Although opioid-related death is generally attributed to respiratory depression from overdose, methadone has been associated with QTc interval prolongation and torsade de pointes. As there is uncertainty about the clinical relevance of QTc prolongation and the frequency of arrhythmia events, the authors evaluated the FDA Adverse Event Reporting System (FAERS) database (November 1997 to June 2011) for a signal of disproportionate reporting of QTc prolongation or torsade de pointes associated with methadone relative to other opioids and antiarrhythmic drugs.
Of methadone-associated adverse events, 1646 (14.9%) involved ventricular arrhythmia or cardiac arrest and 379 (3.4%) involved QTc prolongation or torsade de pointes. Monthly reports of QTc prolongation or torsade de pointes increased following publication of a report describing an association between methadone and arrhythmia (from a mean of 0.3 to a mean of 3.5). The proportional reporting ratio (PRR; fraction of reports involving the reaction of interest for a given drug by the fraction of reports involving the reaction of interest for all other drugs) for methadone and QTc prolongation or torsade de pointes from 1997 to 2011 was well above the significance threshold conventionally assigned to the measure (11.2 [CI, 10.2 to 12.4]) and similar to that for sotalol, amiodarone and dofetilide. Antiretroviral drugs for HIV were the most frequently reported concomitant medications for QTc prolongation or torsade de pointes. Death occurred in 80.9% of ventricular arrhythmia or cardiac arrest cases and 11.1% of cases involving QTc prolongation or torsade de pointes.
The authors say that the increasing frequency of reports of these adverse effects may be due to increased awareness among clinicians, but they suggest that it is also due to other factors - for example increased prescribing, and methadone-related deaths being attributed to a cardiac rather than a respiratory cause. They are unable to determine what the actual determining factors are from their results, but nevertheless they suggest that arrhythmia is an ‘underappreciated contributor to methadone-related morbidity and mortality’.
The limitations discussed include the following:
• The reports to FAERS are voluntary (actual incidence cannot be determined) and reports are not independently adjudicated (e.g. QTc prolongation could have been inaccurately assessed)
• The PRR can be affected by confounding factors
• Increases in adverse event reporting do not necessarily indicate increases in incidence, so causality cannot be established
Based on their findings, the authors propose that a risk evaluation and mitigation strategy (REMS) specific to methadone and designed to reduce arrhythmia may be appropriate.