title: Gender-specific differences in susceptibility to low-dose methadone-associated QTc prolongation in patients with heroin dependence.
abstract: BACKGROUND
  Methadone is associated with QTc prolongation and sudden death in susceptible patients. We sought to investigate whether there is a gender-based difference in susceptibility to methadone-associated QTc prolongation in heroin-dependent patients receiving a low-dose treatment regimen.
  
  
  METHODS
  A cross-sectional assessment of dose and gender effects was performed in 283 patients (229 males, 54 females) who received a 12-lead ECG for QTc measurement 59 days (interquartile range: 36-288 days) after methadone treatment. To determine the effects of methadone over time, a subset of 150 participants (126 men, 24 women) who underwent a 12-lead ECG before and 37 days (interquartile range: 32-44 days) after methadone treatment were selected.
  
  
  RESULTS
  In the cross-sectional study, a significant dose-dependent interaction between methadone and QTc (r = 0.201, P = 0.0007) was observed in individuals receiving a median methadone dose of 40 mg/day (interquartile range: 30-60 mg/day). The methadone-QTc correlation was significant in males (r = 0.210, P = 0.0014) but not in females (r = 0.164, P = 0.2363). The longitudinal assessment of methadone's effects over a 6-month period showed that 60.7% of individuals experienced an increase in QTc compared to baseline data. The adjusted QTc significantly increased from 418.5 to 426.9 milliseconds in males (P < 0.0001), compared to an insignificant change in females (437.7 milliseconds vs 441.1 milliseconds, P = 0.468).
  
  
  CONCLUSIONS
  Low-dose methadone therapy shows dose-dependent QTc prolongation and is associated with significant QTc lengthening within 6 months of treatment initiation. Men are more susceptible than women to low-dose methadone-associated QTc prolongation.
authors.affiliation: Division of Cardiology, Department of Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Kuan-Cheng
authors.initials: KC
authors.lastname: Chang
authors.forename: Chieh-Liang
authors.initials: CL
authors.lastname: Huang
authors.forename: Hsin-Yueh
authors.initials: HY
authors.lastname: Liang
authors.forename: Shih-Sheng
authors.initials: SS
authors.lastname: Chang
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Wang
authors.forename: Wen-Miin
authors.initials: WM
authors.lastname: Liang
authors.forename: Hsien-Yuan
authors.initials: HY
authors.lastname: Lane
authors.forename: Chu-Huang
authors.initials: CH
authors.lastname: Chen
authors.forename: Shoei K
authors.initials: SK
authors.lastname: Stephen Huang
mesh_terms: D000200:Action Potentials; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D002681:China; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology; D006556:Heroin Dependence / Q000534:rehabilitation*; D006801:Humans; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology; D008137:Longitudinal Studies; D008297:Male; D008691:Methadone / Q000008:administration & dosage / Q000009:adverse effects*; D008875:Middle Aged; D058850:Opiate Substitution Treatment / Q000009:adverse effects*; D011237:Predictive Value of Tests; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D008691:Methadone