Background

Torsades de pointes (TdP) is a polymorphic ventricular tachycardia characterised by fluctuation of the QRS complexes around the electrocardiographic baseline and a prolonged QT interval.1 The onset of this arrhythmia often follows a pause in the cardiac cycle followed by a longer cycle length and is frequently found in the setting of bradycardia. The arrhythmia generally is often self-terminating; however, in some cases, it is capable of progressing to ventricular fibrillation.2 TdP is frequently precipitated by the use of drugs that are metabolised by the cytochrome P450 (CYP) enzyme system or that adversely influence the ion channels responsible for cardiac depolarisation and repolarisation.1 Drugs that prolong the QT interval frequently do so because of their propensity to activate a delayed sodium channel or block the outward rectifier potassium channel, mediated by the HERG (for “human ether-à-go-go related gene”) gene (also known as the KCHN2 ion channel).3 Both channels facilitate the flow of their respective ions into or out of the myocardial cells and ultimately elicit repolarisation. The extent to which the potassium channel is blocked is inversely dependent upon heart rate (HR) and extracellular potassium concentration.4 Blockade of the HERG potassium channel results in prolongation of the action potential and the QT interval. Bradycardia is a common feature of TdP as the quantity of myocardial contractions directly affects the movement of potassium extracellularly.1 Generally, the QT interval lengthens as the HR decreases.

There have been numerous publications that have detailed the propensity of methadone3^,5^–15 and three prior reports of voriconazole16^–18 causing QT interval prolongation on electrocardiogram (ECG) and TdP when administered as monotherapy, respectively. Also, research has identified several characteristics common to the population of patients treated with methadone that may serve as risk factors for developing TdP. For example, patients requiring methadone maintenance for heroin withdrawal are typically former intravenous drug abusers who tend to be coinfected with hepatitis and/or HIV, both of which have been identified as risk factors for TdP.13^,19^–21 These patients also are more likely to abuse cocaine, another independent risk factor for the development of TdP.22^–24 Methadone and voriconazole are substrates of CYP3A4, CYP2C9 and CYP2C19, and voriconazole is an inhibitor of CYP3A4.25^,26 Methadone is also extensively metabolised by 2B6.27^–29 Voriconazole administration has been reported to increase methadone concentrations.15 The marked inhibition by voriconazole of 2B6 has only recently been elucidated in in vitro analyses and is likely a major contributing factor in the pharmacokinetic interaction profile of voriconazole. We report a case of presumed methadone-associated and voriconazole-associated TdP in a patient with HIV, hepatitis C virus (HCV) and recent cocaine use. Healthcare professionals should be vigilant in identifying drug interactions with methadone and voriconazole as well as underlying medical conditions that predispose patients to TdP.

Case presentation

A 57-year-old, 74.6-kg man with HIV and a medical history of opioid addiction, infective endocarditis, bacterial pneumonia, HCV and orbital Aspergillus infection presented to the emergency department (ED) with a 1-month history of palpitations, syncope and witnessed seizure-like activity which increased in frequency over the past week. The patient reported no family history of sudden cardiac death. In the ED, the patient experienced bradycardia (HRs ranging from 48 to 60 beats/min) and several episodes of self-terminating TdP on telemetry (fig 1) with a prolonged QTc interval ranging from 484 ms to greater than 600 ms. He was given a 150 mg intravenous bolus of amiodarone and given an intravenous infusion of amiodarone at a rate of 1 mg/min. An isoproterenol infusion was also started at a rate of 0.05 mcg/kg/min to increase his resting HR to 80 to 90 beats/min.

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Figure 1

Initial presenting electrocardiogram in the Emergency Department.

Upon further evaluation, it was discovered that the patient had been admitted to our institution approximately 4 months prior for Aspergillus meningitis at which time he also underwent a sphenoidectomy and ethmoidectomy. During that hospitalisation, the patient was given voriconazole and discharged on a dose of 200 mg orally twice daily. Approximately 2 weeks prior to this admission, he presented to another hospital with similar issues and was diagnosed with an “abnormal heart rhythm.” He was discharged from the outside hospital and was taking voriconazole 200 mg orally twice daily and his other chronic medications which included methadone 125 mg orally once daily (for opioid addiction), abacavir 300 mg orally twice daily, nevirapine 400 mg orally daily and tenofovir 300 mg orally at bedtime. Prior to this hospitalisation, his methadone dose had been steadily titrated upwards from an initial dose of 30 mg once daily to the most recent dose of 125 mg once daily, at which he had been stable for approximately 1 month prior to this hospital admission.

In the ED, the patient’s urine toxicology drug screen was positive for cocaine and marijuana. Laboratory analysis revealed a serum magnesium concentration of 2.2 mEq/litre (1.5–2.0 mEq/litre), serum potassium 3.7 mEq/litre (3.5–5.0 mEq/litre), serum calcium 8.6 mg/dl (8.5–10.5 mEq/litre), serum creatinine 1.2 mg/dl, troponin 0.2 ng/ml (<0.4 ng/ml), creatine kinase (CK) 258 U/litre (38–174 U/litre) and CD4 count 478 cells/ml (500–1500 cells/ml). During his stay in the ED, the patient experienced several additional episodes of self-terminating TdP. No intravenous magnesium was administered.

Treatment

A 12-lead ECG performed at the time of admission to the coronary intensive care unit (CCU) revealed sinus rhythm, HR of 60 beats/min, premature ventricular and supraventricular complexes, right bundle branch block and a bifasicular block, in addition to a prolonged QTc interval (484 ms). Voriconazole was discontinued and the patient’s other home medications were continued, including methadone 125 mg orally once daily, tenofovir 300 mg orally at bedtime, nevirapine 400 mg orally once daily and abacavir 300 mg orally twice daily. Within the first 6 h following admission to the CCU, the patient experienced two additional episodes of TdP (fig 2). The amiodarone infusion was discontinued and the isoproterenol infusion dose was increased to 0.07 mcg/kg/min. On day 2 of hospitalisation, he was treated with intravenous potassium 60 mEq followed by oral potassium 40 mEq for a serum potassium level of 2.5 mEq/litre. His troponin also increased to 0.7 ng/ml and CK was reported as 258 U/litre. His ECG on day 2 demonstrated premature ventricular complexes, a QTc interval of 537 ms and a HR of 114 beats/min (fig 3). On day 4, the isoproterenol infusion was discontinued. An echocardiogram was performed on this day and showed an interventricular septal motion abnormality (likely related to bundle branch block), and pulmonary hypertension (pulmonary artery systolic pressure =37 mm Hg, right atrial pressure =5 mm Hg) with a left ventricular ejection fraction of 55%. On the evening of day 4, the patient’s HR was 48 beats/min and the QTc was 594 ms.

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Figure 2

Self-terminating torsades de pointes (TdP) occurring within the first 6 h of hospital admission.

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Figure 3

Sinus tachycardia with prolonged QTc on day 2 of hospitalisation.

On the morning of day 5, the patient again experienced a self-terminating episode of TdP and isoproterenol infusion was restarted at 0.07 mcg/kg/min. His QTc interval had lengthened to 623 ms and he had developed T-wave abnormalities on 12-lead ECG. His serum potassium level was 4.5 mEq/litre. Also on day 5, the patient’s methadone dose was decreased to 110 mg once daily and subsequently to 90 mg once daily during the course of hospital admission. Amphotericin B lipid complex 300 mg intravenous once daily was given day 5 for treatment of orbital Aspergillus infection and was continued until the time of hospital discharge on day 13. The isoproterenol infusion was discontinued again on day 6. The QTc interval remained consistently in a range of 500 ms to 623 ms and the patient remained bradycardic (HR 48 to 53 beats/min) without further episodes of TdP. Figure 4 shows lead V3 over the course of admission between discontinuation of voriconazole and lowering of the methadone dose from days 2 to 10. The corrected QT interval progressively shorted and the morphology of the T wave changed slightly. Terminal T wave inversion was noted on day 8, and the U wave persisted although it became slightly less prominent on days 8–10 compared to days 2–4.

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Figure 4

Composite of lead V3 from day 2 to day 10 of hospitalisation following discontinuation of voriconazole and lowering of methadone dose.

Outcome and follow-up

An implantable cardioverter-defibrillator (ICD) with dual chamber pacing capabilities was placed on day 11 for prevention of sudden cardiac death. He tolerated the procedure well and without any complications, but his T-wave abnormalities and prolonged QTc interval (515 ms) persisted. He was paced at 70 beats/min with intrinsic atrioventricular conduction noted on 12-lead ECG (fig 5). Because of the concern regarding poor penetration of amphotericin B intraorbitally and into the cerebrospinal fluid, this drug was discontinued and voriconazole was restarted at a lower dose of 100 mg orally twice daily on day 13. The patient was consequently discharged from the hospital on day 13. Upon discharge, he was prescribed nevirapine 400 mg orally once daily, tenofovir 300 mg orally at bedtime, abacavir 300 mg orally twice daily, voriconazole 100 mg orally twice daily and methadone 90 mg orally once daily with a 7-day taper to a goal dose of 60 mg once daily. His QTc interval at the time of discharge was 486 ms, HR remained around 50–60 beats/min, and his T wave abnormalities on ECG had resolved (fig 4). Device interrogation over the next 3.5 years indicated no ventricular events and he remains atrial paced at 80 beats/min for the past 1.5 years.

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Figure 5

Paced rhythm following implantation of implantable cardioverter-defibrillator.

Discussion

This patient had a number of medical conditions and was taking several medications that may have predisposed him to developing QT interval prolongation and subsequent TdP. Methadone, cocaine and voriconazole have all independently been shown to prolong the QT interval.3^–8^,10^–12^,15^–17^,21^,22 Methadone blocks the ionic current through cardiac HERG potassium channels (KCNH2) and has long been associated with inhibition of repolarisation, QT interval prolongation and TdP.3^,11^–13^,21^,23 It also increases the refractory period and enhances the inotropic response to sympathetic nerve stimulation.15 Delayed repolarisation may precipitate TdP. Methadone shares structural similarity to verapamil and produces a negative chronotropic effect which may be associated with calcium channel blockade.10^,22 Since TdP is a pause-dependent arrhythmia, bradycardia may promote TdP initiation. The risk of developing methadone-induced TdP appears dose dependent, as there are numerous studies that report a positive correlation between daily dose of methadone and QTc interval prolongation.3^,7^,10^–12 An earlier study of 41 patients reported that 66% of patients taking methadone had ECG abnormalities with 32% experiencing bradycardia and 34% had QT interval prolongation.30 Kornick et al found a log-dose relationship between methadone and the length of the QTc interval.3 In a case-control study of 167 patients on methadone maintenance, Krantz et al found that daily doses higher than 60 mg were associated with an increased risk for the development of QTc interval prolongation and degeneration into TdP.11 Our patient was receiving a high dose of methadone (125 mg) and the dose had been recently increased.

QT interval prolongation and TdP have been reported in recreational users of cocaine as well as in cocaine overdose.23 Cocaine blocks sodium channels in a “fast on-off manner”, similar to Vaughan Williams class Ic antiarrhythmics such as flecanide.23 In addition, cocaine blocks the HERG potassium channel.23 Krantz et al reported on the development of TdP in a patient who coingested cocaine and methadone with their measured methadone concentration being low during hospitalisation, suggesting cocaine itself is associated with TdP.22 Therefore, because of similar electrophysiological effects, coingestion of cocaine with methadone may have contributed to the development of TdP in the patient reported in our case.

It is well documented that the azole antifungals have the potential to increase the QT interval and cause TdP.31 While voriconazole has not been specifically studied, other azole antifungals have been shown to prolong the QT interval secondary to their ability to inhibit cardiac repolarisation currents, including HERG.32^,33 To date, three other cases of voriconazole-associated TdP have been published.16^–18 In the first published report, a 15-year-old girl, being treated with chemotherapy for acute lymphoblastic leukaemia, experienced bradycardia and TdP approximately 3 weeks after the addition of voriconazole 300 mg intravenously twice daily for Fusarium pansinusitis.17 Her baseline QTc interval had been normal and her bradycardia and QT prolongation resolved following discontinuation of voriconazole.17 In the second reported case, a 62-year-old woman with acute myelogenous leukaemia and Aspergillus flavus experienced bradycardia and two episodes of TdP (QTc interval >500 ms) approximately 3 weeks after initiating voriconazole 300 mg orally twice daily.18 Her baseline QTc interval was normal and her bradycardia and QT prolongation resolved following discontinuation of voriconazole. Her voriconazole concentrations were reported to be normal at the time of the event. Because the infection was only responsive to voriconazole, the patient was rechallenged with a lower dose, 100 mg, 4 days following discontinuation of the first course. At 4 h following the administration of the 100 mg oral dose, the patient developed bradycardia and QT prolongation.18 The third case of voriconazole-associated TdP was reported in a 14-year-old girl with acute myeloid leukaemia who had received 300 mg intravenous voriconazole twice daily for 5 days for neutropaenic fever.16 The patient was externally defibrillated successfully and her QT interval was noted to be 500 ms. Her voriconazole serum concentration was reported to be elevated at the time of the event. The patient had underlying long QT syndrome as 1 month following discontinuation of voriconazole antifungal treatment, her QTc interval remained prolonged at 455 ms. Following a second cardiac arrest, an implantable defibrillator was placed. The authors postulated that voriconazole unmasked congenital long QT syndrome.16

These patients developed TdP within 5 days to 3 weeks following initiation of voriconazole. Our patient reported symptoms consistent with TdP approximately 3 months following initiation of voriconazole but coinciding with the increase in methadone dose. Female gender is a reported risk factor for the development of TdP.34^,35 All of the patients in the aforementioned voriconazole cases were female. Ours is the first report of voriconazole-associated TdP in a man.

Methadone is primarily metabolised by CYP2B6 and CYP3A4, and to a lesser extent by CYP2D6, CYP2C9 and CYP2C19.25^,27^,28^,35 Methadone is an inhibitor of CYP2D6 but not CYP3A4.24 Cocaine is a potent inhibitor of CYP2D6 and a substrate for CYP3A4.24 Voriconazole is also a substrate for CYP2C19, CYP2C9 and CYP3A436 as well as an inhibitor of CYP2B6,27^,28 CYP2C9,24^,36 CYP3A4 and possibly CYP2C19.36^,37 Voriconazole is not a substrate or inhibitor of CYP2D6.24 In a pharmacokinetic study of 23 male patients receiving chronic methadone doses of between 20 mg and 100 mg orally daily, the addition of voriconazole 200 mg orally twice daily increased the mean peak concentration of methadone by 31% and increased the mean area under the curve (AUC) of the active R and S enantiomers of methadone by 47% and 103%, respectively.26 There were no significant changes in QTc interval reported.26 Nevirapine, in contrast, is a CYP3A4 inducer and when coadministered with methadone, has resulted in a 63% reduction in the methadone AUC.38 Neither abacavir or tenofovir have been reported to be substrates for or inhibitors of CYP3A4, CYP2C9, CYP2C19, or CYP2D6.24 This information suggests that voriconazole may directly increase methadone concentrations and that at least initially, cocaine may have potentiated this effect. We did not measure concentrations of either methadone or voriconazole, however, so this hypothesis remains speculative. Had the institution measured plasma concentrations of methadone, an earlier intervention with a dosage reduction may have attenuated the interaction and avoided the episodes of TdP.

Some suggest that a constellation of factors, rather than a single causative agent, may be responsible for the majority of cases of TdP in patients receiving methadone. Patients enrolled in methadone maintenance programmes are prone to electrolyte imbalances, cocaine abuse and various other complicating circumstances, such as HCV and HIV. In a retrospective cohort study of 1648 patients admitted to a single hospital over a 3-year period, the use of opiates, female gender, hypokalaemia, liver dysfunction and coinfection of HIV and hepatitis C predicted longer QT intervals.19 In one report, hypokalaemia was reported to be more frequent in patients who were receiving high-dose methadone (> 200 mg) and antiretrovirals and experienced prolonged QT intervals and TdP.13 Ehret et al identified independent risk factors for prolongation of the QT interval in patients receiving methadone including hypokalaemia,7 liver dysfunction7 (which may accompany HCV) and the presence of concomitant CYP3A4 inhibitors.7 All of these factors collectively provide a setting in which TdP is more likely to occur. The patient in our case had many of these risk factors including recent cocaine use, HCV and HIV coinfection, hypokalaemia (reported on hospital day 2), and was receiving a potent CYP3A4 inhibitor (voriconazole). Although the patient had no record of hepatic dysfunction, no measurement of liver function, such as liver function tests, were performed during hospitalisation.

In our case, cessation of both agents was not feasible. Therefore, an ICD was placed. The strategy of using an ICD in patients receiving methadone and experiencing TdP was recently reported by Patel et al.39 Eight patients receiving methadone doses of between 70 mg and 600 mg daily received ICDs for prolonged QTc (510 ms to 690 ms) and TdP. Over an average of 27 months, one patient died of unknown causes and three patients had appropriate shocks for multiple episodes of TdP.39

Since these episodes of TdP began shortly after the patient started taking the voriconazole, the association of voriconazole with development of TdP can be ranked as 9 on the Naranjo probability scale of adverse reactions. Consequently, it is “probable” that this combination of drugs was responsible for this proarrhythmic event.40

Given the propensity of numerous common drugs to induce QTc interval prolongation either alone or on combination, it is prudent for healthcare practitioners to be cognisant of these risks. Frequently, the more complex patient may be encountered with multiple disease states and a complicated medication regimen. As recommended by the recently released consensus guidelines for QT interval screening during methadone treatment, it is imperative that practitioners are zealous in their evaluation of drug combinations.41 Based on a wealth of case reports and drug information, concomitant administration of either voriconazole or methadone with any drug having the ability to prolong the QT interval or to impair clearance of either methadone or voriconazole is potentially dangerous. Clinicians need to weigh the risks versus benefits of administering these combinations carefully prior to their initiation. Monitoring of the 12-lead ECG for QT interval prolongation should be performed frequently upon initiation of these drug therapies and with each dose change. Consideration should be given to placement of an ICD in patients who are receiving these drugs and develop TdP and/or significant prolongation of the QTc interval on 12-lead ECG.