Substitution of (R,S)-methadone by (R)-methadone: Impact on QTc interval.

Détails

ID Serval
serval:BIB_2447D2DCD9A6
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Substitution of (R,S)-methadone by (R)-methadone: Impact on QTc interval.
Périodique
Archives of internal medicine
Auteur⸱e⸱s
Ansermot N., Albayrak O., Schläpfer J., Crettol S., Croquette-Krokar M., Bourquin M., Déglon J.J., Faouzi M., Scherbaum N., Eap C.B.
ISSN
1538-3679 (Electronic)
ISSN-L
0003-9926
Statut éditorial
Publié
Date de publication
22/03/2010
Peer-reviewed
Oui
Volume
170
Numéro
6
Pages
529-536
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
Methadone is administered as a chiral mixture of (R,S)-methadone. The opioid effect is mainly mediated by (R)-methadone, whereas (S)-methadone blocks the human ether-à-go-go-related gene (hERG) voltage-gated potassium channel more potently, which can cause drug-induced long QT syndrome, leading to potentially lethal ventricular tachyarrhythmias.
To investigate whether substitution of (R,S)-methadone by (R)-methadone could reduce the corrected QT (QTc) interval, (R,S)-methadone was replaced by (R)-methadone (half-dose) in 39 opioid-dependent patients receiving maintenance treatment for 14 days. (R)-methadone was then replaced by the initial dose of (R,S)-methadone for 14 days (n = 29). Trough (R)-methadone and (S)-methadone plasma levels and electrocardiogram measurements were taken.
The Fridericia-corrected QT (QTcF) interval decreased when (R,S)-methadone was replaced by a half-dose of (R)-methadone; the median (interquartile range [IQR]) values were 423 (398-440) milliseconds (ms) and 412 (395-431) ms (P = .06) at days 0 and 14, respectively. Using a univariate mixed-effect linear model, the QTcF value decreased by a mean of -3.9 ms (95% confidence interval [CI], -7.7 to -0.2) per week (P = .04). The QTcF value increased when (R)-methadone was replaced by the initial dose of (R,S)-methadone for 14 days; median (IQR) values were 424 (398-436) ms and 424 (412-443) ms (P = .01) at days 14 and 28, respectively. The univariate model showed that the QTcF value increased by a mean of 4.7 ms (95% CI, 1.3-8.1) per week (P = .006).
Substitution of (R,S)-methadone by (R)-methadone reduces the QTc interval value. A safer cardiac profile of (R)-methadone is in agreement with previous in vitro and pharmacogenetic studies. If the present results are confirmed by larger studies, (R)-methadone should be prescribed instead of (R,S)-methadone to reduce the risk of cardiac toxic effects and sudden death.

Mots-clé
Adult, Aged, Analgesics, Opioid/administration & dosage, Electrocardiography/drug effects, Female, Heart Conduction System/drug effects, Humans, Isomerism, Male, Methadone/administration & dosage, Middle Aged
Pubmed
Web of science
Open Access
Oui
Création de la notice
24/03/2010 12:06
Dernière modification de la notice
20/08/2019 13:02
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