Hypnotics and Opioids
Steven L. Shafer, M.D.
Professor of Anesthesia, Stanford University
Adjunct Professor of Biopharmaceutical Science, UCSF
Editor in Chief, Anesthesia & Analgesia
Disclosure
I have consulted for AstraZeneca
(propofol), Roche (midazolam), Theravance
(THRX-918661), Guilford (Aquavan),
Glaxo (remifentanil).
I have done clinical trials for AstraZeneca
(propofol), Roche (midazolam, novel
benzodiazepines, novel targets), and Glaxo
(remifentanil), Janssen (fentanyl,
alfentanil).
-aminobutyric acid
a.k.a GABA
Most widespread inhibitory neurotransmitter in the CNS
Three classes of receptors
GABAA
Ligand gated ion channel
Cl- channel
Site of action of benzodiazepines, barbiturates, and propofol
Not the site of action of inhaled anesthetics
GABAB
Slow inhibitory post-synaptic potentials, regulates K+ and Ca++
conductance
Not a binding site of anesthetic drugs
GABAC
Also a Cl- channel
Not a binding site of anesthetic drugs
GABAA Receptor
Transmembrane pentamer
composed of 2 , 2 , and 1
or subunits
– Each has a binding site for
GABA
Benzodiazepines
– Bind a cleft of and
subunits
Barbiturates
– Bind subunit
Propofol/Etomidate
– Bind subunit
Antagonist: bicuculine
Midazolam vs. Diazepam
The Introduction of
Versed ®
Midazolam and Diazepam Clinical Pharmacology
(as originally introduced into clinical practice)
Elimination Equipotent
Onset Half-Life Duration Doses
Diazepam "slow" 40 hr "long" 10 mg
Midazolam "fast" 4 hr "short" 5 mg
Result of initial dosing
guidelines
1600 adverse reactions and 86 deaths
associated with midazolam in the first 5
years after its introduction in the United
States.
Department of Health and Human Services, Office of
Epidemiology and Biostatistics, Center for Drug
Evaluation and Research, Data Retrieval Unit HFD-
737, June 27, 1989
Nearly all were associated with midazolam
for sedation during endoscopy
FDA’S REGULATION OF THE NEW DRUG
VERSED
HEARINGS
BEFORE A
SUBCOMMITTEE OF THE
COMMITTEE ON
GOVERNMENT OPERATIONS
HOUSE OF REPRESENTATIVES
ONE HUNDREDTH CONGRESS
SECOND SESSION
MAY 5 AND 10, 1988
Midazolam Sedation for
15
Endoscopy
Sedative Dose (mg)
10
5
0
0 20 40 60 80 100
Age (years)
Adapted from Bell, J Clin Pharmacol 1987 Feb;23(2):241-3
Midazolam-Opioid Interactions
Midazolam ED50 (mg) (young volunteers)
20
15
10
5
0
0 500 1000 1500 Alfentanil (g)
[0] [135] [270] [400] [fentanyl - (g)]
Adapted from Kissen et al, Anesth Analg 72:65-69, 1990
Benzodiazepine EEG Effects
EEG Amplitude within 11.5-30 Hz ( V/sec)
Midazolam Flumazenil
Bretazenil
Ro 19-4603
Blood concentration ( g/ml)
EEG Effects of Midazolam
Adapted from Bührer, CPT 48:555-567, 1990
Revised Midazolam
Comparative Pharmacology
Plasma-Effect Site
Equilibration Half-Life Potency
range (average) range (mean)
1-2.4 min 406-1256 ng/ml
Diazepam (1.6 min) (958 ng/ml)
1.6-6.8 min 94-385 ng/ml
Midazolam
(4.8 min) (190 ng/ml)
Sedation and Amnesia:
Propofol vs. Midazolam
67 volunteers, randomized, open label
50% Memory
Sedation Loss
Midazolam (ng/ml) 64 56
Propofol (g/ml) 70 62
Thiopental (ug/ml) 2.9 4.5
Fentanyl (ng/ml) 0.9 3.2
No difference between relative sedative and amnestic
profiles for propofol and midazolam
Big difference with thiopental and fentanyl from propofol
or midazolam
Vesalis et al, Anesthesiology 1997 87:749-64
Sedation and Amnesia:
Propofol vs Midazolam
Randomzed, blinded cross-over trial in 10
voluneers
Titrated to different levels of sedation:
Propofol Midazolam
Lethargic 1350 208
Asleep 1620 249
– Steep change in effect with small change in concentration
Could not distinguish memory impairment between
propofol and midazolam
de Roode, et al, Anesth Analg 2000 91:1056-61
Propofol PK and age
5
Propofol ( g/ml)
4 25 years old
50 years old
3 75 years old
2
1
Infusion
0
60 120 180 240 300 360
Time in minutes
Schnider et al, Anesthesiology 88:1170-1182, 1998
The elderly brain is more sensitive to propofol
Probability of unconsciousness after a 1 hour infusion
Unconscious
1.0
Probability 0.8 75 50 25
0.6
0.4
0.2
0.0 Conscious
0 2 4 6 8
Plasma propofol concentration (g/ml)
Schnider et al, Anesthesiology 1999 (in press)
After a propofol bolus, everyone
falls asleep quickly
2.0
1.5
Minutes
1.0
0.5
0.0
20 30 40 50 60 70
Age Schnider et al, Anesthesiology 1999 (in press)
But the elderly sleep longer
12
10
Minutes
8
6
4
2
0
20 30 40 50 60 70
Age
Schnider et al, Anesthesiology 1999 (in press)
Propofol dosing and age
Rate to maintain “adequate anesthesia”
350
Infusion rate (g/kg/min)
300
250 25 years old
50 years old
200
75 years old
150
100
0 10 20 30 40 50 60
Time in minutes
Based on data in
Schnider et al, Anesthesiology 88:1170-1182, 1998
Propofol Recovery
50% effect site decrement
curve
60
Minutes to a 50% decrement
Age
20
30 40
60
80
0
0 120 240 360 480 600
Minutes since beginning of infusion
Propofol in the elderly:
bringing it all together
PK: the early distribution pharmacokinetics are
slower in the elderly
PD: the brain is more sensitive
Ke0: no change with age
Lower the dose in the elderly, and they should
wake up just as fast as younger patients
Propofol/Alfentanil Interaction
400
Adapted from Vuyk
Alfentanil Concentration (ng/ml)
et al, Anesthesiology Intubation
83:8-22, 1995 300
Characterizes the Maintenance
concentrations for 200
Emergence
intubation
maintenance
100
on emergence
Concentrations are
0
50% response level 0 2 4 6 8 10
Propofol Concentration (g/ml)
Opioid/Hypnotic Interaction
Conscious,
No Pain Attenuation Responsive
Pain in Pain Pain Afferent
in Projected Stimuli
Maximal Pain Attenuation
Opioid Hypnotic
Unconscious,
Unresponsive
Remifentanil Propofol
Probability of Tolerating
Laryngoscopy
Laryngoscopy
Pr
op
ofo
l ( l)
g/m (ng/m
l) entanil
Remif
Remifentanil Propofol
Probability of Hypnosis Hypnosis
Pr
op
ofo
l ( )
g/m
l) il (n g/ml
ntan
Re mife
Remifentanil Propofol
BIS Interaction, Laryngoscopy
5%
95%
BIS
Pr
op
ofo
l TC l)
I( CI (ng/m
g/m il T
l) ifentan
Rem
Modeling of opioid/hypnotic
interaction
400
Alfentanil Concentration (ng/ml) Intubation
300
Maintenance
200
Emergence
100
0
0 2 4 6 8 10
Propofol Concentration (g/ml)
Adapted from Vuyk et al, Anesthesiology 83:8-22, 1995
ro lnl mn n
o l fti1i t u
p/ e :
o a n s
e i
PfAn0 u f oi
0
4
0
3
0
2
0
1
Minutesinceturnigofinusion
0
Aa0/l
le0n )
f1i(g
n2 m
tn00
0
l3 64
20
0 8
0 20
4 11
0
rom)
Pf(c l
pl /
oo gm
Propofol/Alfentanil: 10 minute infusion
0
0
10 0
2
Al
0
20
fe
4 l)
nta
6 cg/m
nil
0 m
30 8 l(
(ng
0 ofo
rop
1
/m
0 P
l)
40 12
Propofol/Alfentanil: 20 minute infusion
Minutes since turning off infusions
40
30
20
10
0
Al 100 0
fen 200 2
4
/ml)
tan 6
300 8
il 10 m cg
(ng 400 12 fol (
/m Propo
l)
Propofol/Alfentanil: 60 minute infusion
Minutes since turning off infusions
40
30
20
10
0
Al 100 0
fen 200 2
4
/ml)
tan 6
300 8
il 10 m cg
(ng 400 12 fol (
/m Propo
l)
Propofol/Alfentanil: 300 minute infusion
Minutes since turning off infusions
40
30
20
10
0
100
Al
fen 2 00 2 0
4
/ml)
tan 0 6
30 8
il (
400 12 10 l (mcg
ng
/m Propofo
l)
Propofol/Alfentanil: 600 minute infusion
Minutes since turning off infusions
40
30
20
10
0
100
Al
fen 2 00 2 0
4
/ml)
tan 0 6
30 8
il (
400 12 10 l (mcg
ng
/m Propofo
l)
10 Minute Infusion
Fentanyl Alfentanil
Minutes since turning off infusions
Minutes since turning off infusions
40 40
30 30
20 20
10 10
0 0
1 0
Fe 2 Al 10 00
nta 3 2 0 fen 2 2 0
ny 4 4 4
6
/ml) l)
tan 6
l( 300
ng 5 6 10
8
mcg il ( 10
8
cg/m
/m 12 ofol
( ng 400 12
ofo l (m
l) Prop /m
l) Prop
Sufentanil Remifentanil
Minutes since turning off infusions
Minutes since turning off infusions
40 40
30 30
20 20
10 10
0 0
Su 0.10.2 Re 2
fen 0.3 2 0 mi 4 2 0
tan 0.4 4 fen 4
/ml)
6 6
il ( 0.5 8 /ml) tan 6 8
ng .6 12 10 (mcg il ( 8 2 10 (mcg
/m
0
ofol ng 1 ofol
l) Prop /m Prop
l)
600 Minute Infusion
Fentanyl Alfentanil
Minutes since turning off infusions
Minutes since turning off infusions
40 40
30 30
20 20
10 10
0 0
Fe 1 2 0
Al 10 00
nta 3 2 0 fen 2 2 0
ny 4 4 4
/ml)
6 tan 6
l( 8 /ml) 300 8
ng 5 6 10 (mcg il ( 00 12 10 (mcg
/m 12 ofol ng 4
ofol
l) Prop /m
l) Prop
Sufentanil Remifentanil
Minutes since turning off infusions
Minutes since turning off infusions
40 40
30 30
20 20
10 10
0 0
Su 0.10.2 Re 2
fen 0.3 2 0 mi 2 0
tan 0.4 4 fen 4 4
6
/ml) tan 6 6 l)
il ( 0.5 10
8
mcg il ( 0
8
cg/m
ng 0.6 12
ofol ( ng
8 2 1
1 ofo l (m
/m
l) Prop /m
l) Prop
Propofol/Opioid
Propofol Levels (g/ml)
Alfentanil Technique Remifentanil Technique
6
4 Maintenance
Maintenance
2
Emergence Emergence
0
0 120 240 360 480 600 120 240 360 480 600
Time (Minutes) Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 19
Propofol/Opioid
Percent Decrease on Emergence
Alfentanil Technique Remifentanil Technique
100
75
Remifentanil
Propofol
50
Propofol
25 Alfentanil
0
0 120 240 360 480 600 120 240 360 480 600
Time (Minutes) Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 19
Propofol/Opioid
Time to Awakening
Alfentanil Technique Remifentanil Technique
20
15
10
5
0
0 120 240 360 480 600 120 240 360 480 600
Time (Minutes) Time (Minutes)
Shafer SL, ASA Refresher Course, Chapter 19, 19
Propofol/Remifentanil TIVA
400
Remifentanil:
Infusion Rates
300 Remifentanil (ng/kg/min)
200
0.25 g/kg/min 100
0 Propofol (g/kg/min)
Propofol: 20
Recovery Time
15
80 g/kg/min 10
5
0
Requires 0 120 240 360 480 600
controlled Time (Minutes)
ventilation Shafer SL, ASA Refresher Course, Chapter 19, 1
Little tolerance for interruption of remifentanil
or propofol infusion
Interaction on Ventilatory Depression
Nieuwenhuijs et al, Anesthesiology 2003,98:312-22
Propofol/opioid vs Isoflurane/opioid
20
Minutes Required for Emergence
15
60-80% Isoflurane Decrement
10
50-67% Propofol Decrement
5
0
0 10 20 30 40 50 60
Duration of Anesthesia
Propofol/opioid vs Isoflurane/opioid
120
Minutes Required for Emergence
90
50-67% Propofol
Decrement
60
30
60-80% Isoflurane Decrement
0
0 120 240 360 480 600
Duration of Anesthesia
Propofol Formulations
Cyclodextrin
Propofol
– water-soluble cyclic
carbohydrates
– Egan et al:
Equivalent PK/PD to
Diprivan
Anesthesiology 2001;
95:A490
Baker MT, Naguib M. . Anesthesiology. 2005;103:860-76.
Propofol Formulations
Propofol micelles
– Formulations are clear
– Associated with substantial
increase in pain on
injection
– “Cleofol” recently been
introduced in India.
89% incidence of severe pain
on injection
Venous phlebitis
Damages infusion sets,
“should only be used for
patients who demand a pure
vegetarian induction agent”
Baker MT, Naguib M. . Anesthesiology. 2005;103:860-76.
Propofol Prodrug
“Aquavan”
– Water soluble
– VERY slow onset – 10
minutes or so
– Difficult to titrate
Recent phase III data
suggest that perhaps it
is titratable
Causes “a transient unpleasant
– Being developed for sensation of burning or
procedural sedation tingling of moderate severity
in the anal and genital
region.”
Baker MT, Naguib M. . Anesthesiology. 2005;103:860-76.
Novel GABAergic Hypnotic:
THRX-918661
Pig EEG study:
• 20 minute infusion (n=4)
100
80
BIS value
60 THRX-918661 (1.5mg/kg/min)
Diprivan (0.5mg/kg/min)
40
20
Infusion
0
0 5 10 15 20 25 30 35 40 45 50 55 60
Time (mins)
Beattie et al, SIVA UK, May
THRX-918661 vs propofol in Rats
70
60
Duration (mins) of loss
of the righting reflex
50
Diprivan (20mins)
40 Diprivan (3hrs)
30 Diprivan (5hrs)
20
THRX-918661 (20mins)
10
THRX-918661 (3hrs)
THRX-918661 (5hrs)
0
120
Duration (mins) for
90
total recovery
60
30
0
Beattie et al, SIVA UK, May
THRX-918661 vs. propofol in Rats
THRX- 918661 Propofol
3mg/kg i.v.
10mg/kg i.v.
30mg/kg i.v. 10mg/kg i.v.
Beattie et al, SIVA UK, May
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 Opioid Induced
Hyperalgesia
Pure agonists (intravenous)
Intraoperative Postoperative
– Fentanyl – Morphine
– Alfentanil – Hydromorphone
– Sufentanil – Meperidine
– Remifentanil – Methadone
Distinguishing Characteristics
Pharmacokinetics
– Rate of Onset
– Rate of Offset
Pharmacodynamics
– Potency
– Most have one or two peculiarities
Opioid Onset
100 Hydromorphone
Methadone
Percent of peak effect
Meperidine
site concentration
Morphine
80
Sufentanil
60
Fentanyl
40
Alfentanil
20
Remifentanil
0
0 5 10 15 20
Minutes since bolus injection
Opioid Onset
100 Morphine
Percent of peak effect
site concentration
80
Hydromorphone
60
40
Meperidine
20 Methadone
Fentanyl
Sufentanil
Alfentanil
Remifentanil
0
0 30 60 90 120
Minutes since bolus injection
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
Releases histamine
Not as full efficacy as fentanyl series of opioids
Morphine Onset
100
Percent of peak effect
site concentration
80
60
40
20
0
0 30 60 90 120
Minutes since bolus injection
Simulation of Morphine
Time Course
Dahan et al. Anesthesiology.
2004;101:1201-9.
Morphine Pharmacokinetics
100
Percent of initial concentration
10
1
0.1
0.01
0 240 480 720 960 1200 1440
Minutes since bolus injection
Fentanyl
Pharmacologically “clean”
100% efficacious (in contrast to morphine)
The first of the “fentanyl” series
(obviously…)
Available in transdermal, submucosal,
sublingual, and (soon) inhaled forms.
Free!
Morphine vs. Fentanyl PK
100
Percent of initial concentration
Morphine
10
Fentanyl
1
0 5 10 15 20 25 30
Minutes since bolus injection
Morphine vs. Fentanyl PK
100
Percent of initial concentration
10
1
Fentanyl
Morphine
0.1
0.01
0 240 480 720 960 1200 1440
Minutes since bolus injection
Morphine vs. Fentanyl Onset
100
Percent of peak effect
site concentration
Morphine
80
60
Fentanyl
40
20
0
0 5 10 15 20
Minutes since bolus injection
Morphine vs. Fentanyl Onset
100 Morphine
Percent of peak effect
site concentration
80
60
40
20
Fentanyl
0
0 30 60 90 120
Minutes since bolus injection
Morphine vs. Fentanyl PK
100
Percent of initial concentration
10
1
Fentanyl
Morphine
0.1
0.01
0 240 480 720 960 1200 1440
Minutes since bolus injection
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
Comparative Hydromorphone PK
100
Percent of initial concentration
Morphine
10
Fentanyl
Hydromorphone
1
0 5 10 15 20 25 30
Minutes since bolus injection
Comparative Hydromorphone PK
100
Percent of initial concentration
10
1
Fentanyl
Morphine
Hydromorphone
0.1
0.01
0 240 480 720 960 1200 1440
Minutes since bolus injection
Hydromorphone Onset
100 Hydromorphone
Percent of peak effect
site concentration
Morphine
80
60
Fentanyl
40
20
0
0 5 10 15 20
Minutes since bolus injection
Hydromorphone Onset
100 Morphine
Percent of peak effect
site concentration
80
Hydromorphone
60
40
20
Fentanyl
0
0 30 60 90 120
Minutes since bolus injection
Comparative Hydromorphone PK
100
Percent of initial concentration
10
1
Fentanyl
Morphine
Hydromorphone
0.1
0.01
0 240 480 720 960 1200 1440
Minutes since bolus injection
Sufentanil
10 fold more potent than fentanyl
Slightly slower onset than fentanyl
More rapid recovery (“context sensitive half
time”) than fentanyl
Very clean pharmacologically
Comparative Sufentanil PK
100
Percent of initial concentration
10
Sufentanil
Morphine
Fentanyl
1
0 5 10 15 20 25 30
Minutes since bolus injection
Comparative Sufentanil PK
100
Percent of initial concentration
10
1
0.1
0.01
0 240 480 720 960 1200 1440
Minutes since bolus injection
Sufentanil Onset
100 Hydromorphone
Percent of peak effect
site concentration
Morphine
80
Sufentanil
60
Fentanyl
40
20
0
0 5 10 15 20
Minutes since bolus injection
Sufentanil Onset
100 Morphine
Percent of peak effect
site concentration
80
Hydromorphone
60
40
20
Fentanyl
Sufentanil
0
0 30 60 90 120
Minutes since bolus injection
50% effect site
decrement curves
120
Minutes required
fentanyl
90
alfentanil
60
30 sufentanil
0
0 120 240 360 480 600
Minutes since beginning of infusion
Minto et al, Anesthesiology 86:10-23,
Meperidine
Bad Drug! No 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
Possibly useful as a local anesthetic
Meperidine Onset
100 Hydromorphone
Percent of peak effect
Meperidine
site concentration
Morphine
80
Sufentanil
60
Fentanyl
40
20
0
0 5 10 15 20
Minutes since bolus injection
Meperidine Onset
100 Morphine
Percent of peak effect
site concentration
80
Hydromorphone
60
40
Meperidine
20
Fentanyl
Sufentanil
0
0 30 60 90 120
Minutes since bolus injection
Alfentanil
Less potent than fentanyl
Much more rapid onset (including more
rapid onset of rigidity and respiratory
depression)
Much more evanescent 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
Onset of fentanyl series opioids
sufentanil
100
Percent of peak effect site
opioid concentration
80
fentanyl
60
alfentanil
40
20
remifentanil
0
0 2 4 6 8 10
Minutes since bolus injection
Minto et al, Anesthesiology 86:10-23,
Comparative Onset of
Alfentanil and Remifentanil
Hydromorphone
100
Percent of peak effect
80
site concentration
Morphine
60 Fentanyl
40
Alfentanil
20
Remifentanil
0
0 5 10 15 20
Minutes since bolus injection
Remifentanil Metabolism
• Extremely rapid
• Not influenced by:
• Hepatic disease
• Renal disease
• Pseudocholinesterase deficiency
• Administration of neostigmine
• Very young age
• Modest decrease in elderly patients
The remifentanil
“Unit Disposition Function” 0.1
0.1
• Expected plasma
concentration 0.01 0.01
Unit dispostion function
• following bolus of 1 unit
0.001 0.001
0 10 20
• Age range: 20-85 yrs
0.0001
• Very rapid decrease 0.00001
0.000001
• Less variability than with 0 60 120 180 240
other anesthetic drugs Time (minutes)
Minto et al, Anesthesiology 86:10-23,
PK of fentanyl series opioids
100
Percent of peak plasma
opioid concentration
10
fentanyl
1 sufentanil
alfentanil
remifentanil
0.1
0 120 240 360 480 600
Minutes since bolus injection
Minto et al, Anesthesiology 86:10-23,
50% effect site
decrement curves
120
Minutes required
fentanyl
90
alfentanil
60
30 sufentanil
remifentanil
0
0 120 240 360 480 600
Minutes since beginning of infusion
Minto et al, Anesthesiology 86:10-23,
Methadone
Longest terminal half-life (about 1 day)
May accumulate during titration to steady
state
VERY BAD IDEA TO SEND PATIENTS
HOME ON METHADONE
Supplied as a racemic mixture
L methadone is an opioid agonist
D methadone is an NMDA antagonist
Underutilized in anesthesia practice
Methadone Onset
100 Hydromorphone
Methadone
Percent of peak effect
Meperidine
site concentration
Morphine
80
Sufentanil
60
Fentanyl
40
Alfentanil
20
Remifentanil
0
0 5 10 15 20
Minutes since bolus injection
Methadone Onset
100 Morphine
Percent of peak effect
site concentration
80
Hydromorphone
60
40
Meperidine
20 Methadone
Fentanyl
Sufentanil
Alfentanil
Remifentanil
0
0 30 60 90 120
Minutes since bolus injection
Methadone PK
100
Percent of initial concentration
10 Meperidine
Sufentanil
Alfentanil
Morphine
Fentanyl
Remifentanil
1
0 5 10 15 20 25 30
Minutes since bolus injection
Methadone PK
100
Percent of initial concentration
10
1
0.1
Remifentanil
0.01
0 240 480 720 960 1200 1440
Minutes since bolus injection
Context Sensitive Half Time
300
yl
Minutes to 50% decrement
an
nt
in plasma concentration
Fe
240
in e
180 Meperid
120
one
thad
Me
Alfentanil
60
Sufentanil Morphine
Hydromorphone
Remifentanil
0
0 120 240 360 480 600
Rise to Steady State
Remifentanil
100
Fraction of Steady State
80
il e
an ridin
nt epe
Alfe M
phone
60 Hydromor
tanil
Sufen
ine nyl
r ph F enta
Mo
e
40 Methadon
20
0
0 120 240 360 480 600
Infusion Duration
Intraoperative potency:
100 g/hour fentanyl at 2 hours
Sufentanil 10 g/hr
Remifentanil 0.04 g/kg/min
Morphine 3.5 mg/hr
Methadone 2 mg/hr
Hydromorphone 0.4 mg/hr
Post Op Analgesia: 1
Just use fentanyl for post-op analgesia
– 25 g q 5 min
Max of 250 in young patients, 150 in elderly
– 3-5 minute peak onset provides rapid relief, but no so
rapid that the patient stops breathing
– Rapid peak makes it easy to titrate
– Nurses are familiar with it
– Logical choice for PCA
– Free
– If you can’t get the patient comfortable with fentanyl,
you won’t succeed with another opioid
possible exception of methadone
Post Op Analgesia: 2
Hydromorphone 0.2 mg q 10 min
– Max of 6 mg in young patients, 3 mg in elderly
– 5-10 minute peak onset provides rapid relief,
but no so rapid that the patient stops breathing
– Still easy to titrate
– Nurses are familiar with it
– Also a logical choice for PCA
– Inexpensive
Opioid Induced Hyperalgesia
Increase in pain sensitivity following exposure to
opioids
Well documented in animal models of pain
Evidence in humans is accumulating
Mechanical nociceptive pathways appear more
sensitive then thermal (heat) nociceptive pathways
NMDA antagonists (i.e., ketamine) blocks
hyperalgesia
Suggests a spinal mechanism
Clark and Angst, Anesthesiology 2006;104:570
OIH: High Dose Opioids
Pain and hypersensitivity are observed in opioid addicts
during withdrawal.
– Addicts on methadone maintenance have increased sensitivity in
various pain models compared with addicts not on methadone
maintenance
High dose fentanyl (22 g/kg) and remifentanil (0.3
g/kg/min) have been associated with increased pain and
opioid requirements in the post operative period.
– Associated with very high opioid doses.
– Not always replicated (0.23 g/kg/min remifentanil did not cause
hyperalgesia).
– Seen with IT opioids (25 g fentanyl)
– Nearly impossible to distinguish “hyperalgesia” from “tolerance”
in patients in such trials.
Efficacy of ketamine at blocking effect suggests it is hyperalgesia, not
tolerance.
Clark and Angst, Anesthesiology 2006;104:570
OIH: Naloxone Infusions
Two studies suggested very low naloxone infusions
improved post-operative analgesia in women undergoing
hysterectomy:
Gan et al, Anesthesiology 1997;87:1075
Joshi et al, Anesthesiology 1999;90:1007
Subsequent studies failed to reproduce these results:
Cepeda et al, Pain 2002;96:73
Cepeda et al, Pain 2004;107:41
Clark and Angst, Anesthesiology 2006;104:570
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 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)
Evidence of 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
Gavril Pasternak, Life Sciences 2001:68, 2213
Naloxonazine
Selectively antagonizes morphine analgesia
in animals
1 is considered naloxonazine sensitive
Does not antagonize morphine-induced
ventilatory depression or GI effects
2 is considered naloxonazine insensitive
Gavril Pasternak, Life Sciences 2001:68, 2213
1 selective agonists?
Despite evidence now 25 years old of
differential response to angatonists, 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 pharmacofore
Don’t hold your breath…
Next best thing:
give opioids, manage side effects
Treat constipation, ileus with peripheral
antagonists
Treat ventilatory depression with 5HT4
agonists
Peripheral antagonist:
ADL 8-2698, alvimopan
Restricted to the gut
– very little systemic absorption
– unable to cross blood-brain barrier
Peripheral antagonist:
ADL 8-2698, alvimopan
Liu et al, CPT 2001,
69:66
Methylnaltrexone
Invented by Leon Goldberg, University
of Chicago
Effective for a variety of opioid side
effects including
– Opioid induced constipation
– Pruritis
– Post-operative ileus
Being developed for IV/SQ/Oral
Progenics
– Phase III trials
5HT4(a)
Abundantly expressed in Pre-Boetzinger Complex
Controls ventilation
Stimulate adenylyl cyclase
BIMU8 is a specific agonist of 5HT4(a)
Novartis: endo-N-(8-methyl-8-azabicyclo [3.2.1]oct-3-yl)-2,3-dihydro-(1-methyl) ethyl-2-oxo-
1H-benzimidazole-1-carboxamide
Co-locate in PBC with opioid receptors
Manze et al, Science 2003
5HT4(a)
Manze et al, Science 2003 301:226
BIMU8 reverse fentanyl ventilatory depression
Manzke et al, Science 2003 301:226
Unfortunately
Based on the Manzke work, the 5HT4
nonspecific agonists have been tried for
efficacy in reversing opioid induced
ventilatory depression.
They don’t work.
Need to await development of 5HT4(a)
specific agonists.