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JOHN STRINGER, PHARM.D., is Postgraduate Year 1 Resident, Pharmacy, Saint Barnabas Behavioral Health Center, Toms River, NJ. CHRISTOPHER WELSH, M.D., is Assistant Professor of Psychiatry, Department of Psychiatry, Division of Alcohol and Drug Abuse, School of Medicine; and ANTHONY TOMMASELLO, M.S., PH.D., is Associate Professor, Pharmaceutical Health Services Research, and Director, Office of Substance Abuse Studies, School of Pharmacy, University of Maryland, Baltimore.

Address correspondence to Dr. Stringer at the Pharmacy, Saint Barnabas Behavioral Health Center, 1691 U.S. Highway 9, CN 2025, Toms River, NJ 08754 (jstrin13{at}yahoo.com).

Purpose. The association of methadone with Q-T interval prolongation and torsades de pointes (TdP) is reviewed, and recommendations for preventing Q-T interval prolongation in methadone users are provided. Summary. Abnormalities in voltage-gated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given the high mortality rates seen in untreated illicit opioid users and the clear efficacy of methadone in treating opioid addiction, the risk of using methadone, even in a patient with other risk factors for Q-T interval prolongation, may outweigh the alternative of no pharmacologic treatment. A baseline electrocardiogram (ECG), personal and family history of syncope, and a complete medication history should be obtained before a patient begins treatment with methadone. Given the apparent synergistic effects of parenteral methadone and chlorobutanol, oral methadone should be used whenever possible. Conclusion. Q-T interval prolongation and TdP associated with the use of methadone are potentially fatal adverse effects. A thorough patient history and ECG monitoring are essential for patients treated with this agent, and alterations in treatment options may be necessary. Index terms: Dosage; Drug interactions; Electrocardiography; Long QT syndrome; Methadone; Mortality; Opiates; Sex; Torsades de pointes; Toxicity