Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models

Eva Sverrisdóttir; David John Richard Foster; Richard Neil Upton; Anne Estrup Olesen; Trine Meldgaard Lund; Charlotte Gabel-Jensen; Asbjørn Mohr Drewes; Lona Louring Christrup; Mads Kreilgaard

doi:10.1016/j.ejps.2014.10.003

Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models

Eva Sverrisdóttir, David John Richard Foster, Richard Neil Upton, Anne Estrup Olesen, Trine Meldgaard Lund, Charlotte Gabel-Jensen, Asbjørn Mohr Drewes, Lona Louring Christrup, Mads Kreilgaard

14 Citations (Scopus)

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 30 mg 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 21 ng/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.

Original language	English
Journal	European Journal of Pharmaceutical Sciences
Volume	66
Pages (from-to)	50-58
Number of pages	9
ISSN	0928-0987
DOIs	https://doi.org/10.1016/j.ejps.2014.10.003
Publication status	Published - 23 Jan 2015

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10.1016/j.ejps.2014.10.003

http://www.sciencedirect.com/science/article/pii/S0928098714003856

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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 30 mg 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 21 ng/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.",

author = "Eva Sverrisd{\'o}ttir and Foster, {David John Richard} and Upton, {Richard Neil} and Olesen, {Anne Estrup} and Lund, {Trine Meldgaard} and Charlotte Gabel-Jensen and Drewes, {Asbj{\o}rn Mohr} and Christrup, {Lona Louring} and Mads Kreilgaard",

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year = "2015",

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doi = "10.1016/j.ejps.2014.10.003",

language = "English",

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T1 - Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models

AU - Sverrisdóttir, Eva

AU - Foster, David John Richard

AU - Upton, Richard Neil

AU - Olesen, Anne Estrup

AU - Lund, Trine Meldgaard

AU - Gabel-Jensen, Charlotte

AU - Drewes, Asbjørn Mohr

AU - Christrup, Lona Louring

AU - Kreilgaard, Mads

PY - 2015/1/23

Y1 - 2015/1/23

N2 - 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 30 mg 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 21 ng/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.

AB - 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 30 mg 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 21 ng/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.

U2 - 10.1016/j.ejps.2014.10.003

DO - 10.1016/j.ejps.2014.10.003

M3 - Journal article

C2 - 25315409

SN - 0928-0987

VL - 66

SP - 50

EP - 58

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

ER -

Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models

Abstract

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