title: Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors.
abstract: 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 second((1/2)) 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.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, Geneva University Hospital, 24 Rue Micheli-du-Crest, CH-1211 Geneva 14, Switzerland.
authors.forename: Georg B
authors.initials: GB
authors.lastname: Ehret
authors.forename: Cathy
authors.initials: C
authors.lastname: Voide
authors.forename: Marianne
authors.initials: M
authors.lastname: Gex-Fabry
authors.forename: Jocelyne
authors.initials: J
authors.lastname: Chabert
authors.forename: Dipen
authors.initials: D
authors.lastname: Shah
authors.forename: Barbara
authors.initials: B
authors.lastname: Broers
authors.forename: Valérie
authors.initials: V
authors.lastname: Piguet
authors.forename: Thierry
authors.initials: T
authors.lastname: Musset
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Gaspoz
authors.forename: Arnaud
authors.initials: A
authors.lastname: Perrier
authors.forename: Pierre
authors.initials: P
authors.lastname: Dayer
authors.forename: Jules A
authors.initials: JA
authors.lastname: Desmeules
mesh_terms: D000293:Adolescent; D000328:Adult; D004562:Electrocardiography; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000453:epidemiology / Q000503:physiopathology; D008297:Male; D008691:Methadone / Q000009:adverse effects*; D008875:Middle Aged; D009294:Narcotics / Q000009:adverse effects*; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors; D015819:Substance Abuse, Intravenous / Q000534:rehabilitation*
chemical_list: D009294:Narcotics; D008691:Methadone