Analgesia is a labeled indication for all of the approved drugs I will be discussing.
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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 Ventilatory depression Muscle Rigidity Nausea, Vomiting Pruritis Urinary retention Ileus Addiction potential
6 Pure m 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 Nov;101(5):
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 :1333
16 Fentanyl morph 4: Inhaled liposomal fentanyl Hung et al, Anesthesiology :277-84
17 Fentanyl morph 5: Inhaled fentanyl aerosol Mather et al, Br J Clin Pharmacol :37
18 Fentanyl morph 6: Effervescent Fentanyl (OraVescent) Pather et al,
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
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 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 Fentanyl Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine Hydromorphone Volumes (l) V V V Clearances (l/min) Cl Cl Cl Exponents (min -1 ) a b g Half Lives (min) t 1/2 a t 1/2 b t 1/2 g Blood Brain Equilibration k e0 (min -1 ) t 1/2 k e0 (min) Tpeak (min) VD Peak Effect (l)
30 Comparative Opioid PK 100 Percent of initial concentration Remifentanil Sufentanil Alfentanil Meperidine Minutes since bolus injection Methadone Fentanyl Hydromorphone Morphine
31 Comparative Opioid PK Percent of initial concentration Remifentanil Minutes since bolus injection Methadone Hydromorphone Meperidine Sufentanil Alfentanil Morphine Fentanyl
32 Comparative Onset of Opioid Drug Effect Percent of peak effect site concentration Hydromorphone Methadone Meperidine Morphine Sufentanil Fentanyl Alfentanil Minutes since bolus injection Remifentanil
33 Context Sensitive Half Time 300 Minutes to 50% decrement in plasma concentration Fentanyl Meperidine Methadone Sufentanil Infusion Duration Alfentanil Remifentanil Morphine Hydromorphone
34 50% Effect Site Decrement Time 300 Minutes to 50% decrement in effect site concentration Fentanyl Morphine Meperidine Hydromorphone Methadone Sufentanil Infusion Duration Alfentanil Remifentanil
35 20% Effect Site Decrement Time 120 Minutes to 20% decrement in effect site concentration Morphine Hydromorphone Meperidine Fentanyl Infusion Duration Methadone Sufentanil Alfentanil Remifentanil
36 Rise to Steady State 100 Remifentanil Fraction of Steady State Alfentanil Sufentanil Morphine Fentanyl Meperidine Hydromorphone Methadone Infusion Duration
37 Relative Potency Fentanyl Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine Hydromorphone MEAC (ng/ml) Equipotent bolus dose (mg) (mg) (mg) (mg) (mg) (mg) (mg) (mg) at peak effect at 10 minutes at 30 minutes at 60 minutes , Equipotent infusion rate (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr) at 1 hour at 2 hours at 4 hours at 6 hours at 12 hours at 24 hours
38 50 mg g fentanyl at 10 minutes Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine Hydromorphone 197 mg 4.4 mg 72 mg 5.3 mg 1.4 mg 28 mg 1.9 mg
39 50 mg/hour fentanyl at 2 hours Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine Hydromorphone 332 mg/hr 9.6 mg/hr 182 mg/hr 3.3 mg/hr 2.3 mg/hr 38 mg/hr 1.8 mg/hr
40 m 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 m 1 is considered naloxonazine sensitive Does not antagonize morphine-induced ventilatory depression or GI effects m 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, m 1 ) Has a unique antagonist, 3-O-methylnaxtrexone Also antagonizes heroin self administration, little affect on morphine Subtype of m 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,
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: ) Recently a peptide based carrier demonstrated 4 fold increase in uptake and potency (JPET 2005:12 epub). Some data show higher affinity for m 1, and lower affinity for m 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 :120)
48 m 1 selective agonists? Despite evidence now 25 years old of differential response to antagonists, nobody has found a m 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
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