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Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series
INTRODUCTION: The use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depressio...
Autores principales: | , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2011
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201932/ https://www.ncbi.nlm.nih.gov/pubmed/21985665 http://dx.doi.org/10.1186/1752-1947-5-513 |
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author | Lu, Wenjie J Zhou, Weidong Kreutz, Yvonne Flockhart, David A |
author_facet | Lu, Wenjie J Zhou, Weidong Kreutz, Yvonne Flockhart, David A |
author_sort | Lu, Wenjie J |
collection | PubMed |
description | INTRODUCTION: The use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depression and cardiac arrhythmias. The mechanisms underlying these unpredictable effects are frequently unclear. Here, to the best of our knowledge we present the first report of an association between accidental methadone overexposure and increased plasma protein binding, a new potential mechanism for drug interactions with methadone. CASE PRESENTATION: We describe here the cases of two patients who experienced markedly different responses to the same dose of methadone during co-administration of letrozole. Both patients were post-menopausal Caucasian women who were among healthy volunteers participating in a clinical trial. Under the trial protocol both patients received 6 mg of intravenous methadone before and then after taking letrozole for seven days. One woman (aged 59) experienced symptoms consistent with opiate overexposure after the second dose of methadone that were reversed by naloxone, while the other (aged 49) did not. To understand the etiology of this event, we measured methadone pharmacokinetics in both patients. In our affected patient only, a fourfold to eightfold increase in methadone plasma concentrations after letrozole treatment was observed. Detailed pharmacokinetic analysis indicated no change in metabolism or renal elimination in our patient, but the percentage of unbound methadone in the plasma decreased 3.7-fold. As a result, the volume of distribution of methadone decreased approximately fourfold. The increased plasma binding in our affected patient was consistent with observed increases in plasma protein concentrations. CONCLUSIONS: The marked increase in the total plasma methadone concentration observed in our patient, and the enhanced pharmacodynamic effect, appear primarily due to a reduced volume of distribution. The extent of plasma methadone binding may help to explain the unpredictability of its pharmacokinetics. Changes in volume of distribution due to plasma binding may represent important causes of clinically meaningful drug interactions. |
format | Online Article Text |
id | pubmed-3201932 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2011 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-32019322011-10-27 Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series Lu, Wenjie J Zhou, Weidong Kreutz, Yvonne Flockhart, David A J Med Case Reports Case Report INTRODUCTION: The use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depression and cardiac arrhythmias. The mechanisms underlying these unpredictable effects are frequently unclear. Here, to the best of our knowledge we present the first report of an association between accidental methadone overexposure and increased plasma protein binding, a new potential mechanism for drug interactions with methadone. CASE PRESENTATION: We describe here the cases of two patients who experienced markedly different responses to the same dose of methadone during co-administration of letrozole. Both patients were post-menopausal Caucasian women who were among healthy volunteers participating in a clinical trial. Under the trial protocol both patients received 6 mg of intravenous methadone before and then after taking letrozole for seven days. One woman (aged 59) experienced symptoms consistent with opiate overexposure after the second dose of methadone that were reversed by naloxone, while the other (aged 49) did not. To understand the etiology of this event, we measured methadone pharmacokinetics in both patients. In our affected patient only, a fourfold to eightfold increase in methadone plasma concentrations after letrozole treatment was observed. Detailed pharmacokinetic analysis indicated no change in metabolism or renal elimination in our patient, but the percentage of unbound methadone in the plasma decreased 3.7-fold. As a result, the volume of distribution of methadone decreased approximately fourfold. The increased plasma binding in our affected patient was consistent with observed increases in plasma protein concentrations. CONCLUSIONS: The marked increase in the total plasma methadone concentration observed in our patient, and the enhanced pharmacodynamic effect, appear primarily due to a reduced volume of distribution. The extent of plasma methadone binding may help to explain the unpredictability of its pharmacokinetics. Changes in volume of distribution due to plasma binding may represent important causes of clinically meaningful drug interactions. BioMed Central 2011-10-10 /pmc/articles/PMC3201932/ /pubmed/21985665 http://dx.doi.org/10.1186/1752-1947-5-513 Text en Copyright ©2011 Lu et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Case Report Lu, Wenjie J Zhou, Weidong Kreutz, Yvonne Flockhart, David A Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series |
title | Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series |
title_full | Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series |
title_fullStr | Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series |
title_full_unstemmed | Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series |
title_short | Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series |
title_sort | methadone adverse reaction presenting with large increase in plasma methadone binding: a case series |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3201932/ https://www.ncbi.nlm.nih.gov/pubmed/21985665 http://dx.doi.org/10.1186/1752-1947-5-513 |
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