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Comparative Opioid Pharmacology: Evidence Based Rationale Steven L. Shafer, M.D. Palo Alto VA Health Care System Stanford University School of Medicine University of California at San Francisco Please Fasten Safety Belts Prior to Take Off Pharmacokinetics: Volume of Distribution

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comparative opioid pharmacology evidence based rationale

Comparative Opioid Pharmacology:Evidence Based Rationale

Steven L. Shafer, M.D.

Palo Alto VA Health Care System

Stanford University School of Medicine

University of California at San Francisco

pharmacokinetics half life
Pharmacokinetics: Half-Life
  • The time required for drug concentrations to decrease by 50%.
three compartment model
Three Compartment Model

100

Rapid

10

Concentration

Intermediate

Slow

1

0

120

240

360

480

600

Minutes since bolus injection

opioid pharmacokinetics
Opioid Pharmacokinetics

100

10

Percent of peak plasma opioid concentration

fentanyl

1

sufentanil

alfentanil

0.1

360

480

600

240

0

120

Minutes since bolus injection

context sensitive half time
Context-Sensitive Half-Time

120

fentanyl

90

alfentanil

Minutes required

60

sufentanil

30

0

240

360

480

600

0

120

Minutes since beginning of infusion

20 decrement time
20% Decrement Time

60

fentanyl

40

Minutes required

alfentanil

20

sufentanil

0

240

360

480

600

0

120

Minutes since beginning of infusion

80 decrement time
80% Decrement Time

300

fentanyl

240

alfentanil

180

Minutes required

120

sufentanil

60

0

240

360

480

600

0

120

Minutes since beginning of infusion

awake eeg
Awake EEG

Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992

profound opioid eeg effect
Profound Opioid EEG Effect

Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992

eeg time course with fentanyl
EEG Time Course with Fentanyl

Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

eeg time course with alfentanil
EEG Time Course with Alfentanil

Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

valid benefits of alfentanil
Valid Benefits of Alfentanil
  • Bolus injections where quick onset is desired.
  • Long infusions where rapid recovery is desired.
  • For everything else, sufentanil gave fastest recovery among the opioids available in 1990.
slide20

Sufentanil vs. Fentanyl

  • Higher lipid solubility:
  • Shorter beta elimination half-life:
  • More rapid induction:
  • Improved hemodynamic stability:
  • More rapid recovery:
slide22

Comparison of sufentanil - O2 and Fentanyl - O2 for coronary artery surgery

de Lange S, Boscoe MJ, Stanley TH, Pace N.

Anesthesiology 56:112-118, 1982

slide28

Sufentanil vs. Fentanyl

  • Higher lipid solubility: irrelevant
  • Shorter beta elimination half-life: incorrect
  • More rapid induction: incorrect
  • Improved hemodynamic stability: never shown
  • More rapid recovery: yes, despite its

long half-life!

mac reduction
MAC Reduction

Lang et al, Anesthesiology 85, 721-728, 1996

propofol alfentanil interaction
Propofol/Alfentanil Interaction

400

  • Adapted from Vuyk et al, Anesthesiology 83:8-22, 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)

slide37

Propofol Anesthesia and Rational Opioid Selection

Determination of Optimal EC50-EC95 Propofol-Opioid

Concentrations that Assure Adequate Anesthesia and a Rapid

Return on Consciousness

Jaap Vuyk, M.D., Ph.D., Martijn J. Mertens, M.D., Erik Olofsen, M.Sc., Anton G.L. Burm, M.Sc, Ph.D.

James G. Bovill, M.D., Ph.D., F.F.A.R.C.S.I.

Anesthesiology 1997; 87:1549-62

slide44

10 Minute Infusion

Alfentanil

Fentanyl

Remifentanil

Sufentanil

slide45

600 Minute Infusion

Alfentanil

Fentanyl

Remifentanil

Sufentanil

slide47

Propofol/Opioid Recovery

40

35

30

25

Fentanyl

Minutes for Recovery

20

Alfentanil

15

Sufentanil

10

5

Remifentanil

0

0

120

240

360

480

600

Infusion Duration (minutes)

pk pd references
PK/PD References
  • Fentanyl/Alfentanil
      • Scott and Stanski, JPET 1987 240:159-66.
  • Sufentanil
      • Scott et al, Anesthesiology 1991 74:34-42
  • Remifentanil
      • Minto et al, Anesthesiology 1997 86:10-23
  • Morphine
      • Lotsch et al, Clin Pharmacol Ther 2002 72:151-62.
  • Methadone
      • Inturrisi et al, Clin Pharmacol Ther 1990 47:565-77
  • Methodology
      • Shafer and Varvel, Anesthesiology 1991 74:53-63
      • Youngs and Shafer, Anesthesiology 1994 81:833-42
      • Vuyk et al, Anesthesiology 1997 87:1549-62
slide49

Presentation can be downloaded from:

http//:anesthesia.stanford.edu

1. Navigate to “Online Lectures” 2. Navigate to “Pharmacology” 3. Download “Comparative Opioid Pharmacology” 4. Use broadband connection: presentation is 6 MB