Eva Sverrisdóttir (1), David Foster (2), Richard Upton (2), Anne Estrup Olesen (3), Trine Meldgaard Lund (1), Lona Louring Christrup (1), Mads Kreilgaard (1)
(1) Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; (2) Australian Centre for Pharmacometrics, School of Pharm and Med Sci, UniSA, Adelaide, SA; (3) Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Denmark
Objectives: To develop a population pharmacokinetic-pharmacodynamic (PK-PD) model describing the concentration-effect relationships for morphine on experimental pain caused by skin heat and muscle pressure.
Methods: Data were analysed from a study in 39 healthy volunteers who received 30 mg oral morphine or placebo. Blood samples were collected up to 150 min post dose, while experimental skin heat and muscle pressure pain was induced at time 0, 15, 30, 45, 60, and 150 min. Nociceptive input was increased until the subjects reported a pain score of 7 on a 0-10 visual analogue scale, where 5 is the pain detection threshold. The PK-PD relationships of morphine, M6G, and M3G were analysed with non-linear mixed effects modelling (NONMEM v. 7.2, ICON Plc) using a sequential approach. One- and two-compartment models were fitted to morphine, M6G, and M3G plasma concentration-time data. First order and transit compartment absorption models were tested. The placebo-response of both pain metrics was fitted to slope 0, linear, and quadratic effect versus time models. The drug effect was tested as proportional or additive to the placebo-response. Drug effect was fitted to slope 0, linear, and Emax models of effect versus plasma or effect compartment concentration. Morphine, M6G, or M3G were tested as the concentration driving analgesia. The influence of the covariates sex, height, weight, body mass index (BMI), and age was also tested. Model selection criteria included Akaike Information Criterion (AIC) and diagnostic plots.
Results: The plasma concentration-time profiles of morphine, M6G, and M3G were best described with a one-compartment distribution, and the absorption of morphine was best described with a six transit compartment model with a combined additive and proportional residual error model. The placebo-response for skin heat was best described by a linear model with between-occasion variability (BOV) on baseline, and additive residual error model. For muscle pressure, a slope 0 model with BOV on baseline and proportional error model best described the placebo response. Morphine’s effect on both skin heat and muscle pressure was proportional to the placebo-response and described by a linear model with between subject variability (BSV) on drug effect slope and an effect compartment for muscle pressure. Drug slopes were 0.000406 °C/ng/ml for skin heat and 0.0156 kPa/ng/ml for muscle pressure. The inclusion of covariates did not improve the models.
Conclusions: The data were characterised by high inter and intra individual variability. In contrast to previous studies, the placebo-response showed minimal change with time. A linear concentration-effect relationship of morphine was identified for both pain metrics. However, drug effect slopes were marginal in relation to clinical relevance.
Reference: PAGE 22 () Abstr 2959 [www.page-meeting.org/?abstract=2959]
Poster: CNS