Comparative Opioid Pharmacology and Total IntraVenous Anesthesia

1
Comparative Opioid Pharmacology andTotal
IntraVenous Anesthesia
Steven L. Shafer, M.D. Adjunct Professor of
Anesthesia, Stanford University Adjunct Professor
of Biopharmaceutical Science, UCSF Attending
Anesthesiologist, Columbia University Editor in
Chief, Anesthesia Analgesia
2
Disclosure

• I have done clinical trials for and Glaxo
  (remifentanil), Janssen (fentanyl, alfentanil),
  and been a consultant for Glaxo and Janssen.

3
Distinguishing Characteristics

• Pharmacokinetics
• Rate of Onset
• Rate of Offset
• Pharmacodynamics
• Potency
• Most have one or two peculiarities

4
Opioid Onset
100
Hydromorphone
Methadone
Meperidine
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
Alfentanil
20
Remifentanil
0
0
5
10
15
20
Minutes since bolus injection
5
Opioid Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
Meperidine
20
Methadone
Fentanyl
Sufentanil
Alfentanil
0
Remifentanil
0
30
60
90
120
Minutes since bolus injection
6
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

7
Morphine Onset
100
80
60
site concentration
Percent of peak effect
40
20
0
0
30
60
90
120
Minutes since bolus injection
8
Simulation of MorphineTime Course
Dahan et al. Anesthesiology. 20041011201-9.
9
Morphine Pharmacokinetics
10
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!

11
Morphine vs. Fentanyl PK
12
Morphine vs. Fentanyl PK
13
Morphine vs. Fentanyl Onset
100
80
Morphine
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
14
Morphine vs. Fentanyl Onset
100
Morphine
80
60
site concentration
Percent of peak effect
40
20
Fentanyl
0
0
30
60
90
120
Minutes since bolus injection
15
Morphine vs. Fentanyl PK
16
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

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Comparative Hydromorphone PK
18
Comparative Hydromorphone PK
19
Hydromorphone Onset
100
Hydromorphone
80
Morphine
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
20
Hydromorphone Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
20
Fentanyl
0
0
30
60
90
120
Minutes since bolus injection
21
Comparative Hydromorphone PK
22
Sufentanil

• 10 fold more potent than fentanyl
• Slightly slower onset than fentanyl
• More rapid recovery (context sensitive half
  time) than fentanyl
• Very clean pharmacologically

23
Comparative Sufentanil PK
100
10
Percent of initial concentration
Sufentanil
Morphine
Fentanyl
Hydromorphone
1
0
5
10
15
20
25
30
Minutes since bolus injection
24
Comparative Sufentanil PK
100
10
Percent of initial concentration
1
Sufentanil
Fentanyl
Hydromorphone
0.1
Morphine
0.01
0
240
480
720
960
1200
1440
Minutes since bolus injection
25
Sufentanil Onset
100
Hydromorphone
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
26
Sufentanil Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
20
Fentanyl
Sufentanil
0
0
30
60
90
120
Minutes since bolus injection
27
50 effect sitedecrement curves
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
28
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

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Meperidine Onset
100
Hydromorphone
Meperidine
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
20
0
0
5
10
15
20
Minutes since bolus injection
30
Meperidine Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
Meperidine
20
Fentanyl
Sufentanil
0
0
30
60
90
120
Minutes since bolus injection
31
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

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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

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Onset of fentanyl series opioids
sufentanil
100
80
fentanyl
Percent of peak effect site opioid concentration
60
alfentanil
40
20
remifentanil
0
0
2
4
6
8
10
Minutes since bolus injection
Minto et al, Anesthesiology 8610-23, 1997
34
Comparative Onset ofAlfentanil and Remifentanil
35
Remifentanil Metabolism

• Extremely rapid
• Not influenced by
• Hepatic disease
• Renal disease
• Pseudocholinesterase deficiency
• Administration of neostigmine
• Very young age
• Modest decrease in elderly patients

36
PK of fentanyl series opioids
100
10
Percent of peak plasma opioid concentration
fentanyl
1
sufentanil
alfentanil
remifentanil
0.1
0
120
240
360
480
600
Minutes since bolus injection
Minto et al, Anesthesiology 8610-23, 1997
37
50 effect sitedecrement curves
120
fentanyl
90
alfentanil
Minutes required
60
sufentanil
30
remifentanil
0
0
120
240
360
480
600
Minutes since beginning of infusion
Minto et al, Anesthesiology 8610-23, 1997
38
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

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Methadone Onset
100
Hydromorphone
Methadone
Meperidine
80
Morphine
Sufentanil
60
site concentration
Percent of peak effect
Fentanyl
40
Alfentanil
20
Remifentanil
0
0
5
10
15
20
Minutes since bolus injection
40
Methadone Onset
100
Morphine
80
Hydromorphone
60
site concentration
Percent of peak effect
40
Meperidine
20
Methadone
Fentanyl
Sufentanil
Alfentanil
0
Remifentanil
0
30
60
90
120
Minutes since bolus injection
41
Methadone PK
100
Methadone
10
Meperidine
Percent of initial concentration
Sufentanil
Alfentanil
Morphine
Fentanyl
Hydromorphone
Remifentanil
1
0
5
10
15
20
25
30
Minutes since bolus injection
42
Methadone PK
100
10
Percent of initial concentration
Methadone
1
Sufentanil
Fentanyl
Meperidine
Hydromorphone
0.1
Morphine
Alfentanil
Remifentanil
0.01
0
240
480
720
960
1200
1440
Minutes since bolus injection
43
I thought this was a lecture about Total
IntraVenous Anesthesia
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Some anesthetics enhancepain sensitivity at very
low concentrations.
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Dundee in 1960

• Pain sensitivity in gynecologic patients after a
  halothane anesthetic.

Dundee, JW and Moore, J. Alterations in Response
to Somatic Pain Associated with Anesthesia IV
The Effect of Sub-Anaesthetic Concentrations of
Inhalation Agents. BJA 32453-9.
46
Inhaled Anesthetics Have Pronociceptive Effects
at 0.1 Minimum Alveolar Anesthetic Concentration
Yi Zhang, Edmond I Eger, II, Robert C. Dutton,
and James M. Sonner Anesth Analg 2000 91
462-466.
47
Flood Model of Volatile Anesthetic Effect on Pain
Sensitivity

• ED50 for pain enhancement effect Is 0.16
  isoflurane.
• ED50 for pain relieving effect is 0.8
  isoflurane.

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Isoflurane fentanyl vs. Propofol Fentanyl
49
Patients anesthetized with isoflurane used more
morphine in the first post-operative day
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What is TIVA in 2007?

• Pure
• Propofol _at_ 50-75 mg/kg/min
• Remifentanil _at_ 0.1-0.3 mg/kg/min
• BIS
• Cheating
• Propofol _at_ 20-75 mg/kg/min
• Remifentanil _at_ 0.01-0.3 mg/kg/min
• Or 50 ?g fentanyl every 30-60 min
• 70 Nitrous Oxide

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Propofol/opioid vs Isoflurane/opioid
52
Propofol/opioid vs Isoflurane/opioid
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Propofol/Alfentanil Interaction
400

• Adapted from Vuyk et al, Anesthesiology 838-22,
  1995
• Characterizes the concentrations for
• intubation
• maintenance
• on emergence
• Concentrations are 50 response level

Intubation
300
Maintenance
200
Alfentanil Concentration (ng/ml)
Emergence
100
0
0
2
4
6
8
10
Propofol Concentration (mg/ml)
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10 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
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600 Minute Infusion
Alfentanil
Fentanyl
Remifentanil
Sufentanil
58
Easy Propofol - Remifentanil

• Add 1 mg of remifentanil to your 50 cc propofol
  syringe
• Remifentanil concentration will be 20 mg/ml
• Run Propofol at 60-80 ?g/kg/min
• Approach gives a bit less remi than you might
  otherwise use.
• Use with 70 N2O, or increase propofol dose to
  75-100 mg/kg/min

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Steves TIVA Approach

• Unremarkable IV induction
• Propofol, fentanyl, relaxant
• After induction, just run 66-70 nitrous oxide.
  Dont start propofol/remi until BP recovers.
• Remifentanil
• Start _at_ 0.1 mg/kg/min
• Maintain _at_ 0.05-0.3 mg/kg/min
• Propofol
• Start _at_ 75 mg/kg/min
• Maintain _at_ 25-76 mg/kg/min
• Either monitor BIS, or dont fully paralyze

60
Transition to postoperative analgesia

• Local Anesthesia
• Methadone 5-10 mg
• 45-60 minutes before the end of anesthesia
• Fentanyl 50-100 mg
• 5-10 minutes before the end of anesthesia
• Morphine 5-10 mg
• 15-30 minutes before the end of anesthesia

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