Comparative Opioid Pharmacology Disclosure Analgesia is a labeled

Comparative Opioid Pharmacology

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

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

Classical Opioid Pharmacology Ø High dose opioids are associated with hemodynamic stability Ø High dose opioids attenuate the stress response

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

Pure agonists Ø Intraoperative Ø Fentanyl Ø Alfentanil Ø Sufentanil Ø Remifentanil Ø Postoperative Ø Morphine Ø Hydromorphone Ø Methadone

Morphine The prototypical opioid

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

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

Fentanyl The ever morphing molecule

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

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

Fentanyl morph 1: Duragesic

Fentanyl morph 2: Actiq

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

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

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

Fentanyl morph 6: Effervescent Fentanyl (Ora. Vescent) Pather et al, http: //www. drugdeliverytech. com/cgi-

Sufentanil Newly morphing molecule

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

Sufentanil morph 1: Implantable sufentanil delivery http: //www. drugdeliverytech. com/cgibin/articles. cgi? id. Article=115

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

Hydromorphone A better morphine

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

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

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

Methadone The Under-Utilized Opioid

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

Fundamental PK/PD Parameters

Comparative Opioid PK

Comparative Opioid PK

Comparative Onset of Opioid Drug Effect

Context Sensitive Half Time

50% Effect Site Decrement Time

20% Effect Site Decrement Time

Rise to Steady State

Relative Potency

50 g fentanyl at 10 minutes

50 g/hour fentanyl at 2 hours

Opioid Receptor

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

Naloxonazine Ø Selectively antagonizes morphine analgesia in animals Ø 1 is considered naloxonazine sensitive Ø Does not antagonize morphine-induced ventilatory depression or GI effects Ø 2 is considered naloxonazine insensitive Gavril Pasternak, Life Sciences 2001: 68, 2213

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

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

Antisense lowers morphine analgesia (no effect on m 6 g) Gavril Pasternak, Life Sciences 2001: 68, 2213

Antisense lowers m 6 g analgesia (no effect on morphine) Gavril Pasternak, Life Sciences 2001: 68, 2213

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

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

“Power corrupts, Power. Point corrupts absolutely”