Evaluation of Methadone-Induced QTc Prolongation in a Veteran Population

Estimates of the annual incidence of sudden cardiac death (SCD) vary from 180,000 to  456,000.¹ About 80% to 85% of the cases of SCD are due to a ventricular arrhythmia.² One type of ventricular arrhythmia, torsades de pointes (TdP), is caused by a prolongation of the QT interval. Because the QT interval is dependent on heart rate, clinicians use the corrected QT (QTc) interval, which has been adjusted for heart rate. The HHS recommends using a gender-independent threshold of 450 msec to define QTc prolongation when conducting research.³ Additionally, a QTc interval > 500 msec is associated with an increased risk for TdP.⁴ Female gender, hypokalemia, hypomagnesemia, and medical conditions such as congenital long QT syndrome, heart failure, and left ventricular hypertrophy can predispose a person to QTc prolongation.⁵

Methadone is a synthetic opioid used for chronic pain management or for opioid or heroin addiction. In 2006, the FDA issued a public health advisory, which was followed by the addition of a black box warning to the labeling of methadone regarding cardiac abnormalities that caused serious adverse effects, including QT prolongation, TdP, and death.⁶ Additional recommendations to evaluate the pharmacokinetic and pharmacodynamic drug interactions were also added to the labeling.

Related: Reducing Opioid Use for Chronic Pain

Several prospective studies, cross-sectional studies, and retrospective reviews have reported QTc prolongation with methadone.^7-14 Many cases of QTc prolongation and TdP have been in patients receiving methadone in large doses (> 100 mg/d); however, incidences have also occurred in those receiving typical doses of methadone for addiction treatment.^8,15,16 Multiple studies have demonstrated that methadone-induced QTc prolongation is dose-dependent.^8,17-20 In an observational study of 90 subjects who were undergoing methadone maintenance treatment, the subjects taking < 60 mg/d of methadone had a 7.7 msec prolongation of the QTc interval, which was significantly less QTc prolongation than in those receiving 60 mg/d to 109 mg/d (15.6 msec, P < .001) and 110 mg/d to 150 mg/d (17.4 msec, P = .001).²¹

However, in the current literature there are few studies evaluating the QTc prolonging effects of methadone when used in lower doses for pain, such as those used at the Southern Arizona VA Health Care System (SAVAHCS).⁸ Given the increased risk of cardiac arrhythmias, it is important to understand the effects of methadone on the QTc interval in a veteran patient population using methadone at lower doses for pain. Understanding this risk can help clinicians develop strategies and protocols for the safe use of methadone.

The purpose of this study was to evaluate the effect of methadone on the QTc interval among patients at SAVAHCS. The primary objective was to determine whether methadone prolongs the QTc interval when used for pain. Secondary outcomes included evaluations of the (1) QTc interval when stratified by the QTc interval obtained while prescribed methadone; (2) effects of low, medium, and high doses of methadone on the QTc interval; (3) effects of the concurrent use of QTc prolonging medications on the QTc interval; and (4) effects of the concurrent use of strong inhibitors of methadone clearance on the QTc interval. It was hypothesized that methadone, when used for pain, causes a significant prolongation of the QTc interval, and methadone-induced QTc prolongation is dose-dependent. It was also hypothesized that the QTc interval will be more prolonged when methadone is used concurrently with other medications with a known or conditional risk of TdP or with medications that are strong inhibitors of methadone clearance.

Methods

Full Institutional Review Board approval was obtained prior to initiating this retrospective pre-post study. This study used the electronic medical records (EMRs) of SAVAHCS from July 1, 2004, to July 31, 2012, to compare the QTc interval of patients on stable doses of methadone with the baseline QTc interval. Patients included were aged 18 to 87 years and dispensed a new prescription for methadone between January 1, 2006, and July 31, 2010. Patients must have been adherent to methadone as defined by a medication possession ratio of ≥ 0.8. Patients without a baseline electrocardiogram (ECG) within the 18 months prior to starting methadone, without at least 1 follow-up ECG 7 days to 2 years after the initial prescription, who had a diagnosis of heart failure, or used an implanted cardiac defibrillator or pacemaker as indicated by ICD-9 codes were excluded.

Information collected from the EMR included demographics (age and gender), the QTc interval before starting methadone (pre-QTc), the first QTc interval recorded while prescribed methadone (post-QTc) at a stable dose (defined as ≥ 7 days without a dose change), methadone total daily dose at the time of the post-QTc, concurrent QTc prolonging medications used at the time of each ECG, time elapsed between pre-QTc and post-QTc, time elapsed between the pre-QTc and initiation of methadone, and time elapsed between starting methadone and the post-QTc. All ECGs were recorded using a 12-lead ECG by the MAC 5500 Resting ECG Analysis System (GE Healthcare), which automatically calculates the QTc interval.