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STUDY OBJECTIVE Methadone is associated with QT interval prolongation and torsades de pointes. The objective of this study was to (a) determine the incidence of QT interval prolongation among patients on maintenance methadone therapy in an urban opioid treatment program (OTP), (b) compare characteristics of patients who developed methadone-associated QT prolongation with those who did not develop QT prolongation, and (c) investigate the relationship between QT interval prolongation and stereospecific serum methadone and metabolite [2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations. DESIGN Prospective study. SETTING Urban opioid treatment program (OTP). PATIENTS n = 93 patients on maintenance methadone therapy in an urban OTP. INTERVENTION Patients underwent a 12-lead electrocardiogram (ECG) prior to initiating methadone and again during steady-state maintenance methadone therapy. In a subset (n = 43), blood was obtained to determine serum (S)- and (R)-methadone and (S)- and (R)-EDDP concentrations, which were compared in patients who developed Bazett's-corrected QT (QTc) prolongation [≥470 ms (men) or ≥480 ms (women) and/or ≥60 ms lengthening from pretreatment value] with those who did not have QTc prolongation. MEASUREMENTS AND MAIN RESULTS Mean [± standard deviation (SD)] age was 36 ± 12 years; 73% were female, and 74% were white. QTc prolongation occurred in 14 (15.1%) patients. Patients who developed QTc prolongation were older (41 ± 13 vs. 35 ± 9 years, p = 0.03) and had a longer pre-methadone QTc compared with those who did not have QTc prolongation (429 ± 11 vs. 420 ± 20 ms, respectively, p = 0.02). Serum (S)-methadone concentrations were higher in patients with QTc prolongation compared to patients without prolongation (199 ± 81 vs. 128 ± 68 ng/ml, respectively, p = 0.01), whereas the difference in serum (R)-methadone concentrations between the groups did not reach significance (189 ± 68 vs. 125 ± 60 ng/ml, respectively, p = 0.08). Serum (R)-methadone concentrations correlated with QTc intervals [R2 = 0.15 (95% confidence interval (CI) 0.11-0.62, p = 0.0009)]. The correlation between serum (S)-methadone concentrations and QTc did not reach significance [R2 = 0.08 (95% CI -0.01 to 0.54, p = 0.06)]. Serum (S)-and (R)-EDDP concentrations were not significantly different between the groups and did not significantly correlate with QTc intervals. CONCLUSIONS Approximately 15% of patients taking maintenance methadone therapy developed QT interval prolongation. Both serum (S)- and (R)-methadone concentrations, but not (S)- or (R)-EDDP, contribute to methadone-associated QT prolongation.