1 Introduction

Methadone, a long-acting synthetic opioid, is an effective maintenance therapy for opioid addiction [1]. Methadone, like most medications that prolong the QT interval, blocks the cardiac IKr channel and prolongs the action potential [2]. An increasing number of cases of methadone-associated Torsades de Pointes (TdP) have been reported over the last several years [3–11]. We present a retrospective case series of patients on methadone maintenance treatment (MMT) with QT prolongation (QTP) and ventricular arrhythmias.

2 Materials and methods

Beth Israel Medical Center is a tertiary care, urban hospital with the largest MMT program in the United States. It services 6,500 MMT patients in 18 clinics across New York City. All MMT patients with QT prolongation and ventricular arrhythmias admitted to our hospital between July 2007 and April 2009 were included. Follow-up information was obtained for clinical purposes from the MMT programs and via phone interview with the patients.

3 Results

Twelve consecutive patients admitted to our Cardiology service at Beth Israel Medical Center (nine men, mean age 53.9 ± 5.4 years) with methadone-associated QTP and ventricular arrhythmias were included (Fig. 1). One of these patients has been previously reported [3]. Clinical characteristics are delineated in Table 1. ECG or telemetry documentation of arrhythmia was available in all patients. Eight patients had an additional predisposing factor for ventricular arrhythmias (four with electrolyte abnormalities, four with other QT prolonging medications). The average methadone dose was 135 mg (range 35–250 mg). All patients had preserved left ventricular ejection fraction (60.9% ± 8.0%) at the time of enrollment. Two patients had implantable defibrillators which were initially placed at other institutions for methadone-associated TdP.

Fig. 1
figure 1

Syncope and TdP in a 50-year-old man on 35 mg of methadone maintenance therapy

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Table 1 Clinical characteristics
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Follow-up is available in 11 patients with a mean follow-up of 7.3 months (range 1–18 months). All patients survived the presenting arrhythmia. Initial treatment included decreased methadone dose and magnesium, isoproterenol and temporary pacing as indicated if TdP was present.

Transition to buprenorphine was accomplished as follows: Methadone was either discontinued completely or rapidly tapered depending on the patient’s maintenance dose. Opiate withdrawal was treated with short-acting morphine and benzodiazepines as needed to keep the patient comfortable. Depending on the MMT dose, between 3 and 7 days later, the short-acting opioid was held for 6–12 h. When the patient was in moderate withdrawal as measured by the Clinical Opiate Withdrawal Scale, the observed buprenorphine induction was initiated. Buprenorphine was started at 2 mg s/l and if tolerated, increased by 4 mg s/l every 2–4 h until the patient ceased to report withdrawal symptoms or craving. The maximum daily dose was 32 mg.

Successful transition to buprenorphine was accomplished in three patients. QT interval normalized and none of these patients had recurrent arrhythmias (Fig. 2). Methadone dose was reduced in five patients with improvement of QT interval and resolution of arrhythmia. All continue to follow-up in MMT programs. Four patients, including both with ICDs, refused or did not tolerate a reduction in their methadone dose. Both ICD patients presented to Beth Israel Medical Center with ICD storm secondary to TdP, and one patient had two subsequent hospitalizations for ICD storm.

Fig. 2
figure 2

Admission EKG of a 55-year-old man on 160 mg methadone maintenance therapy (a) and following transition to buprenorphine (b)

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4 Discussion

QT prolongation due to MMT is well described [4, 5]. However, serious ventricular arrhythmias are reportedly rare [6]. The current series is significant for a large number of cases over a short time and the inclusion of patients on a relatively low dose of methadone. The apparent rise in reports of TdP in MMT patients over the last decade may signal a growing problem [7–11]. As in previous reports, the majority of patients in our series had an additional predisposing factor for TdP [5, 6, 9]. However, the average methadone dose in our population (135 mg), including one patient on 35 mg, is lower than that reported in prior studies [9, 12].

Many studies and decades of clinical experience support methadone’s efficacy as a treatment for opioid dependence [1, 13]. Methadone dramatically reduces illicit opioid abuse and prevents a number of major complications including drug overdose, criminal behavior, HIV, and hepatitis C infection [14]. Further, the absence of a suitable alternative in patients requiring high-dose MMT makes management of patients with methadone-associated TdP problematic.

Implantable cardioverter-defibrillators (ICD) have been advocated for patients with TdP on methadone [12]. While ICDs are effective at preventing death in these patients, the ICD option is fraught with difficulty as evidenced by the procedure-related complications and recurrent shocks noted in this group [12]. Indeed, the two ICD patients in our series suffered arrhythmia storms secondary to TdP. Thus, an alternative to MMT that is not associated with ventricular arrhythmias would be preferable.

Buprenorphine, a partial µ-opiate–receptor agonist and a κ-opiate–receptor antagonist, is an effective maintenance therapy for a select group of opioid-dependent patients [1, 15–17]. Buprenorphine does not block IKr and does not cause QTP. We previously described conversion from methadone to buprenorphine in a patient with methadone-associated TdP [3]. There are practical limitations to expanded buprenorphine use including restricted access and efficacy not equivalent to MMT, particularly when high doses are required [18]. Despite these limitations, buprenorphine therapy should be attempted in patients who manifest ventricular arrhythmias on MMT.

4.1 Limitations

The main limitation of this case series is the short duration of follow-up. Assessment of long-term risk of either recurrent ventricular arrhythmias or opioid abuse relapse requires extended follow-up. However, our initial patient who presented with TdP and was transitioned to buprenorphine has remained free of recurrent arrhythmia for 18 months. Further, we have not performed a systematic evaluation of MMT patients looking for QT prolongation or ventricular arrhythmias. Thus, we may be identifying a high risk subgroup of MMT patients.

5 Conclusion

We present the largest reported series of patients with methadone-associated QTP and ventricular arrhythmias. This is an increasingly relevant and important question given the recent proliferation of reports of arrhythmias in patients on methadone. Optimal management of these patients is challenging. Risk of ventricular arrhythmias must be weighed against the crucial benefit that opioid agonist pharmacotherapy provides. Avoidance of additional medications that prolong the QT interval and prevention of hypokalemia and hypomagnesemia in those who are at increased risk is vital. In addition, symptoms suggestive of arrhythmia such as syncope or palpitations in patients on MMT should be rigorously investigated.

Buprenorphine is a useful alternative in patients with documented ventricular arrhythmias on MMT. ICDs should be reserved for patients who are not candidates for buprenorphine or a reduced methadone dose. Future research analyzing the risks and benefits of the various strategies would be helpful.