Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone: High Frequency in Hospitalized Patients and Risk Factors | Cardiology | JAMA Internal Medicine | JAMA Network
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Original Investigation
June 26, 2006

Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone: High Frequency in Hospitalized Patients and Risk Factors

Author Affiliations

Author Affiliations: Divisions of Clinical Pharmacology and Toxicology (Drs Ehret, Voide, Chabert, Piguet, Dayer, and Desmeules), General Internal Medicine (Drs Ehret, Gaspoz, and Perrier), and Cardiology (Dr Shah) and Departments of Psychiatry, Clinical Research Unit (Dr Gex-Fabry) and Community Health (Dr Broers and Mr Musset), Geneva University Hospital, Geneva, Switzerland. Dr Ehret is currently with the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Md.

Arch Intern Med. 2006;166(12):1280-1287. doi:10.1001/archinte.166.12.1280

Background  Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown.

Methods  We performed a systematic, retrospective study comparing active or former intravenous drug users receiving methadone and those not receiving methadone among all patients hospitalized over a 5-year period in a tertiary care hospital. A total of 167 patients receiving methadone fulfilled the inclusion criteria and were compared with a control group of 80 injection drug users not receiving methadone. In addition to methadone dose, 15 demographic, biological, and pharmacological variables were considered as potential risk factors for QT prolongation.

Results  Among 167 methadone maintenance patients, the prevalence of QTc prolongation to 0.50 second½ or longer was 16.2% compared with 0% in 80 control subjects. Six patients (3.6%) in the methadone group presented torsades de pointes. QTc length was weakly but significantly associated with methadone daily dose (Spearman rank correlation coefficient, 0.20; P<.01). Multivariate regression analysis allowed attribution of 31.8% of QTc variability to methadone dose, cytochrome P-450 3A4 drug-drug interactions, hypokalemia, and altered liver function.

Conclusions  QT interval prolongation in methadone maintenance patients hospitalized in a tertiary care center is a frequent finding. Methadone dose, presence of cytochrome P-450 3A4 inhibitors, potassium level, and liver function contribute to QT prolongation. Long QT syndrome can occur with low doses of methadone.