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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

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 BeltsPrior to Take Off


Pharmacokinetics: Volume of Distribution


Pharmacokinetics: Clearance


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 Half-Lives (minutes)


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


Three Compartment Modelplus an “Effect Site”


Effect Site Concentrations


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!


Normalized Plasma Opioid Concentrations


Normalized Effect Site Opioid Concentrations


Rise to Steady State with Infusion


20% Effect Site Decrement Curve


50% Effect Site Decrement Curve


80% Effect Site Decrement Curve


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


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