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Comparative Opioid Pharmacology

Comparative Opioid Pharmacology. dr shabeel pn. Disclosure. Analgesia is a labeled indication for all of the approved drugs I will be discussing.

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Comparative Opioid Pharmacology

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  1. Comparative Opioid Pharmacology dr shabeel pn

  2. Disclosure • Analgesia is a labeled indication for all of the approved drugs I will be discussing. • I’ve consulted with Glaxo (remifentanil), Abbott (remifentanil), Janssen (Duragesic), Alza (Duragesic), Anesta (Actiq), and Delex (liposomal fentanyl)

  3. Classical Opioid Pharmacology • Analgesia • modest to profound with no ceiling effect • Sedation • modest to profound, but has a ceiling effect • unconsciousness cannot be assured • Reduces MAC • with a ceiling effect • Synergy with hypnotics • modest at causing sedation • profound at suppressing movement response to noxious stimulation

  4. Classical Opioid Pharmacology • High dose opioids are associated with hemodynamic stability • High dose opioids attenuate the stress response

  5. Classical Opioid Pharmacology • Urinary retention • Ileus • Addiction potential • Ventilatory depression • Muscle Rigidity • Nausea, Vomiting • Pruritis

  6. Intraoperative Fentanyl Alfentanil Sufentanil Remifentanil Postoperative Morphine Hydromorphone Methadone Pure m agonists

  7. MorphineThe prototypical opioid

  8. Morphine • Endogenous Ligand • Slow rise to peak effect • Absolute peak analgesic effect is at 90 minutes after bolus injection! • Active metabolite • Morphine-6-glucuronide is unlikely to contribute to analgesic effects at standard OR doses. Will contribute to effects with chronic dosing • Especially in renal failure • Not as full efficacy as fentanyl series of opioids

  9. Simulation of MorphineTime Course Dahan et al. Anesthesiology. 2004 Nov;101(5):1201-9.

  10. FentanylThe ever morphing molecule

  11. Fentanyl • Among the pharmacologically cleanest opioid • The first of the “fentanyl” series (obviously…) • Available in transdermal, submucosal, sublingual, and (soon) inhaled forms.

  12. How we think of fentanyl:(small part of the market)

  13. Fentanyl morph 1:Duragesic

  14. Fentanyl morph 2: Actiq

  15. Fentanyl morph 3:E-trans fentanyl Viscusi et al, JAMA 2004 291:1333

  16. Fentanyl morph 4:Inhaled liposomal fentanyl Hung et al, Anesthesiology 1995 83:277-84

  17. Fentanyl morph 5:Inhaled fentanyl aerosol Mather et al, Br J Clin Pharmacol 1998 46:37

  18. Fentanyl morph 6:Effervescent Fentanyl (OraVescent) Pather et al, http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=5

  19. SufentanilNewly morphing molecule

  20. Sufentanil • 10 fold more potent than fentanyl • Slightly slower onset • More rapid recovery • Very clean pharmacologically

  21. Sufentanil morph 1:Implantable sufentanil delivery http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=115

  22. Meperidine • Bad Drug! Little role in the management of pain • Toxic metabolite • Normeperidine  seizures • Renally excreted • Negative inotrope • Causes tachycardia (anticholinergic) • Complex interactions • MAO syndrome when combined with MAO inhibitors • Useful for shivering, perhaps as a local anesthetic

  23. HydromorphoneA better morphine

  24. Hydromorphone • A rapid onset morphine • No histamine release • About 8 fold more potent than morphine • No active metabolite • Good choice for PCA, post-op analgesia

  25. Alfentanil • Less potent than fentanyl • Much more rapid onset (including more rapid onset of rigidity and respiratory depression) • Much more evenascent effect with a single bolus • With brief infusions will be almost indistinguishable from fentanyl, except for potency

  26. Remifentanil • Similar potency to fentanyl • Pharmacokinetics are in a class by themselves (ester metabolism) • Reduce the dose by about 2/3s in the elderly • No pharmacokinetic interactions • Onset is similar to alfentanil

  27. MethadoneThe Under-Utilized Opioid

  28. Methadone • Longest terminal half-life (about 1 day) • May accumulate during titration to steady state • Supplied as a racemic mixture • L methadone is an opioid antagonist • D methadone is an NMDA antagonist

  29. Fundamental PK/PD Parameters

  30. Comparative Opioid PK

  31. Comparative Opioid PK

  32. Comparative Onset of Opioid Drug Effect

  33. Context Sensitive Half Time

  34. 50% Effect Site Decrement Time

  35. 20% Effect Site Decrement Time

  36. Rise to Steady State

  37. Relative Potency

  38. 50 g fentanyl at 10 minutes

  39. 50 g/hour fentanyl at 2 hours

  40.  Opioid Receptor

  41. Evidence of m opioid subtypes • Only about 50% cross tolerance between morphine, methadone, fentanyl • Explains why rotating opioids in chronic pain is probably a good idea • CXBK mouse is insensitive to morphine, but has normal response to M6G and fentanyl • Selective response to opioid antagonists • Morphine-6-glucuronide, the outlier Gavril Pasternak, Life Sciences 2001:68, 2213

  42. Naloxonazine • Selectively antagonizes morphine analgesia in animals • m1 is considered naloxonazine sensitive • Does not antagonize morphine-induced ventilatory depression or GI effects • m2 is considered naloxonazine insensitive Gavril Pasternak, Life Sciences 2001:68, 2213

  43. Morphine-6-glucuronide • Active metabolite of morphine, about 100 fold more potent intrathecally, but enters the CNS VERY slowly • Has analgesic activity in the CXBK mouse that is insensitive to morphine • Actions blocked by naloxonazine (hence, m1) • Has a unique antagonist, 3-O-methylnaxtrexone • Also antagonizes heroin self administration, little affect on morphine • Subtype of m1 • MOR-1 knockout (exon 1) has normal sensitivity to morphine-6-glucuronide Gavril Pasternak, Life Sciences 2001:68, 2213

  44. MOR-1 gene splice variants(gene=OPRM) Gavril Pasternak, http://www.mskcc.org/mskcc/html/11384.cfm

  45. Antisense lowers morphine analgesia(no effect on m6g) Gavril Pasternak, Life Sciences 2001:68, 2213

  46. Antisense lowers m6g analgesia(no effect on morphine) Gavril Pasternak, Life Sciences 2001:68, 2213

  47. Morphine-6-glucuronide • Very slow transit across blood brain barrier. • Not a substrate for p-glycoprotein, but appears to be a substrate for probenecid inhibited transporters (Anesthesiology 2004:101 1394) • Recently a peptide based carrier demonstrated 4 fold increase in uptake and potency (JPET 2005:12 epub). • Some data show higher affinity for 1, and lower affinity for 2, compared to morphine. • Some suggestion that M6G is associated with less ventilatory depression for the amount of analgesia • (e.g., Romberg et al, Anesthesiology 2004 100:120)

  48. 1 selective agonists? • Despite evidence now 25 years old of differential response to antagonists, nobody has found a 1 selective agonist • Biggest argument against it: Paul Janssen spent years looking for one, screening over 70,000 possible ligands • Reason for hope: perhaps our improved knowledge of MOR-1 splice variants will help identify the required pharmacophore • Don’t hold your breath…

  49. “Power corrupts,PowerPoint corrupts absolutely” dr shabeel pn

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