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Opioid Pharmacology

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  • 1. Comparative Opioid Pharmacology
  • 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. Pure  agonists
    • Intraoperative
      • Fentanyl
      • Alfentanil
      • Sufentanil
      • Remifentanil
    • Postoperative
      • Morphine
      • Hydromorphone
      • Methadone
  • 7. Morphine The 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 Morphine Time Course Dahan et al. Anesthesiology. 2004 Nov;101(5):1201-9.
  • 10. Fentanyl The 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. Sufentanil Newly 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. Hydromorphone A 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. Methadone The 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  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
      •  1 is considered naloxonazine sensitive
    • Does not antagonize morphine-induced ventilatory depression or GI effects
      •  2 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,  1 )
    • Has a unique antagonist, 3-O-methylnaxtrexone
        • Also antagonizes heroin self administration, little affect on morphine
    • Subtype of  1
    • 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