
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 • The time required for drug concentrations to decrease by 50%.
Three Compartment Model 100 Rapid 10 Concentration Intermediate Slow 1 0 120 240 360 480 600 Minutes since bolus injection
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 120 fentanyl 90 alfentanil Minutes required 60 sufentanil 30 0 240 360 480 600 0 120 Minutes since beginning of infusion
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 300 fentanyl 240 alfentanil 180 Minutes required 120 sufentanil 60 0 240 360 480 600 0 120 Minutes since beginning of infusion
Awake EEG Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992
Profound Opioid EEG Effect Gregg K, Varvel JR, Shafer SL. J Pharmacokinet Biopharm 20, 611-635, 1992
EEG Time Course with Fentanyl Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985
EEG Time Course with Alfentanil Scott J, Ponganis KV, Stanski DR. Anesthesiology 62:234-241, 1985
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.
Sufentanil vs. Fentanyl • Higher lipid solubility: • Shorter beta elimination half-life: • More rapid induction: • Improved hemodynamic stability: • More rapid recovery:
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
Relative PotencyFentanyl vs. Sufentanil Sufentanil Fentanyl
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 Lang et al, Anesthesiology 85, 721-728, 1996
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)
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
10 Minute Infusion Alfentanil Fentanyl Remifentanil Sufentanil
600 Minute Infusion Alfentanil Fentanyl Remifentanil Sufentanil
Optimal Maintenance Propofol / Opioid Concentrations Sufentanil (ng/ml)
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 • 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
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