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Published in: Critical Care 1/2007

Open Access 01-02-2007 | Research

Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships

Authors: Bruno Mégarbane, Xavier Declèves, Vanessa Bloch, Christophe Bardin, François Chast, Frédéric J Baud

Published in: Critical Care | Issue 1/2007

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Abstract

Introduction

Methadone, the most widely delivered maintenance therapy for heroin addicts, may be responsible for life-threatening poisonings with respiratory depression. The toxicokinetics and the toxicokinetic/toxicodynamic (TK/TD) relationships of methadone enantiomers have been poorly investigated in acute poisonings. The aim of this study was to describe the relationships between methadone-related respiratory effects and their corresponding concentrations.

Methods

We report a 44-year-old methadone-maintained patient who ingested a 240-mg dose of methadone. He was found comatose with pinpoint pupils and respiratory depression. He was successfully treated with intravenous naloxone infusion over the course of 31 hours at a rate adapted to maintain normal consciousness and respiratory rate. We performed a TK/TD analysis of the naloxone infusion rate needed to maintain his respiratory rate at more than 12 breaths per minute (as toxicodynamics parameter) versus plasma R,S- and R-methadone concentrations (as toxicokinetics parameter), determined using an enantioselective high-performance liquid chromatography assay.

Results

Initial plasma R,S-methadone concentration was 1,204 ng/ml. Decrease in plasma R- and S-methadone concentrations was linear and demonstrated a first-order pharmacokinetics (maximal observed concentrations 566 and 637 ng/ml, half-lives 16.1 and 13.2 hours, respectively). TK/TD correlation between naloxone infusion rate and R,S- and R- methadone concentrations fitted well a sigmoidal E max model (concentration associated with a half-maximum effect [EC50] 334 and 173 ng/ml, Hill coefficient 10.0 and 7.8, respectively). In our chronically treated patient, EC50 values were in the range of previously reported values regarding methadone analgesic effects, suggesting that plasma methadone concentrations to prevent withdrawal are lower than those associated with methadone analgesic effects.

Conclusion

After the ingestion of a toxic dose of a racemic mixture, plasma R- and S-enantiomer concentrations decreased in parallel. Despite large inter-individual variability in methadone toxicokinetics and toxicodynamics, TK/TD relationships would be helpful for providing quantitative data regarding the respiratory response to methadone in poisonings. However, further confirmatory TK/TD data are needed.
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Metadata
Title
Case report: quantification of methadone-induced respiratory depression using toxicokinetic/toxicodynamic relationships
Authors
Bruno Mégarbane
Xavier Declèves
Vanessa Bloch
Christophe Bardin
François Chast
Frédéric J Baud
Publication date
01-02-2007
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2007
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc5150

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