1. 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

2. Please Fasten Safety BeltsPrior to Take Off

3. Pharmacokinetics: Volume of Distribution

4. Pharmacokinetics: Clearance

5. Pharmacokinetics: Half-Life • The time required for drug concentrations to decrease by 50%.

6. Three Compartment Model 100 Rapid 10 Concentration Intermediate Slow 1 0 120 240 360 480 600 Minutes since bolus injection

7. Opioid Half-Lives (minutes)

9. 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

10. 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

11. 20% Decrement Time 60 fentanyl 40 Minutes required alfentanil 20 sufentanil 0 240 360 480 600 0 120 Minutes since beginning of infusion

12. 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

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

14. Profound Opioid EEG Effect Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992

15. EEG Time Course with Fentanyl Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

16. EEG Time Course with Alfentanil Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985

17. Three Compartment Modelplus an “Effect Site”

18. Effect Site Concentrations

19. 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.

20. Sufentanil vs. Fentanyl • Higher lipid solubility: • Shorter beta elimination half-life: • More rapid induction: • Improved hemodynamic stability: • More rapid recovery:

22. 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

25. Relative PotencyFentanyl vs. Sufentanil Sufentanil Fentanyl

28. 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!

29. Normalized Plasma Opioid Concentrations

30. Normalized Effect Site Opioid Concentrations

31. Rise to Steady State with Infusion

32. 20% Effect Site Decrement Curve

33. 50% Effect Site Decrement Curve

34. 80% Effect Site Decrement Curve

35. MAC Reduction Lang et al, Anesthesiology 85, 721-728, 1996

36. 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)

37. 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

44. 10 Minute Infusion Alfentanil Fentanyl Remifentanil Sufentanil

45. 600 Minute Infusion Alfentanil Fentanyl Remifentanil Sufentanil

46. Optimal Maintenance Propofol / Opioid Concentrations Sufentanil (ng/ml)

47. 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)

48. 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

49. 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