Levo-alpha-acetylmethadol (LAAM) induced QTc-prolongation - results from a controlled clinical trial

Abstract

Background: Due to potential proarrhythmic side-effects levo-alpha-Acetylmethadol (LAAM) is currently not available in EU countries as maintenance drug in the treatment of opiate addiction. However, recent studies and meta-analyses underline the clinical advantages of LAAM with respect to the reduction of heroin use. Thus a reappraisal of LAAM has been demanded. The aim of the present study was to evaluate the relative impact of LAAM on QTc-interval, as a measure of pro-arrhythmic risk, in comparison to methadone, the current standard in substitution therapy.

Methods: ECG recordings were analysed within a randomized, controlled clinical trial evaluating the efficacy and tolerability of maintenance treatment with LAAM compared with racemic methadone. Recordings were done at two points: 1) during a run-in period with all patients on methadone and 2) 24 weeks after randomisation into methadone or LAAM treatment group. These ECG recordings were analysed with respect to QTc-values and QTc-dispersion. Mean values as well as individual changes compared to baseline parameters were evaluated. QTc-intervals were classified according to CPMP-guidelines.

Results: Complete ECG data sets could be obtained in 53 patients (31 LAAM-group, 22 methadone-group). No clinical cardiac complications were observed in either group. After 24 weeks, patients receiving LAAM showed a significant increase in QTc-interval (0.409s +/- 0.022s versus 0.418s +/- 0.028s, p = 0.046), whereas no significant changes could be observed in patients remaining on methadone. There was no statistically significant change in QTc-dispersion in either group. More patients with borderline prolonged and prolonged QTc-intervals were observed in the LAAM than in the methadone treatment group (n = 7 vs. n = 1; p = 0.1).

Conclusions: In this controlled trial LAAM induced QTc-prolongation in a higher degree than methadone. Given reports of severe arrhythmic events, careful ECG-monitoring is recommended under LAAM medication.

Figure 1

Study design. ECG recordings were done at the beginning of the run-in period and at the end of the treatment period.

Figure 2

Comparison of QTc intervals between run-in and treatment phase separately analysed for the methadone-and LAAM-group. Mean ± SD.

Figure 3

Comparison of QT-dispersion between run-in and treatment phase separately analysed for the methadone-and LAAM-group. Mean ± SD.