Clinical Pharmacokinetics

, Volume 46, Issue 11, pp 965–980

Mechanism-Based Pharmacokinetic-Pharmacodynamic Modelling of the Reversal of Buprenorphine-Induced Respiratory Depression by Naloxone

A Study in Healthy Volunteers
  • Ashraf Yassen
  • Erik Olofsen
  • Eveline van Dorp
  • Elise Sarton
  • Luc Teppema
  • Meindert Danhof
  • Albert Dahan
Original Research Article


Background and objective

Respiratory depression is a potentially life-threatening adverse effect of opioid therapy. It has been postulated that the difficulty of reversing buprenorphine-induced respiratory depression is caused by slow receptor association-dissociation kinetics at the opioid μ receptor. The aim of this study was to characterise the pharmacodynamic interaction between buprenorphine and naloxone in healthy volunteers.


A competitive pharmacodynamic interaction model was proposed to describe and predict the time course of naloxone-induced reversal of respiratory depression. The model was identified using data from an adaptive naloxone dose-selection trial following intravenous administration of buprenorphine 0.2mg/70kg or 0.4mg/70kg.


The pharmacokinetics of naloxone and buprenorphine were best described by a two-compartment model and a three-compartment model, respectively. A combined biophase equilibration-receptor association-dissociation pharmacodynamic model described the competitive interaction between buprenorphine and naloxone at the opioid μ receptor. For buprenorphine, the values of the rate constants of receptor association (kon) and dissociation (koff) were 0.203 mL/ng/min and 0.0172 min−1, respectively. The value of the equilibrium dissociation constant (KD) was 0.18 nmol/L. The half-life (t½) of biophase equilibration was 173 minutes. These estimates of the pharmacodynamic parameters are similar to values obtained in the absence of naloxone co-administration. For naloxone, the half-life of biophase distribution was 6.5 minutes.


Because of the slow receptor association-dissociation kinetics of buprenorphine in combination with the fast elimination kinetics of naloxone, naloxone is best administered as a continuous infusion for reversal of buprenorphine-induced respiratory depression.


  1. 1.
    Baxter AD. Respiratory depression with patient-controlled analgesia. Can J Anaesth 1994; 41: 87–90PubMedCrossRefGoogle Scholar
  2. 2.
    Dahan A, Sarton E, Teppema L, et al. Sex-related differences in the influence of morphine on ventilatory control in humans. Anesthesiology 1998; 88: 903–13PubMedCrossRefGoogle Scholar
  3. 3.
    Davies GK, Tolhurst-Cleaver CL, James TL. Respiratory depression after intrathecal narcotics. Anaesthesia 1980; 35: 1080–3PubMedCrossRefGoogle Scholar
  4. 4.
    Taylor S, Kirton OC, Staff I, et al. Postoperative day one: a high risk period for respiratory events. Am J Surg 2005; 190: 752–6PubMedCrossRefGoogle Scholar
  5. 5.
    Zuurmond WW, Meert TF, Noorduin H. Partial versus full agonists for opioid-mediated analgesia: focus on fentanyl and buprenorphine. Acta Anaesthesiol Belg 2002; 53: 193–201PubMedGoogle Scholar
  6. 6.
    Dahan A, Yassen A, Bijl H, et al. Comparison of the respiratory effects of intravenous buprenorphine and fentanyl in humans and rats. Br J Anaesth 2005; 94: 825–34PubMedCrossRefGoogle Scholar
  7. 7.
    Yassen A, Kan J, Olofsen E, et al. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the respiratory depressant effect of buprenorphine and fentanyl in rats. J Pharmacol Exp Ther 2006; 319: 682–92PubMedCrossRefGoogle Scholar
  8. 8.
    Yassen A, Olofsen E, Romberg R, et al. Mechanism-based PK/PD modeling of the respiratory depressant effect of buprenorphine and fentanyl in healthy volunteers. Clin Pharmacol Ther 2007; 81: 50–8PubMedCrossRefGoogle Scholar
  9. 9.
    Cowan A, Doxey JC, Harry EJ. The animal pharmacology of buprenorphine, an oripavine analgesic agent. Br J Pharmacol 1977; 60: 547–54PubMedCrossRefGoogle Scholar
  10. 10.
    Gal TJ. Naloxone reversal of buprenorphine-induced respiratory depression. Clin Pharmacol Ther 1989; 45: 66–71PubMedCrossRefGoogle Scholar
  11. 11.
    Boas RA, Villiger JW. Clinical actions of fentanyl and buprenorphine: the significance of receptor binding. Br J Anaesth 1985; 57: 192–6PubMedCrossRefGoogle Scholar
  12. 12.
    Kosterlitz HW, Leslie FM, Waterfield AA. Rates of onset and offset of action of narcotic analgesics in isolated preparations. Eur J Pharmacol 1975; 32: 10–6PubMedCrossRefGoogle Scholar
  13. 13.
    Villiger JW, Taylor KM. Buprenorphine: high-affinity binding to dorsal spinal cord. J Neurochem 1982; 38: 1771–3PubMedCrossRefGoogle Scholar
  14. 14.
    van Dorp E, Yassen A, Sarton E, et al. Naloxone reversal of buprenorphine-induced respiratory depression. Anesthesiology 2006; 105: 51–7PubMedCrossRefGoogle Scholar
  15. 15.
    Beal SL, Sheiner LB. NONMEM Project Group. NONMEM user’s guide. San Francisco (CA): University of California at San Francisco, 1999Google Scholar
  16. 16.
    Mandema JW, Verotta D, Sheiner LB. Building population pharmacokinetic-pharmacodynamic models: I. Models for covariate effects. J Pharmacokinet Biopharm 1992; 20: 511–28PubMedGoogle Scholar
  17. 17.
    Jonsson EN, Karlsson MO. Xpose: an S-PLUS based population pharmacokinetic/pharmacodynamic model building aid for NONMEM. Comput Methods Programs Biomed 1999; 58: 51–64PubMedCrossRefGoogle Scholar
  18. 18.
    Ette EI, Williams PJ, Kim YH, et al. Model appropriateness and population pharmacokinetic modeling. J Clin Pharmacol 2003; 43: 610–23PubMedGoogle Scholar
  19. 19.
    Dahan A, DeGoede J, Berkenbosch A, et al. The influence of oxygen on the ventilatory response to carbon dioxide in man. J Physiol 1990; 428: 485–99PubMedGoogle Scholar
  20. 20.
    Yassen A, Olofsen E, Kan J, et al. Animal-to-human extrapolation of the pharmacokinetic and pharmacodynamic properties of buprenorphine. Clin Pharmacokinet 2007; 46: 433–47PubMedCrossRefGoogle Scholar
  21. 21.
    Galynker I, Schlyer DJ, Dewey SL, et al. Opioid receptor imaging and displacement studies with [6-O-[11C]methyl]buprenorphine in baboon brain. Nucl Med Biol 1996; 23: 325–31PubMedCrossRefGoogle Scholar
  22. 22.
    Cassel JA, Daubert JD, DeHaven RN. [(3)H]Alvimopan binding to the micro opioid receptor: comparative binding kinetics of opioid antagonists. Eur J Pharmacol 2005; 520: 29–36PubMedCrossRefGoogle Scholar
  23. 23.
    Weinstein SH, Pfeffer M, Schor JM. Metabolism and pharmacokinetics of naloxone. Adv Biochem Psychopharmacol 1973; 8: 525–35PubMedGoogle Scholar
  24. 24.
    Ngai SH, Berkowitz BA, Yang JC, et al. Pharmacokinetics of naloxone in rats and in man: basis for its potency and short duration of action. Anesthesiology 1976; 44: 398–401PubMedCrossRefGoogle Scholar
  25. 25.
    Mehta V, Phillips JP, Antman AC, et al. Investigation of buprenorphine-induced respiratory depression in anaesthetized patients and its reversibility [abstract]. Br J Anaesth 2005; 94: 399–400PCrossRefGoogle Scholar
  26. 26.
    Bowdle TA. Pharmacology of analgesia. In: Healy TEJ, Knight PR, editors. A practice of anesthesia. London: Wylie and Churchill-Davidson’s, 2003: 543–63Google Scholar
  27. 27.
    Morgan D, Cook CD, Smith MA, et al. An examination of the interactions between the antinociceptive effects of morphine and various mu-opioids: the role of intrinsic efficacy and stimulus intensity. Anesth Analg 1999; 88: 407–13PubMedGoogle Scholar
  28. 28.
    Mizoguchi H, Spaulding A, Leitermann R, et al. Buprenorphine blocks epsilon- and micro-opioid receptor-mediated anti-nociception in the mouse. J Pharmacol Exp Ther 2003; 306: 394–400PubMedCrossRefGoogle Scholar
  29. 29.
    Kogel B, Christoph T, Strassburger W, et al. Interaction of muopioid receptor agonists and antagonists with the analgesic effect of buprenorphine in mice. Eur J Pain 2005; 9: 599–611PubMedCrossRefGoogle Scholar
  30. 30.
    Thomsen AB, Becker N, Eriksen J. Opioid rotation in chronic non-malignant pain patients: a retrospective study. Acta Anaesthesiol Scand 1999; 43: 918–23PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Ashraf Yassen
    • 1
  • Erik Olofsen
    • 2
  • Eveline van Dorp
    • 2
  • Elise Sarton
    • 2
  • Luc Teppema
    • 2
  • Meindert Danhof
    • 1
    • 3
  • Albert Dahan
    • 2
  1. 1.Division of PharmacologyLeiden/Amsterdam Centre for Drug ResearchLeidenThe Netherlands
  2. 2.Department of AnesthesiologyLeiden University Medical CentreLeidenThe Netherlands
  3. 3.LAP&P Consultants BVLeidenThe Netherlands
  4. 4.Leiden/Amsterdam Centre for Drug Research, Division of PharmacologyGorleaus LaboratoriesLeidenThe Netherlands

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