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: 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. (J Cardiovasc Electrophysiol, Vol. 23, pp. 527‐533, May 2012)