Comparative Comparative Opioid Pharmacology

Comparative Opioid Pharmacology 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) 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 Classical Opioid Pharmacology

High dose opioids are associated with hemodynamic stability

High dose opioids attenuate the stress response Classical Opioid Pharmacology

 Ventilatory depression  Urinary retention  Muscle Rigidity  Ileus  Nausea, Vomiting  Addiction potential  Pruritis Pure m agonists

 Intraoperative  Postoperative  Fentanyl  Morphine  Alfentanil  Hydromorphone  Sufentanil  Methadone  Remifentanil 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 (OraVescent)

Pather et al, http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=5 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/cgi-bin/articles.cgi?idArticle=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 2/3s 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

Fentanyl Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine Hydromorphone Volumes (l) V1 12.7 2.2 17.8 4.9 17.8 7.7 18.1 11.5 V2 50 7 47 9 87 12 61 115 V3 295 15 476 5 199 184 166 968 Clearances (l/min) Cl1 0.62 0.20 1.16 2.44 1.26 0.13 0.76 1.33 Cl2 4.82 1.43 4.84 1.75 2.27 2.19 5.44 3.45 Cl3 2.27 0.25 1.29 0.06 0.33 0.38 1.79 0.92 Exponents (min-1) a 0.67 1.03 0.48 0.96 0.23 0.50 0.51 0.51 b 0.037 0.052 0.030 0.103 0.010 0.025 0.031 0.012 g 0.0015 0.0062 0.0012 0.0116 0.0013 0.0005 0.0026 0.0005 Half Lives (min) t 1/2 a 1.03 0.67 1.43 0.73 2.98 1.38 1.37 1.35 t 1/2 b 19 13 23 7 68 28 22 59 t 1/2 g 475 111 562 60 548 1377 271 1261 Blood Brain Equilibration -1 ke0 (min ) 0.147 0.770 0.112 0.525 0.005 0.110 0.067 0.015

t 1/2 ke0 (min) 4.7 0.9 6.2 1.3 139 6.3 10.3 46 Tpeak (min) 3.7 1.4 5.8 1.6 93.8 11.3 8.5 19.6 VD Peak Effect (l) 76.9 6.0 94.9 17.0 590.2 30.9 143.3 383.3 Comparative Opioid PK

100

Methadone 1 Sufentanil Meperidine Fentanyl

Hydromorphone 0.1 Alfentanil Morphine

Remifentanil

Percent of initial concentration initial of Percent 0.01 0 240 480 720 960 1200 1440 Minutes since bolus injection Comparative Opioid PK

100

Methadone

10 Meperidine Sufentanil Alfentanil Morphine Fentanyl Hydromorphone

Remifentanil Percent of initial concentration ofinitial Percent 1 0 5 10 15 20 25 30 Minutes since bolus injection Comparative Onset of Opioid Drug Effect

100 Hydromorphone Methadone Meperidine 80 Morphine

Sufentanil 60

Fentanyl 40

Alfentanil site concentration site 20 Percent of peak effect peak Percent of

Remifentanil 0 0 5 10 15 20 Minutes since bolus injection Context Sensitive Half Time

300

Fentanyl 240

180 Meperidine

120

Methadone 60 Alfentanil Sufentanil Morphine in plasma concentration in plasma Hydromorphone Minutes to 50% decrement 50% to Minutes Remifentanil 0 0 120 240 360 480 600 Infusion Duration 50% Effect Site Decrement Time

300

Fentanyl Morphine 240 Meperidine 180

120 Hydromorphone

Methadone 60 Alfentanil Sufentanil in concentration in effect site Minutes to 50% decrement to 50% Minutes Remifentanil 0 0 120 240 360 480 600 Infusion Duration 20% Effect Site Decrement Time

120

Morphine 90

Hydromorphone

30 Methadone Meperidine Fentanyl Sufentanil in concentration in effect site Minutes to 20% decrement to 20% Minutes Alfentanil Remifentanil 0 0 120 240 360 480 600 Infusion Duration Rise to Steady State

100 Remifentanil

Meperidine Alfentanil 60 Hydromorphone Sufentanil Fentanyl Morphine 40 Methadone

20 Fraction of Steady State Steady of Fraction

0 0 120 240 360 480 600 Infusion Duration Relative Potency

Fentanyl Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine Hydromorphone MEAC (ng/ml) 0.6 14.9 0.056 1.0 8 60 250 6 Equipotent bolus dose (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) at peak effect 50 92 5.5 17 4.9 1.9 37 2.5 at 10 minutes 50 197 4.4 72 5.3 1.4 28 1.9 at 30 minutes 50 174 3.9 282 2.0 0.9 17 0.9 at 60 minutes 50 175 4.8 1,680 1.0 0.9 14 0.6 Equipotent infusion rate (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) at 1 hour 100 323 9 135 5 2 43 2 at 2 hours 100 332 10 182 3 2 38 2 at 4 hours 100 365 12 252 2 3 36 2 at 6 hours 100 409 13 310 2 3 37 2 at 12 hours 100 536 15 436 2 3 40 2 at 24 hours 100 675 16 554 2 3 45 2 50 mg fentanyl at 10 minutes

Alfentanil 197 mg Sufentanil 4.4 mg Remifentanil 72 mg Morphine 5.3 mg Methadone 1.4 mg Meperidine 28 mg Hydromorphone 1.9 mg 50 mg/hour fentanyl at 2 hours

Alfentanil 332 mg/hr Sufentanil 9.6 mg/hr Remifentanil 182 mg/hr Morphine 3.3 mg/hr Methadone 2.3 mg/hr Meperidine 38 mg/hr Hydromorphone 1.8 mg/hr m Opioid Receptor 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 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 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 MOR-1 gene splice variants (gene=OPRM)

Gavril Pasternak, http://www.mskcc.org/mskcc/html/11384.cfm Antisense lowers morphine analgesia (no effect on m6g)

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

Gavril Pasternak, Life Sciences 2001:68, 2213 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 m1, and lower affinity for m2, 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) m1 selective agonists? Despite evidence now 25 years old of differential response to antagonists, nobody has found a m1 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… “Power corrupts, PowerPoint corrupts absolutely”