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https://hdl.handle.net/2440/114712
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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 1742-7843 |
Statement of Responsibility: | 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 |
Published version: | http://dx.doi.org/10.1111/bcpt.12213 |
Appears in Collections: | Aurora harvest 3 Medicine publications |
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