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Opioid Pharmacology


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Opioid Pharmacology

  1. 1. Comparative Opioid Pharmacology
  2. 2. Disclosure <ul><li>Analgesia is a labeled indication for all of the approved drugs I will be discussing. </li></ul><ul><li>I’ve consulted with Glaxo (remifentanil), Abbott (remifentanil), Janssen (Duragesic), Alza (Duragesic), Anesta (Actiq), and Delex (liposomal fentanyl) </li></ul>
  3. 3. Classical Opioid Pharmacology <ul><li>Analgesia </li></ul><ul><ul><ul><li>modest to profound with no ceiling effect </li></ul></ul></ul><ul><li>Sedation </li></ul><ul><ul><ul><li>modest to profound, but has a ceiling effect </li></ul></ul></ul><ul><ul><ul><ul><ul><li>unconsciousness cannot be assured </li></ul></ul></ul></ul></ul><ul><li>Reduces MAC </li></ul><ul><ul><ul><li>with a ceiling effect </li></ul></ul></ul><ul><li>Synergy with hypnotics </li></ul><ul><ul><ul><li>modest at causing sedation </li></ul></ul></ul><ul><ul><ul><li>profound at suppressing movement response to noxious stimulation </li></ul></ul></ul>
  4. 4. Classical Opioid Pharmacology <ul><li>High dose opioids are associated with hemodynamic stability </li></ul><ul><li>High dose opioids attenuate the stress response </li></ul>
  5. 5. Classical Opioid Pharmacology <ul><li>Urinary retention </li></ul><ul><li>Ileus </li></ul><ul><li>Addiction potential </li></ul><ul><li>Ventilatory depression </li></ul><ul><li>Muscle Rigidity </li></ul><ul><li>Nausea, Vomiting </li></ul><ul><li>Pruritis </li></ul>
  6. 6. Pure  agonists <ul><li>Intraoperative </li></ul><ul><ul><li>Fentanyl </li></ul></ul><ul><ul><li>Alfentanil </li></ul></ul><ul><ul><li>Sufentanil </li></ul></ul><ul><ul><li>Remifentanil </li></ul></ul><ul><li>Postoperative </li></ul><ul><ul><li>Morphine </li></ul></ul><ul><ul><li>Hydromorphone </li></ul></ul><ul><ul><li>Methadone </li></ul></ul>
  7. 7. Morphine The prototypical opioid
  8. 8. Morphine <ul><li>Endogenous Ligand </li></ul><ul><li>Slow rise to peak effect </li></ul><ul><ul><ul><li>Absolute peak analgesic effect is at 90 minutes after bolus injection! </li></ul></ul></ul><ul><li>Active metabolite </li></ul><ul><ul><ul><li>Morphine-6-glucuronide is unlikely to contribute to analgesic effects at standard OR doses. Will contribute to effects with chronic dosing </li></ul></ul></ul><ul><ul><ul><ul><li>Especially in renal failure </li></ul></ul></ul></ul><ul><li>Not as full efficacy as fentanyl series of opioids </li></ul>
  9. 9. Simulation of Morphine Time Course Dahan et al. Anesthesiology. 2004 Nov;101(5):1201-9.
  10. 10. Fentanyl The ever morphing molecule
  11. 11. Fentanyl <ul><li>Among the pharmacologically cleanest opioid </li></ul><ul><li>The first of the “fentanyl” series (obviously…) </li></ul><ul><li>Available in transdermal, submucosal, sublingual, and (soon) inhaled forms. </li></ul>
  12. 12. How we think of fentanyl: (small part of the market)
  13. 13. Fentanyl morph 1: Duragesic
  14. 14. Fentanyl morph 2: Actiq
  15. 15. Fentanyl morph 3: E-trans fentanyl Viscusi et al, JAMA 2004 291:1333
  16. 16. Fentanyl morph 4: Inhaled liposomal fentanyl Hung et al, Anesthesiology 1995 83:277-84
  17. 17. Fentanyl morph 5: Inhaled fentanyl aerosol Mather et al, Br J Clin Pharmacol 1998 46:37
  18. 18. Fentanyl morph 6: Effervescent Fentanyl (OraVescent) Pather et al,
  19. 19. Sufentanil Newly morphing molecule
  20. 20. Sufentanil <ul><li>10 fold more potent than fentanyl </li></ul><ul><li>Slightly slower onset </li></ul><ul><li>More rapid recovery </li></ul><ul><li>Very clean pharmacologically </li></ul>
  21. 21. Sufentanil morph 1: Implantable sufentanil delivery
  22. 22. Meperidine <ul><li>Bad Drug! Little role in the management of pain </li></ul><ul><li>Toxic metabolite </li></ul><ul><ul><li>Normeperidine  seizures </li></ul></ul><ul><ul><li>Renally excreted </li></ul></ul><ul><li>Negative inotrope </li></ul><ul><li>Causes tachycardia (anticholinergic) </li></ul><ul><li>Complex interactions </li></ul><ul><ul><li>MAO syndrome when combined with MAO inhibitors </li></ul></ul><ul><li>Useful for shivering, perhaps as a local anesthetic </li></ul>
  23. 23. Hydromorphone A better morphine
  24. 24. Hydromorphone <ul><li>A rapid onset morphine </li></ul><ul><li>No histamine release </li></ul><ul><li>About 8 fold more potent than morphine </li></ul><ul><li>No active metabolite </li></ul><ul><li>Good choice for PCA, post-op analgesia </li></ul>
  25. 25. Alfentanil <ul><li>Less potent than fentanyl </li></ul><ul><li>Much more rapid onset (including more rapid onset of rigidity and respiratory depression) </li></ul><ul><li>Much more evenascent effect with a single bolus </li></ul><ul><li>With brief infusions will be almost indistinguishable from fentanyl, except for potency </li></ul>
  26. 26. Remifentanil <ul><li>Similar potency to fentanyl </li></ul><ul><li>Pharmacokinetics are in a class by themselves (ester metabolism) </li></ul><ul><li>Reduce the dose by about 2/3s in the elderly </li></ul><ul><li>No pharmacokinetic interactions </li></ul><ul><li>Onset is similar to alfentanil </li></ul>
  27. 27. Methadone The Under-Utilized Opioid
  28. 28. Methadone <ul><li>Longest terminal half-life (about 1 day) </li></ul><ul><li>May accumulate during titration to steady state </li></ul><ul><li>Supplied as a racemic mixture </li></ul><ul><ul><li>L methadone is an opioid antagonist </li></ul></ul><ul><ul><li>D methadone is an NMDA antagonist </li></ul></ul>
  29. 29. Fundamental PK/PD Parameters
  30. 30. Comparative Opioid PK
  31. 31. Comparative Opioid PK
  32. 32. Comparative Onset of Opioid Drug Effect
  33. 33. Context Sensitive Half Time
  34. 34. 50% Effect Site Decrement Time
  35. 35. 20% Effect Site Decrement Time
  36. 36. Rise to Steady State
  37. 37. Relative Potency
  38. 38. 50  g fentanyl at 10 minutes
  39. 39. 50  g/hour fentanyl at 2 hours
  40. 40.  Opioid Receptor
  41. 41. Evidence of  opioid subtypes <ul><li>Only about 50% cross tolerance between morphine, methadone, fentanyl </li></ul><ul><ul><ul><li>Explains why rotating opioids in chronic pain is probably a good idea </li></ul></ul></ul><ul><li>CXBK mouse is insensitive to morphine, but has normal response to M6G and fentanyl </li></ul><ul><li>Selective response to opioid antagonists </li></ul><ul><li>Morphine-6-glucuronide, the outlier </li></ul>Gavril Pasternak, Life Sciences 2001:68, 2213
  42. 42. Naloxonazine <ul><li>Selectively antagonizes morphine analgesia in animals </li></ul><ul><ul><li> 1 is considered naloxonazine sensitive </li></ul></ul><ul><li>Does not antagonize morphine-induced ventilatory depression or GI effects </li></ul><ul><ul><li> 2 is considered naloxonazine insensitive </li></ul></ul>Gavril Pasternak, Life Sciences 2001:68, 2213
  43. 43. Morphine-6-glucuronide <ul><li>Active metabolite of morphine, about 100 fold more potent intrathecally, but enters the CNS VERY slowly </li></ul><ul><li>Has analgesic activity in the CXBK mouse that is insensitive to morphine </li></ul><ul><li>Actions blocked by naloxonazine (hence,  1 ) </li></ul><ul><li>Has a unique antagonist, 3-O-methylnaxtrexone </li></ul><ul><ul><ul><li>Also antagonizes heroin self administration, little affect on morphine </li></ul></ul></ul><ul><li>Subtype of  1 </li></ul><ul><li>MOR-1 knockout (exon 1) has normal sensitivity to morphine-6-glucuronide </li></ul>Gavril Pasternak, Life Sciences 2001:68, 2213
  44. 44. MOR-1 gene splice variants (gene=OPRM) Gavril Pasternak,
  45. 45. Antisense lowers morphine analgesia (no effect on m6g) Gavril Pasternak, Life Sciences 2001:68, 2213
  46. 46. Antisense lowers m6g analgesia (no effect on morphine) Gavril Pasternak, Life Sciences 2001:68, 2213
  47. 47. Morphine-6-glucuronide <ul><li>Very slow transit across blood brain barrier. </li></ul><ul><li>Not a substrate for p-glycoprotein, but appears to be a substrate for probenecid inhibited transporters (Anesthesiology 2004:101 1394) </li></ul><ul><li>Recently a peptide based carrier demonstrated 4 fold increase in uptake and potency (JPET 2005:12 epub). </li></ul><ul><li>Some data show higher affinity for  1 , and lower affinity for  2 , compared to morphine. </li></ul><ul><li>Some suggestion that M6G is associated with less ventilatory depression for the amount of analgesia </li></ul><ul><ul><li>(e.g., Romberg et al, Anesthesiology 2004 100:120) </li></ul></ul>
  48. 48.  1 selective agonists? <ul><li>Despite evidence now 25 years old of differential response to antagonists, nobody has found a  1 selective agonist </li></ul><ul><li>Biggest argument against it: Paul Janssen spent years looking for one, screening over 70,000 possible ligands </li></ul><ul><li>Reason for hope: perhaps our improved knowledge of MOR-1 splice variants will help identify the required pharmacophore </li></ul><ul><ul><ul><li>Don’t hold your breath… </li></ul></ul></ul>
  49. 49. “ Power corrupts, PowerPoint corrupts absolutely” dr shabeel pn