Evaluation of Methadone-Induced QTc Prolongation in a Veteran Population

Discussion

The results of this study suggest that methadone-induced QTc interval prolongation may not be clearly evident at lower doses when used for pain. There was no significant increase in the QTc interval in the low-, medium-, and high-dose methadone groups, nor when analyzing the drug interactions. However, this study was powered based on the primary outcome, and it is possible that the study was underpowered to detect a difference in these secondary outcomes. When stratified by post-QTc, a significant increase in the QTc interval was noted for the group of patients with a post-QTc of 450 msec to 499 msec. The absolute mean differences between the pre-QTc and post-QTc for most of the secondary outcomes are unlikely to be clinically relevant, with the exception of the high-dose methadone group and the group stratified by post-QTc interval of 450 msec to 499 msec.

These results are supported by a prospective pilot study of 64 subjects with advanced cancer, which evaluated the QTc prolonging effects of methadone when used at lower doses (range 3-90 mg/d, median 23 mg/d).²⁶ Only 1 of 64 subjects developed clinically significant QTc interval prolongation (QTc ≥ 500 msec) at the end of the second week of therapy. The mean QTc interval measured at baseline was 427 msec, which increased to a mean of 430 msec after 2 weeks of methadone use (mean dose 23 mg/d) and decreased thereafter (375 msec at 4 weeks with a mean dose of 15 mg/d and 373 msec at 8 weeks with a mean dose 28 mg/d; no P values reported). Additionally, no significant association was found between methadone dose and the QTc interval (P > .05).

This study evaluated the surrogate endpoint of QTc prolongation and found that 2 patients with a pre-QTc < 500 msec (434 msec and 409 msec) had a post-QTc > 500 msec (518 msec and 547 msec). These subjects were both in the high-dose methadone group receiving 120 mg/d and 60 mg/d of methadone, respectively. It is unclear what confounders were present at the time of the post-QTc.

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The study did not evaluate clinically relevant outcomes such as TdP or SCD; however, there is evidence that methadone when used within a therapeutic dose range is associated with SCD.²⁷ In a prospective evaluation of SCD, 22 subjects using methadone found with therapeutic blood levels were compared with 106 subjects not using methadone. Most subjects were using methadone for pain control or opioid withdrawal. In 5 subjects (23%) in the methadone group, a cardiac abnormality (eg, coronary artery disease) that could have caused SCD was identified compared with 64 subjects (60%) in the group not using methadone (P = .002).

Limitations

There are several limitations of this study. This retrospective study does not allow for conclusions to be direct cause and effect, and the results relied on the EMR and methadone prescription fill dates to determine adherence to methadone, when methadone was initiated, and methadone daily dose. The exclusion criteria for the diagnosis of heart failure and the use of an implanted pacemaker and/or cardioverter defibrillator depended on the accuracy of the ICD-9 codes.

Also, many factors that affect the QTc interval were not assessed, such as potassium and magnesium levels, alcohol, cocaine, and amphetamine use. In addition, over-the-counter medications and medications obtained outside of SAVAHCS were not assessed. It is possible that any of those factors could be confounding variables. Furthermore, a majority of the subjects were male, and subjects with heart failure and those using an implanted pacemaker and/or cardioverter defibrillator were excluded from the study. In clinical practice, the results of the study cannot be generalized to those excluded patient populations. Additionally, the effect size of QTc prolongation observed was lower than was expected. Therefore, this study may not have been powered adequately to detect smaller differences in QTc prolongation.

Another limitation of the study is the high exclusion rate: about 90%. A majority of the patients were excluded due to the lack of ECG monitoring. The reason for obtaining an ECG was not assessed, and many subjects likely had an ECG obtained incidentally. Due to the high exclusion rate, selection bias may have been introduced into the study. Therefore, the 10% of subjects included in the study may not be representative of veterans using methadone for pain.

Very few studies of the effects of methadone on QTc prolongation in veterans have been published. A retrospective chart review by Fareed and colleagues sought to identify whether patients are at high risk for cardiac arrhythmias by adding an onsite ECG screening at baseline and annually for patients using methadone as part of a methadone maintenance program at the Atlanta VAMC.¹¹ The patients in the study were an average age of 56 years, and 93% were male. The mean daily methadone dose was 90 ± 48 mg/d, and the mean duration of treatment was 38 ± 31 months. The mean QTc interval was significantly longer at the most recent QTc interval while using methadone compared with the baseline QTc interval (442 ± 25 msec vs 417 ± 30 msec, respectively; P < .001). Six percent of patients had a significant prolongation of the QTc interval from baseline to > 500 msec, and 27% had a significant prolongation of the QTc interval from baseline to 450 msec to 500 msec (P < .05).