ul><li>Peripheral nerves </li></ul></ul>
  7. 7. Mu Receptor <ul><li>Modulates input from mechanical, chemical, and thermal stimuli </li></ul><ul><li>Supraspinal & spinal analgesia </li></ul><ul><li>Respiratory depression </li></ul><ul><li>Miosis </li></ul><ul><li>Euphoria </li></ul><ul><li>Sedation </li></ul><ul><li>Decreased GI motility, biliary spasm, urinary retention </li></ul>
  8. 8. Kappa Receptor <ul><li>Influences thermal nociception </li></ul><ul><li>Modulates chemical visceral pain </li></ul><ul><li>Supraspinal & spinal analgesia </li></ul><ul><li>Dysphoria </li></ul><ul><li>Psychomimetic effects </li></ul><ul><li>Miosis </li></ul><ul><li>Respiratory depression </li></ul><ul><li>Sedation </li></ul><ul><li>Endocrine effects </li></ul>
  9. 9. Delta Receptor <ul><li>Influences mechanical and inflammatory pain </li></ul><ul><li>Analgesia </li></ul><ul><li>Nausea </li></ul><ul><li>Physical dependence </li></ul>
  10. 10. Opioid Variability <ul><li>Receptor individuality </li></ul><ul><li>Variations in absorption </li></ul><ul><li>Variations in clearance </li></ul><ul><li>Variations in metabolic pathways </li></ul><ul><ul><li>Molecular implications </li></ul></ul>
  11. 11. Metabolism <ul><li>CYP450 system </li></ul><ul><ul><li>Genetic polymorphism – variations in metabolism </li></ul></ul><ul><ul><li>2 isoforms </li></ul></ul><ul><ul><ul><li>2D6 isoform </li></ul></ul></ul><ul><ul><ul><ul><li>Codeine, oxycodone, hydrocodone </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Lacking in 10% of caucasians ( “poor metabolizers”) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Potential competitors: neuroleptics, TCAs, SSRIs </li></ul></ul></ul></ul><ul><ul><ul><li>3A4 isoform </li></ul></ul></ul><ul><ul><ul><ul><li>Fentanyl, methadone </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Inhibited by some agents (macrolides) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Induced by some agents (anticonvulsants) </li></ul></ul></ul></ul>
  12. 12. Metabolism <ul><li>Uridine diphosphate glucuronosyltransferase (UGT) system </li></ul><ul><ul><li>Agents with hydroxyl groups </li></ul></ul><ul><ul><ul><li>Morphine </li></ul></ul></ul><ul><ul><ul><li>Hydromorphone </li></ul></ul></ul><ul><ul><ul><li>Oxymorphone </li></ul></ul></ul><ul><ul><li>Adds glucuronic acid moiety </li></ul></ul><ul><ul><ul><ul><li>Hydromorphone 3-glucuronide </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Morphine 6-glucuronide/morphine 3-glucuronide </li></ul></ul></ul></ul>
  13. 13. Excretion <ul><li>Majority of metabolites are excreted via kidneys </li></ul><ul><ul><li>Renal impairment may predispose to metabolite accumulation </li></ul></ul><ul><ul><ul><li>More likely with UGT system, especially morphine </li></ul></ul></ul><ul><li>Some glucuronide conjugates are excreted in bile </li></ul><ul><ul><li>Methadone is primarily excreted in feces </li></ul></ul>
  14. 14. Administration <ul><li>Intrathecal </li></ul><ul><ul><li>Often used in peri-op and terminally ill patients </li></ul></ul><ul><li>Intravenous </li></ul><ul><ul><li>Avoids first past </li></ul></ul><ul><ul><li>Rapid onset </li></ul></ul><ul><li>Intramuscular </li></ul><ul><li>Subcutaneous </li></ul><ul><li>Oral </li></ul><ul><li>Rectal </li></ul><ul><li>Sublingual </li></ul><ul><li>Buccal </li></ul><ul><li>Intranasal </li></ul><ul><li>Transdermal </li></ul><ul><ul><li>Allows for continuous administration in orally intolerant patient </li></ul></ul>
  15. 15. Administration Considerations <ul><li>Nature of pain </li></ul><ul><ul><li>Acute vs. chronic </li></ul></ul><ul><ul><li>Nociceptive vs. neuropathic (decreased potency and therapeutic window) </li></ul></ul><ul><ul><li>Goals for onset and duration </li></ul></ul><ul><li>Patient characteristics </li></ul><ul><ul><li>Opioid naïve </li></ul></ul><ul><ul><li>GI motility </li></ul></ul><ul><ul><li>Hepatic or renal impairment </li></ul></ul><ul><ul><li>Ability to tolerate oral delivery </li></ul></ul>
  16. 16. Administration <ul><li>Fixed dosing </li></ul><ul><ul><li>Advantages: </li></ul></ul><ul><ul><ul><li>Consistent delivery, theoretically reaching steady state </li></ul></ul></ul><ul><ul><ul><li>Avoids peaks and troughs </li></ul></ul></ul><ul><ul><li>Disadvantages: </li></ul></ul><ul><ul><ul><li>Unwanted side effects or toxicity in naïve patients </li></ul></ul></ul><ul><ul><ul><li>Difficult to predict exact requirement (morphine may take 24 hours to reach steady state, methadone may take 1 week) </li></ul></ul></ul>
  17. 17. Administration <ul><li>PRN dosing </li></ul><ul><ul><li>Advantages: </li></ul></ul><ul><ul><ul><li>Useful in assessing patient ’s analgesia threshold and medication requirements </li></ul></ul></ul><ul><ul><li>Disadvantages: </li></ul></ul><ul><ul><ul><li>Peaks and troughs </li></ul></ul></ul>
  18. 18. Administration <ul><li>Long acting & controlled release agents </li></ul><ul><ul><li>Convenient dose intervals </li></ul></ul><ul><ul><li>Useful in achieving steady state </li></ul></ul><ul><ul><li>Morphine, oxycodone, oxymorphone, hydromorphone, etc. </li></ul></ul><ul><ul><li>Methadone </li></ul></ul><ul><ul><ul><li>Intrinsically longer plasma half-life </li></ul></ul></ul><ul><ul><ul><li>Of use in GI motility issues such as short gut </li></ul></ul></ul>
  19. 19. Adverse Effects <ul><li>Constipation </li></ul><ul><ul><li>Opioid receptors concentrated in antrum and proximal small bowel </li></ul></ul><ul><ul><li>Decreased gastric motility </li></ul></ul><ul><ul><li>Receptors activated irrespective of route of administration </li></ul></ul><ul><ul><li>Laxatives, stool softeners, bulking agents, opioid antagonists (methylnaltrexone) </li></ul></ul>
  20. 20. Adverse Effects <ul><li>Nausea/Emesis </li></ul><ul><ul><li>Mechanism </li></ul></ul><ul><ul><ul><li>Activation of medullary chemoreceptor trigger zone </li></ul></ul></ul><ul><ul><ul><li>Stimulation of receptors in vestibular apparatus </li></ul></ul></ul><ul><ul><ul><li>Decreased gastric motility </li></ul></ul></ul><ul><ul><li>Usually transient </li></ul></ul><ul><ul><li>Ondansetron, prochlorperazine, meclizine, scopolamine </li></ul></ul><ul><ul><li>Consider decreasing dose or rotating opioid </li></ul></ul>
  21. 21. Adverse Effects <ul><li>Pruritus </li></ul><ul><ul><li>More frequent with IV or neuraxial routes </li></ul></ul><ul><ul><li>Tolerance develops quickly </li></ul></ul><ul><ul><li>Mechanism </li></ul></ul><ul><ul><ul><li>Direct central effect </li></ul></ul></ul><ul><ul><ul><ul><li>Receptor binding in spinal cord and brain </li></ul></ul></ul></ul><ul><ul><ul><li>Related to histamine release </li></ul></ul></ul><ul><ul><ul><ul><li>Activates C-fiber itch receptors </li></ul></ul></ul></ul><ul><ul><li>Often limited to face and perineum </li></ul></ul><ul><ul><li>Antihistamines, low-dose nalbuphine (mu-antagonist, kappa-agonist), naloxone </li></ul></ul>
  22. 22. Adverse Effects <ul><li>Sedation </li></ul><ul><ul><li>Usually transient </li></ul></ul><ul><ul><li>Restrict driving x 1 week </li></ul></ul><ul><ul><li>Reduce dose, increase interval, consider psychostimulants </li></ul></ul>
  23. 23. Adverse Effects <ul><li>Respiratory Depression </li></ul><ul><ul><li>Mu-receptor-induced depression of brainstem centers </li></ul></ul><ul><ul><li>Often delayed up to 12 hours after epidural and intrathecal administration </li></ul></ul><ul><ul><li>Opposed by painful stimuli </li></ul></ul><ul><ul><li>Caution with other sedating medications </li></ul></ul>
  24. 24. Adverse Effects <ul><li>Tolerance: fixed dose results in decreasing analgesia </li></ul><ul><ul><li>Consider opioid rotation </li></ul></ul><ul><ul><ul><li>Improved analgesia due to incomplete tolerance and differing receptor affinity </li></ul></ul></ul><ul><ul><ul><li>May respond with analgesia to half the equianalgesic dose </li></ul></ul></ul>
  25. 25. Adverse Effects <ul><li>Physical dependence </li></ul><ul><ul><li>Physiologic state that manifests when a medication is abruptly stopped, resulting in withdrawal syndrome </li></ul></ul><ul><ul><li>Noradrenergic neurons within locus coeruleus are implicated </li></ul></ul><ul><ul><ul><li>Norepinephrine levels in the brain are altered </li></ul></ul></ul><ul><ul><ul><li>α - and β - agonists attenuate symptoms </li></ul></ul></ul>
  26. 26. Adverse Effects <ul><li>Withdrawal </li></ul><ul><ul><li>Irritability, anxiety, insomnia, diaphoresis, yawning, rhinorrhea, lacrimation, chills, myalgias, fevere, abdominal cramping, nausea, diarrhea, tachycardia </li></ul></ul><ul><li>Decrease dose by 10-20% every 48 to 72 hours (usually over 2-3 weeks) </li></ul><ul><ul><li>May supplement with clonidine 0.2-0.4 mg/day </li></ul></ul><ul><ul><ul><li>4 day course for short-acting taper </li></ul></ul></ul><ul><ul><ul><li>14 day course for long-acting taper </li></ul></ul></ul><ul><ul><ul><li>Then taper clonidine over one week </li></ul></ul></ul>
  27. 27. Adverse Effects <ul><li>Addiction </li></ul><ul><ul><li>Prevalence estimate 3-19% </li></ul></ul><ul><ul><li>Characterized by opioid use resulting in physical, psychological or social dysfunction with continued use of agent despite this dysfunction </li></ul></ul><ul><ul><li>Reward pathway in the brain is activated </li></ul></ul><ul><ul><li>Ventral tegmental dopaminergic area and orbitofrontal glutamatergic projections to the nucleus accumbens are implicated </li></ul></ul>
  28. 28. Selected Opioids
  29. 29. Categorization <ul><li>Naturally occurring alkaloids (derived directly from poppy seed) </li></ul><ul><ul><li>Heroin </li></ul></ul><ul><ul><li>Morphine </li></ul></ul><ul><ul><li>Codeine </li></ul></ul><ul><li>Synthetic phenylpiperidines </li></ul><ul><ul><li>Meperidine </li></ul></ul><ul><ul><li>Fentanyl </li></ul></ul><ul><li>Synthetic pseudopiperidines </li></ul><ul><ul><li>Methadone </li></ul></ul><ul><li>Semisynthetic derivatives </li></ul><ul><ul><li>Hydromorphone </li></ul></ul><ul><ul><li>Oxycodone </li></ul></ul><ul><ul><li>Oxymorphone </li></ul></ul>
  30. 30. Classes <ul><li>Full agonists </li></ul><ul><ul><li>Bind selective opioid receptors </li></ul></ul><ul><ul><li>Ceiling to effectiveness limited only by side effects </li></ul></ul><ul><ul><li>Morphine, fentanyl, hydromorphone </li></ul></ul><ul><li>Partial agonists </li></ul><ul><ul><li>Bind selective opioid receptors </li></ul></ul><ul><ul><li>Intrinsic ceiling effect </li></ul></ul><ul><ul><li>Buprenorphine </li></ul></ul>
  31. 31. Classes <ul><li>Mixed agonist-antagonists </li></ul><ul><ul><li>Display antagonism at one receptor and agonism or partial agonism at another </li></ul></ul><ul><ul><li>Intrinsic ceiling effect </li></ul></ul><ul><ul><li>Butorphanol, pentazocine (mu antagonists, kappa agonists) </li></ul></ul><ul><li>Antagonists </li></ul><ul><ul><li>Affinity for selective receptors </li></ul></ul><ul><ul><li>No intrinsic analgesic effect </li></ul></ul><ul><ul><li>Compete with agonist activity </li></ul></ul>
  32. 32. <ul><li>Hydrophilic phenanthrene derivative </li></ul><ul><ul><li>Delayed transport across BBB </li></ul></ul><ul><li>Plasma half-life: 2-3 hours </li></ul><ul><li>Duration of action: 4-5 hours </li></ul><ul><li>Bioavailability: 10-45% </li></ul>Morphine
  33. 33. Morphine <ul><li>Metabolism: </li></ul><ul><ul><li>Primarily liver – caution in cirrhosis </li></ul></ul><ul><ul><ul><li>Major metabolites: </li></ul></ul></ul><ul><ul><ul><ul><li>M6G (5-15%) </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Mu and delta agonist </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>50x more potent than parent </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><li>M3G (50%) </li></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>No apparent opioid agonism </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>May oppose morphine ’s analgesic action </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Allodynia, hyperalgesia, myoclonus, seizure </li></ul></ul></ul></ul></ul><ul><ul><li>Higher levels of metabolites with oral administration (first pass hepatic metabolism) </li></ul></ul><ul><ul><li>Patients receiving chronically high morphine doses metabolize morphine to, and test positive for hydromorphone </li></ul></ul><ul><ul><li>Extrahepatic metabolism in gastric and intestinal epithelia </li></ul></ul><ul><ul><li>Glucuronides may undergo deconjugation back to parent compound by colonic flora and reabsorbed as morphine </li></ul></ul><ul><ul><li>Metabolites excreted by kidney – may accumulate in renal dysfunction </li></ul></ul>
  34. 34. Fentanyl <ul><li>Highly lipophilic </li></ul><ul><li>High affinity for mu receptor </li></ul><ul><li>Relative to morphine </li></ul><ul><ul><li>75-100x more potent </li></ul></ul><ul><ul><li>Faster onset of action </li></ul></ul><ul><ul><li>Shorter acting </li></ul></ul><ul><li>Half-life and onset vary by route of administration </li></ul><ul><li>Metabolism </li></ul><ul><ul><li>CYP3A4 N-dealkylation to norfentanyl </li></ul></ul><ul><li>Transdermal fentanyl: </li></ul><ul><ul><li>Useful in GI issues (nausea/emesis; short gut syndrome) </li></ul></ul><ul><ul><li>Avoid submerging in hot water or exposing to heating pad </li></ul></ul><ul><ul><li>Has not been shown to reduce constipation </li></ul></ul><ul><ul><li>Challenging to titrate </li></ul></ul><ul><ul><ul><li>Variations in perspiration, temperature, fat/muscle bulk </li></ul></ul></ul><ul><ul><ul><li>Therapeutic levels achieved in 1-30 hours (mean 13 hours) </li></ul></ul></ul><ul><ul><ul><li>Steady state levels may take up to 6 days </li></ul></ul></ul><ul><li>Transmucosal fentanyl: </li></ul><ul><ul><li>10-15 minute onset of action </li></ul></ul><ul><ul><li>Useful in acute breakthrough pain </li></ul></ul>
  35. 35. Methadone <ul><li>High absorption </li></ul><ul><li>Bioavailability: 60-95% </li></ul><ul><li>Intrinsic long duration of action </li></ul><ul><li>Multiple receptor activities </li></ul><ul><ul><li>Mu, delta, NMDA </li></ul></ul><ul><ul><li>Serotonin reuptake blockade </li></ul></ul><ul><li>Racemic mixture of D (S-methadone) and L (R-methadone) isomers </li></ul><ul><ul><li>R-methadone accounts for opioid receptor affinity </li></ul></ul><ul><ul><ul><li>Lower affinity for mu and higher affinity for delta than morphine </li></ul></ul></ul><ul><ul><ul><li>Fewer mu related side effects </li></ul></ul></ul>
  36. 36. Methadone <ul><li>Pharmacokinetics and pharmacodynamics render its effects unpredictable </li></ul><ul><ul><li>Slow and variable elimination half life: 8-80 hours (average 27 hours) </li></ul></ul><ul><ul><ul><li>Related to extensive tissue distribution </li></ul></ul></ul><ul><ul><li>Analgesic half life usually ranges from 6-8 hours </li></ul></ul><ul><ul><li>Half life discrepancy is related to biphasic elimination </li></ul></ul><ul><ul><ul><li>Alpha elimination phase lasts 8-12 hours (correlates with period of analgesia) </li></ul></ul></ul><ul><ul><ul><li>Beta elimination phase lasts 30-60 hours (correlates with preventing withdrawal symptoms) </li></ul></ul></ul>
  37. 37. Methadone <ul><li>Morphine-to-methadone ratio may range from 1:5 to 1:20 or higher </li></ul><ul><li>Majority is eliminated via feces </li></ul><ul><li>No known neurotoxic or active metabolites </li></ul><ul><li>Factors affecting absorption and accumulation </li></ul><ul><ul><li>Decreased gastric pH (with use of PPI) increases rate of absorption </li></ul></ul><ul><ul><li>Increased urinary pH decreases methadone clearance </li></ul></ul><ul><ul><li>Excretion unaffected by renal failure/HD </li></ul></ul><ul><ul><li>Avidly binds protein </li></ul></ul>
  38. 38. Methadone <ul><li>Multiple drug interactions </li></ul><ul><ul><li>Primarily related to CYP3A4 sytem </li></ul></ul><ul><ul><li>3A4 is autoinducible: Methadone may increase its own clearance with prolonged use </li></ul></ul><ul><li>Methadone-related deaths </li></ul><ul><ul><li>Usually related to overdose and drug-interactions </li></ul></ul><ul><ul><li>Increase in QT interval (torsade de pointes) </li></ul></ul><ul><ul><ul><li>Magnitude of increase likely not higher than with TCAs </li></ul></ul></ul><ul><li>Other side effects </li></ul><ul><ul><li>Hypoglycemia </li></ul></ul><ul><ul><li>Hyponatremia </li></ul></ul>
  39. 39. Hydromorphone <ul><li>Hydrogenated ketone analogue of morphine </li></ul><ul><li>Strong mu receptor affinity </li></ul><ul><li>Relative to morphine: </li></ul><ul><ul><li>Essentially hydrophilic, but 10x more lipophilic </li></ul></ul><ul><ul><li>Pruritus, sedation, nausea less common </li></ul></ul><ul><ul><li>Oral administration: 5x more potent </li></ul></ul><ul><ul><li>IV administration: 7x more potent </li></ul></ul><ul><li>Half-life: 2.3 hours </li></ul><ul><li>Duration of action: 6-8 hours </li></ul><ul><li>Bioavailability: 24% </li></ul><ul><li>Onset: </li></ul><ul><ul><li>30 minutes after oral dose; 5 minutes after IV dose </li></ul></ul><ul><li>Metabolism: </li></ul><ul><ul><li>Some glucuronidation to H3G </li></ul></ul><ul><ul><ul><li>Lacks analgesic effect </li></ul></ul></ul><ul><ul><ul><li>Possible neurotoxic side effects: allodynia, myoclonus, seizure </li></ul></ul></ul><ul><ul><ul><ul><li>Risk is low except in renal insufficiency </li></ul></ul></ul></ul><ul><li>Parent and metabolite are excreted in kidney </li></ul>
  40. 40. Oxycodone <ul><li>Semisynthetic prodrug </li></ul><ul><ul><li>Mu and kappa affinity </li></ul></ul><ul><li>Metabolism </li></ul><ul><ul><li>O-demethylation by CYP2D6 </li></ul></ul><ul><ul><ul><li>Active metabolite: oxymorphone </li></ul></ul></ul><ul><ul><ul><ul><li>Mu agonist </li></ul></ul></ul></ul><ul><ul><ul><ul><li>14 times more potent than parent compound </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Enteral (IR, ER), parenteral, rectal formulations </li></ul></ul></ul></ul><ul><ul><li>N-demethylation by CYP3A4/5 </li></ul></ul><ul><ul><ul><li>Inactive metabolite: noroxycodone </li></ul></ul></ul><ul><li>Short- and long-acting preparations </li></ul><ul><li>Bioavailability: 60-80% </li></ul><ul><li>Half life 4.5 hours </li></ul><ul><li>Cases of serotonin syndrome with SSRI </li></ul>
  41. 41. Hydrocodone <ul><li>Prodrug, structurally similar to codeine </li></ul><ul><ul><li>6-8 times more potent </li></ul></ul><ul><li>Metabolism </li></ul><ul><ul><li>CYP2D6 </li></ul></ul><ul><ul><ul><li>Hydromorphone </li></ul></ul></ul><ul><ul><li>CYP3A4 </li></ul></ul><ul><ul><ul><li>Noroxycodone </li></ul></ul></ul><ul><li>Typically formulated with ibuprofen or APAP </li></ul><ul><ul><li>Synergistic </li></ul></ul>
  42. 42. Codeine <ul><li>Weak mu agonist (300x less affinity than morphine) </li></ul><ul><li>Effective in chronic non-malignant pain </li></ul><ul><li>Often in combination with APAP, butalbital and caffeine </li></ul><ul><li>Half life of 2.5-3 hours </li></ul><ul><li>Duration of action 4-6 hours </li></ul><ul><li>Onset: 30-60 minutes </li></ul><ul><li>Metabolism </li></ul><ul><ul><li>3% via CYP2D6 O-demethylation to morphine </li></ul></ul><ul><ul><li>80% via UGT2B7 glucuronidation to C6G </li></ul></ul><ul><ul><ul><li>Active metabolite </li></ul></ul></ul><ul><ul><li>Remaining inactive metabolites </li></ul></ul><ul><ul><ul><li>Norcodeine (2%) </li></ul></ul></ul><ul><ul><ul><li>Normorphine (2.4%) </li></ul></ul></ul><ul><ul><li>Metabolites excreted in urine </li></ul></ul>
  43. 43. Meperidine <ul><li>Mu agonist </li></ul><ul><li>Relative to morphine: </li></ul><ul><ul><li>10% as potent </li></ul></ul><ul><ul><li>Faster acting </li></ul></ul><ul><ul><li>Shorter duration </li></ul></ul><ul><li>Half-life: 3 hours </li></ul><ul><li>Metabolism: </li></ul><ul><ul><li>Hepatic demethylation to normeperidine </li></ul></ul><ul><ul><ul><li>Half-life: 12-16 hours </li></ul></ul></ul><ul><ul><li>Potential for neurotoxicity: CNS hyperactivity, seizure, myoclonus </li></ul></ul><ul><ul><ul><li>Naloxone-irreversible </li></ul></ul></ul><ul><ul><ul><li>Avoid with SSRI, MAOI, tramadol, methadone </li></ul></ul></ul><ul><li>Excreted via kidney – caution in renal impairment </li></ul>
  44. 44. Tramadol <ul><li>Synthetic racemic mixture </li></ul><ul><li>Central and peripheral sites of action </li></ul><ul><li>Weak mu receptor affinity (6000x weaker than morphine) </li></ul><ul><ul><li>Only partially inhibited by naloxone </li></ul></ul><ul><li>Bioavailability </li></ul><ul><ul><li>68% after single dose </li></ul></ul><ul><ul><li>90-100% after multiple doses </li></ul></ul><ul><li>Elimination half life 5-6 hours </li></ul><ul><li>Mild central serotonin and norepinephrine reuptake inhibition </li></ul><ul><li>Other purported effects </li></ul><ul><ul><li>Local anesthetic </li></ul></ul><ul><ul><li>Anti-inflammatory </li></ul></ul><ul><ul><li>Reduction of substance P in synovial fluid </li></ul></ul>
  45. 45. Tramadol <ul><li>Metabolism </li></ul><ul><ul><li>O-demethylation via CYP2D6 system to M1 metabolite </li></ul></ul><ul><ul><ul><li>300x higher affinity for mu receptor than parent </li></ul></ul></ul><ul><ul><ul><li>6x more analgesic potency than parent </li></ul></ul></ul><ul><ul><li>Excreted via kidney </li></ul></ul><ul><ul><li>Adjust dose in hepatic and renal dysfunction </li></ul></ul><ul><li>Useful in moderate to severe pain in patients unresponsive or with contraindications to NSAIDs or COX-2 inhibitors </li></ul><ul><ul><li>Titrate to maximum of 400mg/day </li></ul></ul><ul><li>More favorable side effect profile than traditional opioids </li></ul><ul><li>Case reports of bleeding complications with concomitant oral anticoagulants </li></ul><ul><li>Case reports of serotonin syndrome with SSRIs, MAOIs, SNRIs </li></ul>
  46. 46. Partial Agonists <ul><li>Buprenorphine </li></ul><ul><ul><li>Partial agonist at mu and delta receptors </li></ul></ul><ul><ul><li>Antagonist at kappa receptor </li></ul></ul><ul><ul><li>Slow dissociation from mu receptors </li></ul></ul><ul><ul><ul><li>May decrease efficacy of mu receptor antagonist </li></ul></ul></ul><ul><ul><li>Suboxone: formulation with naloxone to treat opioid addiction </li></ul></ul><ul><ul><ul><li>Drug Addiction Treatment Act of 2000 requires certification for administration in treatment of addiction </li></ul></ul></ul><ul><ul><li>Used to treat moderate chronic pain in lower doses </li></ul></ul>
  47. 47. Antagonists <ul><li>Naloxone </li></ul><ul><ul><li>Mu receptor antagonist </li></ul></ul><ul><ul><li>Caution in patients receiving opioids for longer than one week </li></ul></ul><ul><ul><li>Adverse effects: withdrawal, seizure, pain, CHF </li></ul></ul><ul><ul><li>Dose 0.02 mg every two minutes </li></ul></ul><ul><li>Naltrexone </li></ul>
  48. 48. Abuse-Deterrent Formulations <ul><li>OxyContin (oxycodone): sustained release formulation with hard plastic polymer that renders tablet difficult to crush </li></ul><ul><li>Remoxy (oxycodone): sustained release viscous gel cap intended to resist crushing, dissolution, injection or inhalation </li></ul><ul><li>Suboxone (buprenorphine): contains sequestered naloxone, which is released when crushed </li></ul><ul><li>Embeda (morphine): contains sequestered naltrexone, which is released when crushed </li></ul><ul><li>Acurox (oxycodone IR): contains niacin which causes intolerable flushing when injected, inhaled, or taken orally in high doses </li></ul>
  49. 49. Equianalgesic Doses OPIOID ORAL EQUIANALGESIC DOSE (MG) Morphine 10 Meperidine 100 Oxycodone 7 Hydromorphone 2 Methadone 10-20 Oxymorphone 1.5 Butorphanol 2 Buprenorphine 0.3 Hydrocodone 10 Codeine 80 Tramadol 40

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