title: Pharmacokinetic-pharmacodynamic modelling of the analgesic and antihyperalgesic effects of morphine after intravenous infusion in human volunteers.
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 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 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.
authors: Department of Drug Design and Pharmacology, Faculty of Medicines and Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Pernille
authors: P
authors: Ravn
authors: David J R
authors: DJ
authors: Foster
authors: Mads
authors: M
authors: Kreilgaard
authors: Lona
authors: L
authors: Christrup
authors: Mads U
authors: MU
authors: Werner
authors: Erik L
authors: EL
authors: Secher
authors: Ulrik
authors: U
authors: Skram
authors: Richard
authors: R
authors: Upton
mesh_terms: D000328:Adult; D000700:Analgesics / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015992:Body Mass Index; D001835:Body Weight; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004558:Electric Stimulation; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007262:Infusions, Intravenous; D016014:Linear Models; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D010146:Pain / Q000188:drug therapy; D017288:Pain Threshold / Q000187:drug effects; D055815:Young Adult
chemical_list: D000700:Analgesics; D009020:Morphine