Methadone on QT Interval
It is known that methadone, a long-acting synthetic opioid, prolongs the QTc interval in patients with opioid addiction . One previous study suggested that a QTc of > 500 ms was observed in 2% of patients who used > 100 mg of methadone per day, and sudden cardiac death associated with methadone use has been reported at a dose of 29 mg per day . These findings demonstrate that lethal arrhythmias could occur within a wide dose range. In contrast, one study indicated that significant QT prolongation was infrequent in pediatric patients with cancer . The safety of prescribing methadone to cancer patients remains unclear. If the QT interval is within 450–500 ms, methadone may be initiated or continued with frequent monitoring. For methadone-maintained patients with QT prolongation more than 500 ms, a risk minimization strategy should be strongly considered . In the current study, QT and QTc were slightly, but not significantly, prolonged. The current results suggest that low doses of methadone might not significantly prolong the QT or QTc.
Effects of Methadone on Cardiac Repolarization
Several studies have shown that increased QTD was associated with arrhythmogenicity. QTD and the QTD ratio (divided by cycle length and expressed as a percentage) in patients with acute myocardial infarction exhibiting ventricular fibrillation were significantly higher relative to those observed in patients with unstable angina . It has been reported that methadone led to modest increases in QTD and TpTe [5, 8]. The TpTe was associated with increased mortality (a cut-off value of 100 ms) . Moreover, prolongation of the TpTe interval was independently associated with sudden cardiac death when the QTc was normal or not measurable . In the present study, methadone prolonged TpTe, but not QTD, 2 months after treatment initiation (> 100 ms). Generally, QTD indicates the spatial dispersion of cardiac repolarization, whereas TpTe expresses the transmural dispersion of repolarization. Previous study indicated that TpTe could reflect local repolarization . Although the interpretation of these conflicting results remains uncertain, we hypothesize that these results arise owing to the following reasons: (1) sample size was inadequate to detect the spatial dispersion of cardiac repolarization; (2) we did not have multiple TpTe measurements that are required to detect the accurate transmural inhomogeneity; (3) TpTe was more easily influenced by QT prolongation than QTD. In terms of QT prolongation, TpTe/QT or TpTe/QTc may be more sensitive than TpTe. The present study emphasizes that even low doses of methadone might prolong the TpTe. Therefore, the possibility of arrhythmogenicity during the treatment of cancer pain using methadone should be considered.
There was no significant correlation between QT, QTc, QTD, or QTcD, and methadone dose. With respect to TpTe, there was no significant correlation between TpTe/QT or TpTe/QTc and methadone dose. In contrast, TpTe was significantly correlated with each dose of methadone. These contradictions might arise owing to the inadequate sample size of this study. Further study is essential for evaluating the correlation between cardiac repolarization and methadone dose. We suggest that the consideration should be given to discontinue the methadone-maintained patients with TpTe more than 100 ms.
Methadone has been approved in Japan since 2013. It is a comparatively novel opiate, therefore there is limited knowledge regarding the use of methadone in Japanese cancer patients. In the current explorative study, only a small sample of 19 patients was available. Unlike in other countries, there is no established treatment for opioid addiction. Moreover, the use of methadone is still restricted to refractory cancer pain in Japan. Therefore, the consumption of methadone did not increase compared to other countries. In addition, this study was a single-center, retrospective, observational study. To clarify the influence of methadone on cardiac repolarization, further analysis via multi-center prospective studies is essential.
It has been suggested that some cancer types may affect the QT interval. In the univariate logistic regression analysis, breast cancer and gastrointestinal cancer and their supportive drugs could affect QT prolongation . It is likely that the QT interval was affected by the peculiarity of cancer type in several cases in our study.