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Type: Journal article
Title: Pharmacokinetic-pharmacodynamic modelling of the analgesic and antihyperalgesic effects of morphine after intravenous infusion in human volunteers
Author: Ravn, P.
Foster, D.
Kreilgaard, M.
Christrup, L.
Werner, M.
Secher, E.
Skram, U.
Upton, R.
Citation: Basic and Clinical Pharmacology and Toxicology, 2014; 115(3):257-267
Publisher: Wiley
Issue Date: 2014
ISSN: 1742-7835
Statement of
Pernille Ravn, David J.R. Foster, Mads Kreilgaard, Lona Christrup, Mads U. Werner, Erik L. Secher, Ulrik Skram and Richard Upton
Abstract: Using a modelling approach, this study aimed to (i) examine whether the pharmacodynamics of the analgesic and antihyperalgesic effects of morphine differ; (ii) investigate the influence of demographic, pain sensitivity and genetic (OPRM1) variables on between-subject variability of morphine pharmacokinetics and pharmacodynamics in human experimental pain models. The study was a randomized, double-blind, 5-arm, cross-over, placebo-controlled study. The psychophysical cutaneous pain tests, electrical pain tolerance (EPTo) and secondary hyperalgesia areas (2HA) were studied in 28 healthy individuals (15 males). The subjects were chosen based on a previous trial where 100 subjects rated (VAS) their pain during a heat injury (47°C, 7 min., 12.5 cm²). The 33% lowest- and highest pain-sensitive subjects were offered participation in the present study. A two-compartment linear model with allometric scaling for weight provided the best description of the plasma concentration-time profile of morphine. Changes in the EPTo and 2HA responses with time during the placebo treatment were best described by a linear model and a quadratic model, respectively. The model discrimination process showed clear evidence for adding between-occasion variability (BOV) on baseline and the placebo slope for EPTo and 2HA, respectively. The sensitivity covariate was significant on baseline EPTo values and genetics as a covariate on the placebo slope for 2HA. The analgesic and antihyperalgesic effects of morphine were pharmacologically distinct as the models had different effect site equilibration half-lives and different covariate effects. Morphine had negligible effect on 2HA, but significant effect on EPTo.
Keywords: Morphine; healthy volunteers
Rights: © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society)
DOI: 10.1111/bcpt.12213
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