Download Introduction to Remifentanil

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
Muscle Rigidity
Nausea, Vomiting
Pruritis



Urinary retention
Ileus
Addiction potential
Pure m agonists
 Intraoperative
 Fentanyl
 Alfentanil
 Sufentanil
 Remifentanil
 Postoperative
 Morphine
 Hydromorphone
 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 (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
V2
V3
Clearances (l/min)
Cl1
Cl2
Cl3
Exponents (min-1)
a
b
g
Half Lives (min)
t 1/2 a
t 1/2 b
t 1/2 g
Blood Brain Equilibration
ke0 (min-1)
t 1/2 ke0 (min)
Tpeak (min)
VD Peak Effect (l)
12.7
50
295
2.2
7
15
17.8
47
476
4.9
9
5
17.8
87
199
7.7
12
184
18.1
61
166
11.5
115
968
0.62
4.82
2.27
0.20
1.43
0.25
1.16
4.84
1.29
2.44
1.75
0.06
1.26
2.27
0.33
0.13
2.19
0.38
0.76
5.44
1.79
1.33
3.45
0.92
0.67
0.037
0.0015
1.03
0.052
0.0062
0.48
0.030
0.0012
0.96
0.103
0.0116
0.23
0.010
0.0013
0.50
0.025
0.0005
0.51
0.031
0.0026
0.51
0.012
0.0005
1.03
19
475
0.67
13
111
1.43
23
562
0.73
7
60
2.98
68
548
1.38
28
1377
1.37
22
271
1.35
59
1261
0.147
0.770
0.112
0.525
0.005
0.110
0.067
0.015
4.7
3.7
76.9
0.9
1.4
6.0
6.2
5.8
94.9
1.3
1.6
17.0
139
93.8
590.2
6.3
11.3
30.9
10.3
8.5
143.3
46
19.6
383.3
Comparative Opioid PK
Percent of initial concentration
100
10
Methadone
1
Sufentanil
Mep
er
Fentanyl
idine
Hydromorphone
0.1
Alf
en
tan
Remifentanil
Morphin
e
il
0.01
0
240
480
720
960
1200
Minutes since bolus injection
1440
Percent of initial concentration
Comparative Opioid PK
100
Methadone
10
Meperidine
Sufentanil
Alfentanil
Morphine
Fentanyl
Hydromorphone
Remifentanil
1
0
5
10
15
20
25
Minutes since bolus injection
30
Comparative Onset of
Opioid Drug Effect
Hydromorphone
100
Percent of peak effect
site concentration
Methadone
Meperidine
Morphine
80
Sufentanil
60
Fentanyl
40
Alfentanil
20
Remifentanil
0
0
5
10
15
20
Context Sensitive Half Time
Fe
nt
an
yl
Minutes to 50% decrement
in plasma concentration
300
240
ine
Meperid
180
120
one
d
a
th
Me
Alfentanil
60
Sufentanil
Morphine
Hydromorphone
Remifentanil
0
0
120
240
360
480
600
50% Effect Site Decrement Time
Minutes to 50% decrement
in effect site concentration
300
yl
an
t
n
Fe
Morphine
240
Meperidine
180
Hydromorphone
120
one
d
a
h
Met
Alfentanil
60
Sufentanil
Remifentanil
0
0
120
240
360
Infusion Duration
480
600
20% Effect Site Decrement Time
Minutes to 20% decrement
in effect site concentration
120
Morphine
90
60
Hydromorphone
ne
ridi
e
p
Me
30
nyl
a
t
n
Fe
e
Methadon
Sufentanil
Alfentanil
0
0
120
240
360
Infusion Duration
Remifentanil
480
600
Rise to Steady State
Remifentanil
Fraction of Steady State
100
80
il
an
t
n
fe
l
A
60
e
ridin
e
p
Me
l
ntani
Sufe
phone
Hydromor
yl
ine
h
ntan
p
e
r
F
Mo
40
e
Methadon
20
0
0
120
240
360
Infusion Duration
480
600
Relative Potency
MEAC (ng/ml)
Equipotent bolus dose
at peak effect
at 10 minutes
at 30 minutes
at 60 minutes
Equipotent infusion rate
at 1 hour
at 2 hours
at 4 hours
at 6 hours
at 12 hours
at 24 hours
Fentanyl Alfentanil Sufentanil Remifentanil Morphine Methadone Meperidine Hydromorphone
0.6
14.9
0.056
1.0
8
60
250
6
(mg)
(mg)
(mg)
(mg)
(mg)
(mg)
(mg)
(mg)
50
92
5.5
17
4.9
1.9
37
2.5
50
197
4.4
72
5.3
1.4
28
1.9
50
174
3.9
282
2.0
0.9
17
0.9
50
175
4.8
1,680
1.0
0.9
14
0.6
(mg/hr)
(mg/hr)
(mg/hr)
(mg/hr)
(mg/hr)
(mg/hr)
(mg/hr)
(mg/hr)
100
323
9
135
5
2
43
2
100
332
10
182
3
2
38
2
100
365
12
252
2
3
36
2
100
409
13
310
2
3
37
2
100
536
15
436
2
3
40
2
100
675
16
554
2
3
45
2
50 mg fentanyl at 10 minutes
Alfentanil
Sufentanil
Remifentanil
Morphine
Methadone
Meperidine
Hydromorphone
197
4.4
72
5.3
1.4
28
1.9
mg
mg
mg
mg
mg
mg
mg
50 mg/hour fentanyl at 2 hours
Alfentanil
Sufentanil
Remifentanil
Morphine
Methadone
Meperidine
Hydromorphone
332
9.6
182
3.3
2.3
38
1.8
mg/hr
mg/hr
mg/hr
mg/hr
mg/hr
mg/hr
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”