Pharmacokinetic–Pharmacodynamic Modelling of the Analgesic and Antihyperalgesic Effects of Morphine after Intravenous Infusion in Human Volunteers

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.