opioid pharmacology

Comparative Opioid Comparative Opioid PharmacologyPharmacology

DisclosureDisclosure

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 Classical Opioid PharmacologyPharmacology

Analgesiamodest to profound with no ceiling effect

Sedationmodest to profound, but has a ceiling effect

unconsciousness cannot be assured

Reduces MACwith a ceiling effect

Synergy with hypnoticsmodest at causing sedationprofound at suppressing movement response to noxious

stimulation


High dose opioids are associated with hemodynamic stability

High dose opioids attenuate the stress response


Urinary retention Ileus Addiction potential

Ventilatory depression Muscle Rigidity Nausea, Vomiting Pruritis

Pure Pure agonists agonists

IntraoperativeFentanylAlfentanilSufentanilRemifentanil

PostoperativeMorphineHydromorphoneMethadone

MorphineMorphineThe prototypical opioidThe prototypical opioid

MorphineMorphine

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 MorphineSimulation of MorphineTime CourseTime Course

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

FentanylFentanylThe ever morphing moleculeThe ever morphing molecule

FentanylFentanyl

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

Fentanyl morph 1:Fentanyl morph 1:DuragesicDuragesic

Fentanyl morph 2: ActiqFentanyl morph 2: Actiq

Fentanyl morph 3:Fentanyl morph 3:E-trans fentanylE-trans fentanyl

Viscusi et al, JAMA 2004 291:1333

Fentanyl morph 4:Fentanyl morph 4:Inhaled liposomal fentanylInhaled liposomal fentanyl

Hung et al, Anesthesiology 1995 83:277-84

Fentanyl morph 5:Fentanyl morph 5:Inhaled fentanyl aerosolInhaled fentanyl aerosol

Mather et al, Br J Clin Pharmacol 1998 46:37

Fentanyl morph 6:Fentanyl morph 6:Effervescent Fentanyl Effervescent Fentanyl

(OraVescent)(OraVescent)

Pather et al, http://www.drugdeliverytech.com/cgi-bin/articles.cgi?

idArticle=5

SufentanilSufentanilNewly morphing moleculeNewly morphing molecule

SufentanilSufentanil

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

Sufentanil morph 1:Sufentanil morph 1:Implantable sufentanil deliveryImplantable sufentanil delivery

http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=115

MeperidineMeperidine

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

HydromorphoneHydromorphoneA better morphineA better morphine

HydromorphoneHydromorphone

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

AlfentanilAlfentanil

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

RemifentanilRemifentanil

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

MethadoneMethadoneThe Under-Utilized OpioidThe Under-Utilized Opioid

MethadoneMethadone

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 ParametersFundamental PK/PD Parameters

Fentanyl Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine HydromorphoneVolumes (l)

V1 12.7 2.2 17.8 4.9 17.8 7.7 18.1 11.5V2 50 7 47 9 87 12 61 115V3 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 1.33Cl2 4.82 1.43 4.84 1.75 2.27 2.19 5.44 3.45Cl3 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 0.51b 0.037 0.052 0.030 0.103 0.010 0.025 0.031 0.012g 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 1.35t 1/2 b 19 13 23 7 68 28 22 59t 1/2 g 475 111 562 60 548 1377 271 1261

Blood Brain Equilibrationke0 (min-1) 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 19.6VD Peak Effect (l) 76.9 6.0 94.9 17.0 590.2 30.9 143.3 383.3

Comparative Opioid PKComparative Opioid PK

Minutes since bolus injection

0 240 480 720 960 1200 1440

Per

cent

of

initi

al c

once

ntra

tion

0.01

0.1

1

10

100

Methadone

Remifentanil

FentanylSufentanil

Alfentanil

HydromorphoneMorphine

Meperidine

Comparative Opioid PKComparative Opioid PK


0 5 10 15 20 25 30

Per

cent

of i

nitia

l con

cent

ratio

n

1

10

100

Methadone

Remifentanil

Fentanyl

SufentanilAlfentanil

Hydromorphone

Morphine

Meperidine

Comparative Onset of Comparative Onset of Opioid Drug EffectOpioid Drug Effect


0 5 10 15 20

Per

cent

of

peak

eff

ect

site

con

cent

ratio

n

0

20

40

60

80

100Methadone

Remifentanil

Fentanyl

Sufentanil

Alfentanil

Hydromorphone

Morphine

Meperidine

Context Sensitive Half TimeContext Sensitive Half Time

Infusion Duration

0 120 240 360 480 600

Min

utes

to

50%

dec

rem

ent

in p

lasm

a co

ncen

trat

ion

0

60

120

180

240

300

Methadone

Remifentanil

Fenta

nyl

SufentanilAlfentanil

HydromorphoneMorphine

Meperidine

50% Effect Site Decrement Time50% Effect Site Decrement Time

Infusion Duration

0 120 240 360 480 600

Min

utes

to

50%

dec

rem

ent

in e

ffec

t si

te c

once

ntra

tion

0

60

120

180

240

300

Methadone

Remifentanil

Fentanyl

Sufentanil

Alfentanil

Hydromorphone

Morphine

Meperidine

20% Effect Site Decrement Time20% Effect Site Decrement Time

Infusion Duration

0 120 240 360 480 600

Min

utes

to

20%

dec

rem

ent

in e

ffec

t si

te c

once

ntra

tion

0

30

60

90

120

Methadone

Remifentanil

Fentanyl

Sufentanil

Alfentanil

Hydromorphone

Morphine

Meperidine

Rise to Steady StateRise to Steady State

Infusion Duration

0 120 240 360 480 600

Fra

ctio

n of

Ste

ady

Sta

te

0

20

40

60

80

100

Methadone

Remifentanil

FentanylSufentanil

Alfentanil

Hydromorphone

Morphine

Meperidine

Relative PotencyRelative Potency

Fentanyl Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine HydromorphoneMEAC (ng/ml) 0.6 14.9 0.056 1.0 8 60 250 6Equipotent bolus dose (g) (g) (g) (g) (mg) (mg) (mg) (mg)

at peak effect 50 92 5.5 17 4.9 1.9 37 2.5at 10 minutes 50 197 4.4 72 5.3 1.4 28 1.9at 30 minutes 50 174 3.9 282 2.0 0.9 17 0.9at 60 minutes 50 175 4.8 1,680 1.0 0.9 14 0.6

Equipotent infusion rate (g/hr) (g/hr) (g/hr) (g/hr) (mg/hr) (mg/hr) (mg/hr) (mg/hr)at 1 hour 100 323 9 135 5 2 43 2at 2 hours 100 332 10 182 3 2 38 2at 4 hours 100 365 12 252 2 3 36 2at 6 hours 100 409 13 310 2 3 37 2at 12 hours 100 536 15 436 2 3 40 2at 24 hours 100 675 16 554 2 3 45 2

50 50 g fentanyl at 10 minutesg fentanyl at 10 minutes

Alfentanil 197 gSufentanil 4.4 gRemifentanil 72 gMorphine 5.3 mgMethadone 1.4 mgMeperidine 28 mgHydromorphone 1.9 mg

50 50 g/hour fentanyl at 2 hoursg/hour fentanyl at 2 hours

Alfentanil 332 g/hrSufentanil 9.6 g/hrRemifentanil 182 g/hrMorphine 3.3 mg/hrMethadone 2.3 mg/hrMeperidine 38 mg/hrHydromorphone 1.8 mg/hr

Opioid ReceptorOpioid Receptor

Evidence of Evidence of opioid subtypes 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 antagonistsMorphine-6-glucuronide, the outlier

Gavril Pasternak, Life Sciences 2001:68, 2213

NaloxonazineNaloxonazine

Selectively antagonizes morphine analgesia in animals1 is considered naloxonazine sensitive

Does not antagonize morphine-induced ventilatory depression or GI effects2 is considered naloxonazine insensitive


Morphine-6-glucuronideMorphine-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, http://www.mskcc.org/mskcc/html/11384.cfm

MOR-1 gene splice variantsMOR-1 gene splice variants(gene=OPRM)(gene=OPRM)

Antisense lowers Antisense lowers morphinemorphine analgesia analgesia(no effect on m6g)(no effect on m6g)



Antisense lowers Antisense lowers m6gm6g analgesia analgesia(no effect on morphine)(no effect on morphine)

Morphine-6-glucuronideMorphine-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)

11 selective agonists? 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…

““Power corrupts,Power corrupts,PowerPoint corrupts absolutely”PowerPoint corrupts absolutely”

opioid pharmacology

Education

fentanyl morph

fentanyl pharmacokinetics

ghour fentanyl

g fentanyl

morphine analgesia

fentanyl series of opioids

fentanyl selective response

opioid antagonists morphine