Methadone adverse reaction presenting with large increase in plasma methadone binding: A case series

Wenjie J. Lu, Weidong Zhou, Yvonne Kreutz, David A. Flockhart

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number513
JournalJournal of Medical Case Reports
Volume5
DOIs
StatePublished - Oct 11 2011

Fingerprint

Methadone
letrozole
Pharmacokinetics
Drug Interactions
Opiate Alkaloids
Blood Proteins
Clinical Protocols
Naloxone
Protein Binding
Respiratory Insufficiency
Analgesics
Cardiac Arrhythmias
Healthy Volunteers

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Methadone adverse reaction presenting with large increase in plasma methadone binding : A case series. / Lu, Wenjie J.; Zhou, Weidong; Kreutz, Yvonne; Flockhart, David A.

In: Journal of Medical Case Reports, Vol. 5, 513, 11.10.2011.

Research output: Contribution to journalArticle

Lu, Wenjie J. ; Zhou, Weidong ; Kreutz, Yvonne ; Flockhart, David A. / Methadone adverse reaction presenting with large increase in plasma methadone binding : A case series. In: Journal of Medical Case Reports. 2011 ; Vol. 5.
@article{dc5608d6988b4d9397fbd371ae4c098a,
title = "Methadone adverse reaction presenting with large increase in plasma methadone binding: A case series",
abstract = "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.",
author = "Lu, {Wenjie J.} and Weidong Zhou and Yvonne Kreutz and Flockhart, {David A.}",
year = "2011",
month = "10",
day = "11",
doi = "10.1186/1752-1947-5-513",
language = "English (US)",
volume = "5",
journal = "Journal of Medical Case Reports",
issn = "1752-1947",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Methadone adverse reaction presenting with large increase in plasma methadone binding

T2 - A case series

AU - Lu, Wenjie J.

AU - Zhou, Weidong

AU - Kreutz, Yvonne

AU - Flockhart, David A.

PY - 2011/10/11

Y1 - 2011/10/11

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80053609836&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053609836&partnerID=8YFLogxK

U2 - 10.1186/1752-1947-5-513

DO - 10.1186/1752-1947-5-513

M3 - Article

C2 - 21985665

AN - SCOPUS:80053609836

VL - 5

JO - Journal of Medical Case Reports

JF - Journal of Medical Case Reports

SN - 1752-1947

M1 - 513

ER -