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Pharmacokinetic–Pharmacodynamic Modelling of the Analgesic and Antihyperalgesic Effects of Morphine after Intravenous Infusion in Human Volunteers
Author(s) -
Ravn Pernille,
Foster David J.R.,
Kreilgaard Mads,
Christrup Lona,
Werner Mads U.,
Secher Erik L.,
Skram Ulrik,
Upton Richard
Publication year - 2014
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12213
Subject(s) - analgesic , pharmacodynamics , morphine , placebo , pharmacokinetics , anesthesia , hyperalgesia , medicine , covariate , pharmacology , nociception , statistics , alternative medicine , receptor , mathematics , pathology
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 ( OPRM 1) 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 ( EPT o) and secondary hyperalgesia areas (2 HA ) 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 cm 2 ). 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 EPT o and 2 HA 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 EPT o and 2 HA , respectively. The sensitivity covariate was significant on baseline EPT o values and genetics as a covariate on the placebo slope for 2 HA . 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 2 HA , but significant effect on EPT o.