Does Methadone Cause QT Interval Prolongation-Related Major Adverse Cardiac Events? A Systematic Review Protocol.

Abstract

Methadone is a long-acting synthetic opioid drug that has been used to treat opioid use disorder (OUD) for decades [1]. Previous evidence from Cochrane reviews has shown Methadone to be the gold standard for OUD management [2]. It is meant to replace ‘street opioids’ as a form of safe supply but also as a maintenance drug that can be slowly tapered over time [3]. In Canada and the United States, methadone remains one of the most commonly utilized medications for substance use disorder. Currently, more than 400,000 people in the United States access methadone maintenance therapy, a small fraction of those who would be eligible, compared to approximately 75,000 people in Canada [4,5].

The QT interval reflects electrical depolarization and repolarization of both ventricles of the heart on an electrocardiogram [6]. Methadone has been classified by CredibleMeds as a medication with a “known” risk of QT interval prolongation (QTP) [7]. Excessive prolongation of the QT interval predisposes patients to ventricular arrhythmia including torsades de pointes (TdP), and sudden cardiac death [7]. Based on FDA recommendations, we have defined QT-prolongation-related major adverse cardiac events (MACE) as all-death, non-fatal cardiac arrest, ventricular arrhythmia (ventricular tachycardia, ventricular fibrillation and TdP), syncope, or seizure [8,9]. Interruptive warnings about the QT-prolonging effect of ‘known’ QT-prolonging medications in electronic medical records and pharmacy systems are ubiquitous in most developed countries [10]. A landmark systematic review on the effect of computerized decision support including medication decision support, showed no meaningful benefit on patient outcomes [11]. Meanwhile every time a QT- prolonging medication such as methadone is prescribed or dispensed, an interruptive alert is posted to the providers about the risk of MACE. There is a very high override rate of these alerts because of lack of high-quality evidence supporting the alert and lack of incorporation of patient-specific information including the QTc [12]. Medication alerts have also been harmful in some instances, leading to inferior substitution prescribing and more broadly producing a time and decisional conflict burden for providers [10].

Our research group has been systematically reviewing the high-quality evidence on commonly used medications listed as ‘known’ QT-prolonging drugs [8,13-16]. None of these so far has demonstrated an increased risk of MACE compared to placebo. Given the expanding use of methadone in recent years in a population thought to be vulnerable to adverse health outcomes and with limited access to formal health care, the cardiac safety profile of this medication is a concern for clinicians, policymakers, and patients alike. The true incidence of QTP-related major adverse cardiac events (MACE) caused by methadone is unknown.

A preliminary search was conducted in Ovid MEDLINE and Embase to identify any recent systematic reviews or studies addressing our research question. The search yielded over 1,000 records, of which only one appeared potentially comparable. However, this publication is an older narrative review on mechanisms and clinical outcomes and includes all study designs so does not answer our research question [17]. Consequently, there appears to be a notable gap in the current evidence base, supporting the need for the present systematic review to address this underexplored area.