Authors: Yassen, Ashraf¹; Olofsen, Erik²; Eveline van Dorp,²; Sarton, Elise²; Teppema, Luc²; Danhof, Meindert; Dahan, Albert²

Source: Clinical Pharmacokinetics, Volume 46, Number 11, 2007 , pp. 965-980(16)

Publisher: Adis International

Abstract:

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.

Methods: 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.

Results: 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 (k_on) and dissociation (k_off) were 0.203 mL/ng/min and 0.0172 min⁻¹, respectively. The value of the equilibrium dissociation constant (K_D) was 0.18 nmol/L. The half-life (t_½) 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.

Conclusions: 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.

Keywords: Buprenorphine; Naloxone; Pharmacodynamic modelling; Pharmacokinetic modelling; Respiratory insufficiency

Document Type: Research article

Affiliations: 1: 1 Division of Pharmacology, Leiden/Amsterdam Centre for Drug Research, Leiden, The Netherlands 2: 2 Department of Anesthesiology, Leiden University Medical Centre, Leiden, The Netherlands

Publication date: 2007-01-01

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