Ansermot Nicolas, Albayrak Ozgür, Schläpfer Jürg, Crettol Séverine, Croquette-Krokar Marina, Bourquin Michel, Déglon Jean-Jacques, Faouzi Mohamed, Scherbaum Norbert, Eap Chin B
Center for Psychiatric Neurosciences, Department of Psychiatry, Hospital of Cery, Prilly-Lausanne, Switzerland.
Arch Intern Med. 2010 Mar 22;170(6):529-36. doi: 10.1001/archinternmed.2010.26.
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.
美沙酮是以（R，S）-美沙酮的手性混合物形式给药。阿片样物质效应主要由（R）-美沙酮介导，而（S）-美沙酮更有效地阻断人类醚-à-去极化相关基因（hERG）电压门控钾通道，这可导致药物性长QT综合征，进而引发潜在致命的室性快速心律失常。
为研究用（R）-美沙酮替代（R，S）-美沙酮是否可缩短校正QT（QTc）间期，在39例接受维持治疗的阿片类药物依赖患者中，用（R）-美沙酮（半量）替代（R，S）-美沙酮14天。之后再用初始剂量的（R，S）-美沙酮替代（R）-美沙酮14天（n = 29）。同时测定（R）-美沙酮和（S）-美沙酮的谷血浆水平及进行心电图测量。
当用半量的（R）-美沙酮替代（R，S）-美沙酮时，弗里德里西亚校正QT（QTcF）间期缩短；第0天和第14天的中位数（四分位间距[IQR]）值分别为423（398 - 440）毫秒（ms）和412（395 - 431）ms（P = 0.06）。采用单变量混合效应线性模型，每周QTcF值平均降低-3.9 ms（95%置信区间[CI]，-7.7至-0.2）（P = 0.04）。当用初始剂量的（R，S）-美沙酮替代（R）-美沙酮14天时，QTcF值升高；第14天和第28天的中位数（IQR）值分别为424（398 - 436）ms和424（412 - 443）ms（P = 0.01）。单变量模型显示，每周QTcF值平均升高4.7 ms（95% CI，1.3 - 8.1）（P = 0.006）。
用（R）-美沙酮替代（R，S）-美沙酮可降低QTc间期值。（R）-美沙酮更安全的心脏特性与先前的体外和药物遗传学研究结果一致。如果本研究结果能被更大规模研究证实，应开具（R）-美沙酮而非（R，S）-美沙酮以降低心脏毒性作用和猝死风险。
