title: Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models.
abstract: The aim of this study was to develop population pharmacokinetic-pharmacodynamic models for morphine in experimental pain induced by skin heat and muscle pressure, and to evaluate the experimental pain models with regard to assessment of morphine pharmacodynamics. In a randomised, double-blind, placebo-controlled, crossover study, 39 healthy volunteers received an oral dose of 30mg morphine hydrochloride or placebo. Non-linear mixed effects modelling was used to describe the plasma concentrations of morphine and metabolites, and the analgesic effect of morphine on experimental pain in skin and muscle. Baseline pain metrics varied between individuals and occasions, and were described with interindividual and interoccasion variability. Placebo-response did not change with time. For both pain metrics, morphine effect was proportional to baseline pain and was described with a linear model with interindividual variability on drug effect slope and linked to an effect compartment for muscle pressure. The models indicate that a steady-state morphine concentration of 21ng/ml causes 33% and 0.84% increases in stimulus intensity from baseline for muscle pressure and skin heat, respectively. The population pharmacokinetic-pharmacodynamic models developed in this study indicate that mechanical stimulation of muscle is a more clinically relevant pain stimulus for the assessment of morphine pharmacodynamics than thermal stimulation of skin.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Eva
authors.initials: E
authors.lastname: Sverrisdóttir
authors.affiliation: Australian Centre for Pharmacometrics, School of Pharmaceutical and Medical Sciences, City East Campus, North Terrace, University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: David John Richard
authors.initials: DJ
authors.lastname: Foster
authors.affiliation: Australian Centre for Pharmacometrics, School of Pharmaceutical and Medical Sciences, City East Campus, North Terrace, University of South Australia, Adelaide, SA 5000, Australia.
authors.forename: Richard Neil
authors.initials: RN
authors.lastname: Upton
authors.affiliation: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark.
authors.forename: Anne Estrup
authors.initials: AE
authors.lastname: Olesen
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Trine Meldgaard
authors.initials: TM
authors.lastname: Lund
authors.affiliation: Department of Pharmacy, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gabel-Jensen
authors.affiliation: Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Mølleparkvej 4, DK-9000 Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Sdr. Skovvej 11, DK-9000 Aalborg, Denmark.
authors.forename: Asbjørn Mohr
authors.initials: AM
authors.lastname: Drewes
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Lona Louring
authors.initials: LL
authors.lastname: Christrup
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark. Electronic address: mads.kreilgaard@sund.ku.dk.
authors.forename: Mads
authors.initials: M
authors.lastname: Kreilgaard
mesh_terms: D000701:Analgesics, Opioid / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D008954:Models, Biological; D009020:Morphine / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010146:Pain / Q000188:drug therapy*; D011312:Pressure
chemical_list: D000701:Analgesics, Opioid; D009020:Morphine
keywords: Experimental pain; Modelling; Morphine; Morphine-6-glucuronide; Pharmacokinetics/pharmacodynamics