Abstract 13929: Methadone Lengthens Both Early and Late Ventricular Repolarization in Patients Undergoing Maintenance Therapy in an Urban Narcotic Treatment Center

Abstract

Introduction: Methadone, a racemic mixture of S - and R -enantiomers, prolongs the QT interval and causes torsades de pointes. Methadone has been shown to lengthen late ventricular repolarization, represented by the T peak-Tend interval, which is modulated primarily by I Kr and I Ks . However, it is unknown whether methadone prolongs early ventricular repolarization, represented by the heart rate-corrected J-T peak (J-T peak c) interval, which is regulated primarily by L-type calcium and late sodium currents. In addition, the relationship between stereospecific serum methadone and metabolite concentrations and effects on J-T peak c and T peak -T end intervals are unknown. Hypothesis: 1) Methadone lengthens both J-T peak c and T peak -T end , and 2) Methadone effects on J-T peak c and T peak -T end correlate with serum S - and R -methadone and S - and R -metabolite [ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP)] concentrations. Methods: Patients (n=81) on steady state maintenance methadone therapy at an urban narcotic treatment center who had undergone a pre-methadone 12-lead ECG within the previous 6 months were identified and asked to return for a followup ECG during steady-state methadone therapy. In a subset (n=41), blood was obtained to determine serum S - and R -methadone and S - and R -EDDP concentrations. Results: Compared to baseline, methadone lengthened mean ± SD J-T peak c (225 ± 26 vs 232 ± 28 ms, p=0.02) as well as T peak - T end (80 ±14 vs 90 ± 16 ms, p<0.00001). Serum concentrations of S -methadone correlated with J-T peak c [R 2 = 0.41 (95% CI 0.11-0.65), p=0.007]. Serum R -methadone concentrations also correlated with J-T peak c [R 2 = 0.47 (0.17-0.68), p=0.002]. In addition, serum concentrations of S - and R -EDDP correlated with J-T peak c [R 2 = 0.39 (0.09-0.63), p=0.01] and [R 2 = 0.38 (0.07-0.62), p=0.02], respectively. There were no significant correlations between serum S - and R -methadone or S- and R-EDDP concentrations with T peak - T end intervals. Conclusions: Methadone lengthens both early and late ventricular repolarization, suggesting that methadone’s ion channel effects may extend beyond inhibition of I Kr . Serum S - and R -methadone and S -and R -EDDP concentrations are associated with effects on J-T peak c intervals.