Gender-Specific Differences in Susceptibility to Low-Dose Methadone-Associated QTc Prolongation in Patients with Heroin Dependence

Methadone and QT Prolongation. 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: 36288 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: 3244 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: 3060 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. (J Cardiovasc Electrophysiol, Vol. 23, pp. 527-533, May 2012)