Quantifying the Pharmacodynamics of Morphine in the Treatment of Postoperative Pain in Preverbal Children

Sebastiaan C. Goulooze, Tirsa de Kluis, Monique van Dijk, Ilse Ceelie, Saskia N. de Wildt, Dick Tibboel, Elke H.J. Krekels, Catherijne A.J. Knibbe*

*Corresponding author for this work

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Abstract

While the pharmacokinetics of morphine in children have been studied extensively, little is known about the pharmacodynamics of morphine in this population. Here, we quantified the concentration-effect relationship of morphine for postoperative pain in preverbal children between 0 and 3 years of age. For this, we applied item response theory modeling in the pharmacokinetic/pharmacodynamic analysis of COMFORT-Behavior (COMFORT-B) scale data from 2 previous clinical studies. In the model, we identified a sigmoid maximal efficacy model for the effect of morphine and found that in 26% of children, increasing morphine concentrations were not associated with lower pain scores (nonresponders to morphine up-titration). In responders to morphine up-titration, the COMFORT-B score slowly decreases with increasing morphine concentrations at morphine concentrations >20 ng/mL. In nonresponding children, no decrease in COMFORT-B score is expected. In general, lower baseline COMFORT-B scores (2.1 points on average) in younger children (postnatal age <10.3 days) were found. Based on the model, we conclude that the percentage of children at a desirable COMFORT-B score is maximized at a morphine concentration between 5 and 30 ng/mL for children aged <10 days, and between 5 and 40 ng/mL for children >10 days. These findings support a dosing regimen previously suggested by Krekels et al, which would put >95% of patients within this morphine target concentration range at steady state. Our modeling approach provides a promising platform for pharmacodynamic research of analgesics and sedatives in children.

Original languageEnglish
Pages (from-to)99-109
Number of pages11
JournalJournal of Clinical Pharmacology
Volume62
Issue number1
Early online date12 Aug 2021
DOIs
Publication statusPublished - Jan 2022

Bibliographical note

Funding Information:
The authors declare no potential conflicts of interest. Catherijne A.J. Knibbe was supported during this study by Innovational Research Incentives Scheme (Vidi grant, June 2013) of the Netherlands Organization for Scientific Research. One of the clinical studies analyzed here (study 2, by Ceelie et al) was supported by ZonMw Priority Medicines for Children grant 40‐41500‐98.9020. Remaining support was provided from institutional and departmental sources.

Publisher Copyright:
© 2021 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology

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