Prevalence of long QTc interval in methadone maintenance patients

Abstract

Background

There is a concern about cardiac rhythm disorders related to QTc interval prolongation induced by methadone. A cross-sectional study was designed to evaluate the prevalence of long QTc (LQTc) interval in patients in methadone maintenance treatment (MMT) and risk factors for LQTc.

Methods

The study population included 109 subjects (74 males, median age 43 years). Socio-demographic and toxicological variables were recorded, as well as concomitant use of drugs related with QT prolongation, history of heart diseases, and corrected QT interval by heart rate (QTc) in the ECG. Plasma concentrations of (R)-methadone and (S)-methadone enantiomers were determined in 69 subjects.

Results

Ten patients (9.2%) presented a QTc above 440 ms but a QTc above 500 ms was observed in only 2 (1.8%). Patients with QTc above 440 ms compared with the remaining subjects were older (median [25th–75th percentile range]: 49 [39–56] years vs. 37 [33–43]; Wilcoxon's W = 217.5, p = 0.002) and took a higher daily dose of methadone (median [25th–75th percentile range]: 120 [66–228] mg/day vs. 60 [40–110] mg/day; W = 298.5, p = 0.037). Methadone dose correlated with QTc interval (Pearson's r² = 0.291, p = 0.002). Patients with and without long QTc showed no differences in plasma concentrations of (R)-methadone and (S)-methadone enantiomers.

Conclusions

The prevalence of LQTc was 9.2%. An association between LQTc and methadone doses was observed but the relationship with plasma concentrations of methadone enantiomers is unclear.

Introduction

Although there is an increase in life expectancy of heroin users with the introduction of methadone maintenance treatment (MMT) programs (Brugal et al., 2005), there is concern about two important side effects associated with this drug: respiratory depression caused by overdose and cardiac rhythm disorders related to QT interval prolongation (Chugh et al., 2008). QT prolongation can be associated with a congenital long-QT syndrome caused by gene mutations, drug administration, or ionic disorder (Roden, 2008). A QT interval longer than 500 ms increases the risk of polymorphic ventricular tachycardia, as Torsade de pointes (TdP) (Schwartz et al., 1993).

After the initial report by Krantz et al. (2002), other authors have described QT prolongation and/or TdP appearance in MMT (Martell et al., 2003, Krantz et al., 2005, Maremmani et al., 2005, Fredheim et al., 2006, Justo et al., 2006, Peles et al., 2007, Chugh et al., 2008). The mechanism of this increase is related to the inhibitory action of methadone on the hERG voltage-gated potassium channel. It could also be due to the blockade of calcium channels in the cardiac myocyte membrane and the induction of bradycardia (Kornick et al., 2003).

Methadone is a chiral molecule usually administered as a racemate, a 50:50 mixture of two enantiomers ((R)-methadone, and (S)-methadone). (R)-Methadone has a higher affinity for opioid receptors and a greater analgesic potency than the (S)-enantiomer (Eap et al., 2002). Enantiomeric differences are also relevant in protein binding and metabolic disposition. The (R)-/(S)-methadone ratio varies significantly over the 24 h administration interval in steady-state conditions (Foster et al., 2004), and large inter-individual differences can be seen in the (R)-/(S)-methadone ratio (Eap et al., 1996). Despite lacking strong opioid effects, (S)-methadone may be clinically important in adverse responses to (R,S)-methadone as it has been associated with negative mood effects (Mitchell et al., 2004). A recent report described that (S)-methadone could be responsible for QT prolongation effects because it is a stronger blocker of the hERG channel (Eap et al., 2007).

We have designed a cross-sectional study to: (1) evaluate the prevalence of long QTc interval in a low-threshold MMT program; (2) study the possible risk factors associated with the long QTc, paying special attention to methadone dosage and (R)-, (S)- and (R,S)-methadone plasma concentrations.