Chronic methadone therapy complicated by torsades de pointes: a case report

Methadone is commonly used by patients presenting to the Emergency Department (ED). The common, acute side effects of central nervous system depression and respiratory depression are easily recognizable by treating physicians as attributable to methadone; however, the cardiac toxicity of chronic methadone use recently has only been recognized. Both chronic use of large doses and a recent increase in the daily dose of methadone have been associated with QT prolongation and subsequent development of torsades de pointes. We describe the case of a 40-year-old woman whose methadone dose recently had been increased to 135 mg per day. She then presented to the ED with symptomatic torsades de pointes. She was stabilized in the ED by cardioversion and infusions of magnesium sulfate and lidocaine. The markedly prolonged corrected QT interval significantly shortened after discontinuing methadone. Inpatient cardiology evaluation found no other cause for the dysrhythmia. She was definitively treated with reduction of the daily methadone dose and an implanted cardioverter-defibrillator.     

Measurement of QTc in patients receiving chronic methadone therapy

Recent reports suggest that methadone may prolong the QTc interval and cause torsades de pointes. This study was conducted to evaluate the prevalence of QTc prolongation during oral methadone therapy and identify factors associated with prolongation. Patients receiving oral methadone as treatment for chronic pain or addiction were eligible for the study. One hundred four patients who were receiving > or = 20 mg methadone per day for > or = 2 weeks underwent electrocardiograms to measure QTc interval duration. Sixty-three (61%) patients were male and 63 (61%) were receiving methadone maintenance for opioid addiction. The mean (+/- SD) age was 45.3 +/- 9.4 years. The median (range) methadone dose was 110 mg/day (20-1200 mg/day); median (range) number of months on methadone was 12.5 months (1-444 months). The median (range) QTc interval was 428 msec (396-494 msec). Thirty-three percent had QTc prolongation (males 40%, females 20%; P=0.03). No patient had a QTc longer than 500 msec. Significant dose response was observed in males on methadone <12 months (rho=0.60, P=0.02). Our study suggests that methadone may prolong the QTc interval in specific subpopulations but poses little risk of serious prolongation.     

Adenosine Induced Torsades de Pointes in a Child with Congenital Long QT Syndrome

Torsades de pointes is a rare arrhythmia characterized by its bradycardia dependence and increased adrenergic discharge, whether it occurs as a congenital anomaly or as an acquired problem resuiting from drug intoxication or other conditions. There are no reliable tests to assess the propensity toward torsades de pointes or evaluate the efficacy of treatment in these patients. Adenosine can result in marked slowing of sinus and ventricular rate and leads to increased sympathic discharge when given intravenously. We induced torsades de pointes in a child with congenital long QT syndrome (Jervell-Lange-Nielsen syndrome) using 200 μg/kg IV adenosine bolus. Higher dosage of adenosine (600 μg/kg) did not lead to torsades de pointes after β blockade. Adenosine may induce torsades de pointes in patients with the long QT syndrome and may be used as a test to reproduce the clinical arrhythmia. Whether adenosine proves to be useful for assessing the efficacy of treatment will require extensive investigation in larger series of patients.     

A modeling and simulation approach to characterize methadone QT prolongation using pooled data from five clinical trials in MMT patients

Pharmacokinetic (PK)-pharmacodynamic modeling and simulation were used to establish a link between methadone dose, concentrations, and Fridericia rate-corrected QT (QTcF) interval prolongation, and to identify a dose that was associated with increased risk of developing torsade de pointes. A linear relationship between concentration and QTcF described the data from five clinical trials in patients on methadone maintenance treatment (MMT). A previously published population PK model adequately described the concentration-time data, and this model was used for simulation. QTcF was increased by a mean (90% confidence interval (CI)) of 17 (12, 22) ms per 1,000 ng/ml of methadone. Based on this model, doses >120 mg/day would increase the QTcF interval by >20 ms. The model predicts that 1-3% of patients would have ΔQTcF >60 ms, and 0.3-2.0% of patients would have QTcF >500 ms at doses of 160-200 mg/day. Our predictions are consistent with available observational data and support the need for electrocardiogram (ECG) monitoring and arrhythmia risk factor assessment in patients receiving methadone doses >120 mg/day.     

Torsades de pointes associated with fluoroquinolones: importance of concomitant risk factors

The fluoroquinolone antibiotics sparfloxacin, grepafloxacin, gatifloxacin, and levofloxacin have been reported to cause torsades de pointes. Pre-existing risk factors increase vulnerability to this life-threatening arrhythmia. In a 65-year-old woman with a history of hypertension, coronary artery disease, systemic lupus erythematosus, and osteomyelitis, QTc interval prolongation (605 ms) and torsades de pointes developed after the initiation of levofloxacin, 250 mg intravenously once daily. The patient was hypokalemic and mildly hypomagnesemic before the initiation of levofloxacin and at the time of occurrence of torsades de pointes. The QTc interval decreased to 399 ms within hours of discontinuation of the levofloxacin, after which she had no further arrhythmias. In this and the majority of other published cases of fluoroquinolone-associated torsades de pointes, patients had at least 1 risk factor for the arrhythmia, and most had multiple risk factors. Fluoroquinolone antibiotics should be avoided whenever possible in patients with pre-existing risk factors for torsades de pointes.     

QT interval prolongation and torsades de pointes due to a coadministration of metronidazole and amiodarone

This report documents the occurrence of torsades de pointes (TdP) caused by marked QT interval prolongation in the case of a 71-year-old woman receiving both metronidazole and amiodarone for the treatment of pseudomembranous colitis and paroxysmal atrial fibrillation. The case highlights a previously unknown drug interaction. The role of inhibition of cytochrome P-450 CYP3A4 is discussed.     

Inherited long QT syndrome revealed by antifungals drug-drug interaction

A 14-year-old Tahitian girl with acute myeloid leukaemia and a suspected mucormucosis infection was treated with intravenous voriconazole and caspofungin. Because of worsening of fungal infection, voriconazole was switched to posaconazole. During the switch, the patient presented with QT interval prolongation with 'torsades de pointes' and reversible cardiac arrest. Voriconazole plasma level measured 15 h after the last administration was 7 mg/L. Genotyping suggested that the patient was an extensive metabolizer with respect to CYP2C9 and CYP2C19. The association of antifungal agents with pro-arrhythmogenic drugs and other risk factors led to torsades de pointes and the revealing of inherited QT syndrome.     

Greater quinidine-induced QTc interval prolongation in women

BACKGROUND: Prolongation of the electrocardiographic QT interval by drugs is associated with the occurrence of a potentially lethal form of polymorphic ventricular tachycardia termed torsades de pointes. Women are at greater risk than men for development of this adverse event when taking drugs that prolong the QT interval. To determine whether this may be the result of gender-specific differences in the effect of quinidine on cardiac repolarization, we compared the degree of quinidine-induced QT interval lengthening in healthy young men and women. METHODS: Twelve women and 12 men received a single intravenous dose of quinidine (4 mg/kg) or placebo in a single-blind, randomized crossover trial. Total plasma and protein-free concentrations of quinidine and 3-hydroxyquinidine were measured in serum. QT intervals were determined and corrected for differences in heart rate with use of the method of Bazett (QTc = QT/RR1/2). RESULTS: As expected, the mean QTc interval at baseline was longer for women than for men (mean +/- SD; 407 +/- 7 versus 395 +/- 9 ms, P < .05). The slope of the relationship between change in the QTc interval (delta QTc) from baseline to the serum concentration of quinidine was 44% greater for women than for men (mean +/- SE; 42.2 +/- 3.4 versus 29.3 +/- 2.6 ms/microg per mL, P < .001). These results were not influenced by analysis of 3-hydroxyquinidine, free concentrations of quinidine and 3-hydroxyquinidine, or the JT interval. CONCLUSIONS: Quinidine causes greater QT prolongation in women than in men at equivalent serum concentrations. This difference may contribute to the greater incidence of drug-induced torsades de pointes observed in women taking quinidine and has implications for other cardiac and noncardiac drugs that prolong the QTc interval. Adjustment of dosages based on body size alone are unlikely to substantially reduce the increased risk of torsades de pointes in women.     

Torsades de Pointes from Terfenadine and Sotalol Given in Combination

A patient receiving sotalol developed recurrent torsades de pointes following the addition of terfenadine (Seldane) to her medical regimen. A 71-year-old woman with a history of atrial fibrillation successfully suppressed with sotalol, 80 mg bid, was started on terfenadine, 60 mg bid. Eight days later, she developed repeated self-terminating episodes of torsades de pointes. Sotalol and terfenadine were discontinued, and no further arrhythmia was observed after 72 hours of temporary pacing was discontinued.     

Early Afterdepolarizationlike Activity in Patients with Class IA Induced Long QT Syndrome and Torsades de Pointes

Early afterdepolarizations (EADs) have been linked to the mechanism of torsades de pointes in long QT syndrome. The purpose of this study was to investigate the role of EADs in Class IA induced torsades de pointes. We studied nine patients with Class IA induced torsades de pointes at the time this arrhythmia was present (acute period, n = 7) and after Class IA therapy was discontinued (chronic period, n = 6). ECCs and monophasic action potentials were recorded in both periods. In the chronic period, electrophysiological studies were performed before and after disopyramide infusion. In the acute period, QT_c interval was markedly prolonged (655 ± 32 ms^1/2), and EAD-like activity was recorded in all patients. QT_c interval returned to normal (428 ± 45 ms^1/2) and EAD-like activity disappeared after discontinuation of IA drug. Although, in the chronic period, disopyramide infusion prolonged QT_c interval from 428 ± 48 ms^1/2 to 479 ± 31 ms^1/2 and induced EAD in three of six patients, the degree was not as marked as observed in the acute period. EADs may play an important role in the genesis of long QT and torsades de pointes. Disopyramide infusion in the chronic period could not reproduce marked repolarization ahnormalities and torsades de pointes.     

Medikamentös induzierte Verlängerung des QT-Intervalls

Prolongation of the ventricular repolarisation manifests itself as a prolongation of the QT intervall on the surface ECG and represents a major risk for a special form of ventricular tachycardia called "torsades de pointes". Torsades de pointes are often self limited and are associated with palpitations, dizziness or syncope. Degeneration into ventricular fibrillation and sudden cardiac death can occur. In addition to the various forms of the congenital long QT syndrome many drugs, such as antiarrhythmic drugs class IA and III, antibiotics, antihistamines, antidepressants, and methadone are known to prolong the QT interval. Most of these drugs block a specific potassium channel substantially involved in the ventricular repolarisation. In addition, drug interaction or disturbances of drug metabolism may play a major role in the acquired form of the long QT syndrome. The individual risk and the potential of a pharmacologic substance to prolong the QT interval are not predictable. Certain risk factors identify patients at higher risk for drug-induced prolongation of the QT interval. Correctable factors include electrolyte disorders (e.g. hypokalemia) and concomitant administration of different QT prolonging drugs. External defibrillation is the therapy of choice in the hemodynamic unstable patient presenting torsades de pointes. In hemodynamic more stable patients application of intravenous magnesium can terminate torsades de pointes (membrane stabilizing properties). Temporary external or transvenous pacing at high heart rate might terminate incessant torsades de pointes by decreasing QT interval. Repeated ECG controls during therapy with QT prolonging drugs are mandatory, especially when drug doses are changed, additional drugs are prescribed, or in case of vomiting and diarrhea. QT prolongation in individual medical therapy is not always predictable. Therefore, updated lists of drugs with the potential of QT prolongation are available on the Internet (e.g. www.qtdrugs.org ).     

ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment

BACKGROUND AND OBJECTIVE: The in vivo implication of various cytochrome P450 (CYP) isoforms and of P-glycoprotein on methadone kinetics is unclear. We aimed to thoroughly examine the genetic factors influencing methadone kinetics and response to treatment. METHODS: Genotyping for CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, ABCB1, and UGT2B7 polymorphisms was performed in 245 patients undergoing methadone maintenance treatment. To assess CYP3A activity, the patients were phenotyped with midazolam. RESULTS: The patients with lower CYP3A activity presented higher steady-state trough (R,S)-methadone plasma levels (4.3, 3.0, and 2.3 ng/mL x mg for low, medium, and high activity, respectively; P = .0002). As previously reported, CYP2B6*6/*6 carriers had significantly higher trough (S)-methadone plasma levels (P = .0001) and a trend toward higher (R)-methadone plasma levels (P = .07). CYP2D6 ultrarapid metabolizers presented lower trough (R,S)-methadone plasma levels compared with the extensive or intermediate metabolizers (2.4 and 3.3 ng/mL x mg, respectively; P = .04), whereas CYP2D6 poor metabolizer status showed no influence. ABCB1 3435TT carriers presented lower trough (R,S)-methadone plasma levels (2.7 and 3.4 ng/mL . mg for 3435TT and 3435CC carriers, respectively; P = .01). The CYP1A2, CYP2C9, CYP2C19, CYP3A5, and UGT2B7 genotypes did not influence methadone plasma levels. Only CYP2B6 displayed a stereoselectivity in its activity. CONCLUSION: In vivo, CYP3A4 and CYP2B6 are the major CYP isoforms involved in methadone metabolism, with CYP2D6 contributing to a minor extent. ABCB1 genetic polymorphisms also contribute slightly to the interindividual variability of methadone kinetics. The genetic polymorphisms of these 4 proteins had no influence on the response to treatment and only a small influence on the dose requirement of methadone.     

Opioid switching from morphine to methadone causes a minor but not clinically significant increase in QTc time: A prospective 9-month follow-up study

Case reports and retrospective studies suggest that methadone causes an increase in QTc (QT time corrected for heart rate) time and risk of torsades de pointes arrhythmia. No prospective studies in pain patients have been conducted, and data on whether a methadone-induced increase in QTc time persists during long-term treatment have not been reported. Eight chronic nonmalignant pain patients experiencing insufficient pain control or intolerable side effects during treatment with oral morphine switched to oral methadone and were included in this study. Electrocardiograms were obtained at baseline and at follow-up 2 weeks, and 3 and 9 months after the opioid switch. Start of methadone caused a minor but statistically significant increase in QTc time, while fluctuations in QTc during treatment with stable doses of methadone were neither clinically nor statistically significant. We observed no episodes of arrhythmias.     

Use of the rabbit with a failing heart to test for torsadogenicity

Torsades de pointes is a potentially lethal arrhythmia that occurs infrequently but may be drug-induced particularly in patients with pathological substrates. However drugs are usually evaluated for torsadogenicity in normal subjects, thus potentially limiting the sensitivity of studies to predict liability in man. Heart failure is a pathological substrate permissive to drug-induced torsades de pointes. Failing hearts may be produced with a high yield in rabbits with ligation of coronary arteries. Failing myocardium may be documented by reduced left ventricular ejection fraction and elevation of NTproBNP. QTc in failing hearts prolonged only slightly more in failing hearts than in normals in response to torsadogens, but incidence of torsades de pointes increased dramatically. Abnormal calcium cycling resulting in early afterdepolarizations appeared to develop more in hypertrophic myocardial cells located in the border between normal myocardium and infarct. In failing hearts, torsades de pointes appeared to develop more prevalently without greater lengthening of QT than in hearts from normal rabbits. Thus this model appears to be a facile and useful preparation for identifying torsadogenic potential of test articles, and it probably possesses anatomical and physiological substrates that mimic closely the torsadogenic substrates in the many millions of persons possessing failing hearts.     

Torsades de Pointes Due to N-Acetylprocainamide

A 66-year-old female with chronic renal failure received five doses of procainamide and developed marked QT interval prolongation and recurrent episodes of torsades de pointes, which were temporally related to high serum n-acetylprocainamide (NAPA) levels and not to procainamide levels. Repeated hemodialysis was effective in lowering NAPA levels. Torsades de pointes is a potential hazard of NAPA accumulation during procainamide administration to patients with renal insufficiency.     

Mechanisms in Adrenergic Dependent Onset of Torsades de Pointes

Pause dependent onset of torsades de pointes is characteristic in acquired long QT syndromes, and the probable mechanism is reentry facilitated by increased disparity of refractoriness following a long cycle. Adrenergic dependent onset is usual in familial long QT syndromes, and the mechanism is uncertain. In this study with a computer simulation of torsades de pointes, possible mechanisms of adrenergic dependent onset have been identified. Decreased refractory periods facilitated the initiation of torsades de pointes by permitting earlier premature excitation and allowing reentry in the presence of the shorter refractory period that had been further shortened by the earlier excitation. In addition, accelerating rate resulted in responses occurring in the presence of refractory periods set by the prior response so each response was premature with respect to the preceding one. The difference between cycle lengths and refractory period decreased with increasing rate leading to the functional block required for initiation of simulated torsades de pointes. Findings define possible mechanisms in which the adrenergic effects of reduced refractory period duration and increased rate may lead to the initiation of torsades de pointes.     

A Canine Model of Torsades de Pointes

Although quinidine has been reported to induce QT interval prolongation and torsades de pointes clinically, the only experimental model currently available for quinidine-induced torsades de pointes requires the concurrent use of ischemia, reperfusion and cardiac pacing of the isolated, perfused heart. Our purpose in this study was to determine the circumstances under which quinidine might elicit torsades de pointes consistently in the intact dog. We found that maintenance of therapeutic plasma quinidine concentrations, alone, did not induce the arrhythmia. Rather, arrhythmia induction required the additional application of aconitine, which induces early afterdepolarizations and triggered activity. When aconitine was applied to two epicardial sites in dogs having quinidine-induced QT interval prolongation greater than 10%, torsades de pointes occurred in 80% of instances. When QT prolongation was less than 10%, aconitine-induced torsades de pointes was seen in only 21% of animals. Our results suggest that in a previously healthy heart quinidine-induced QT prolongation is, itself, insufficient to induce torsades de pointes consistently, and two independent sites of ectopic activity are needed as well. The ectopic foci appear to modulate one another's impulse initiation or activation sequence, thereby giving rise to the classical "twisting of the points" associated with the arrhythmia.     

Medical toxicologists’ practice patterns regarding drug-induced QT prolongation in overdose patients: A survey in the United States of America,Europe, and Asia Pacific region

Abstract

Objective. To describe practice patterns of medical toxicologists in the United States of America (USA), Europe, and Asia Pacific Region regarding management of drug induced QT prolongation and torsades de pointes in overdose. Methods. A survey was developed to assess current practice patterns and consistency with guidelines published by the American Heart Association (AHA), American College of Cardiology (ACC), and European Society of Cardiology (ESC). It was reviewed by our department research committee and the American College of Medical Toxicology (ACMT). The ACMT, European Association of Poisons Centres and Clinical Toxicologists, and Asia Pacific Association of Medical Toxicology electronically disseminated the survey to their physician members in the USA, Europe and Asia Pacific Region. Results. The overall response rate was 37% (229/617) (36% USA; 32% Europe; 52% Asia Pacific Region). Twelve toxicologists from Asia Pacific Region and Europe used the QT nomogram (Australia-5, New Zealand-1, United Kingdom-1) or QT alone (France-1, Russia-1, Romania-1, Germany-1, Philippines-1), in lieu of the corrected QT (QTc) to determine risks of developing torsades de pointes. Because only those who used QTc could proceed through the remainder of the survey, only 217 could do so. Approximately half of the respondents (52%) did not calculate QTc manually and based decisions on the electrocardiogram machines automated measurement. For those who corrected the QT interval themselves, the most common formula used was Bazett's (40%). There is great variation in the QTc value considered prolonged. Most responders considered QTc greater than 450 ms in men (28%) and 460 ms in women (25%) to be prolonged. Interestingly, approximately 15% of participants did not consider the QTc prolonged until it exceeded 500 ms in both men and women. Given an overdose scenario of a male patient with a QTc of 560 ms, heart rate of 90 beats/minute, 59% would not recommend administering intravenous magnesium sulfate. Forty-five percent and 36% believed magnesium could shorten QTc and prevent torsades de pointes, respectively. In addition, almost 90% believed administering 1–2 boluses of intravenous magnesium is safe, even when serum magnesium is not available. In regards to cardiac pacing of patients with QT prolongation and torsades de pointes, only 38% of the participating toxicologists’ responses agreed with AHA/ACC/ESC recommendations. Furthermore, 21% would not pace a patient who developed torsades de pointes regardless of the scenario. Discussion and conclusions. The results indicate that medical toxicologists have considerable heterogeneity in terms of management practices for overdose patients with QT prolongation and torsades de pointes. Medical toxicologists may benefit from developing evidence-based consensus guidelines for the management of this relatively common finding in overdose of QT-prolonging drugs.     

Cardiac Arrest Associated With Combination Cisapride and Itraconazole Therapy

We report a case of cardiac arrest associated with cisapride in combination with itraconazole and provide a brief review of pertinent literature. Cisapride (Propulsid; Janssen Pharmaceuticals, Titusville, NJ), a gastrointestinal prokinetic drug, has recently been reported to prolong the QT interval. Itraconazole, an oral antifungal agent, is an inhibitor of cytochrome P450 (CYP3A4) metabolism and may elevate serum drug levels of compounds metabolized by this pathway. A 31-year-old woman had a witnessed cardiac arrest while taking the combination of cisapride and itraconazole. Following resucitation, the prolonged QT interval returned to normal after withdrawal of both agents. Echocardiography and cardiac catheterization were within normal limits; electrophysiologic testing failed to induce ventricular tachycardia/ventricular fibrillation. She has had no documented arrhythmias since the arrest. This combination can now be added to a growing list of drugs that may cause torsades de pointes and sudden cardiac death.     

Proarrhythmic effects of a quinidine analog in dogs with chronic A-V block

Summary— The proarrhythmic effects of 3-hydroxy-hydroquinidine (3-OH-HQ) and quinidine were compared in a canine model of QT-dependent ventricular arrhythmias. Eight hypokalemic ([K+] ≤ 3.2 mmol/l) dogs with AV block (around 45 bpm) were given either drug in a randomized order at 2-day intervals. Each drug was given as two 1 hour doses, with a bolus (low dose: 5 mg/kg or high dose: 10 mg/kg) plus infusion (25 or 50 μg/kg/min) protocol. Propranolol infusion was combined with a third hour of the high dose infusion. Electrophysiologic measurements were performed at baseline and 30 minutes after the beginning of each dose and propranolol infusion, and proarrhythmic events were recorded 30 minutes before and during the experiment. Neither drugs altered the ventricular cycle length. Quinidine and 3-OH-HQ prolonged the QT interval similarly and significantly when paced at 60 bpm after the low dose (+ 39 ± 18 and + 28 ± 22 msec, respectively) and after the high dose (+ 51 ± 29 and + 50 ± 22 msec). Quinidine was more arrhythmogenic than 3-OH-HQ: 7/8 dogs (p ≤ 0.05) developed ventricular arrhythmias (isolated, repetitive ventricular beats, or polymorphic ventricular tachycardias) during quinidine infusion (low dose: 4 dogs) compared to 3/8 dogs (NS) during 3-OH-HQ infusion (low dose: 1 dog). Addition of propranolol-induced bradycardia (around 30 bpm) caused torsades de pointes (wave burst arrhythmias) or polymorphic ventricular tachycardias after both drugs (in 3 dogs after quinidine and in 2 dogs after 3-OH-HQ). Thus 3-OH-HQ was slightly less arrhythmogenic than quinidine in this model of torsades de pointes, but the addition of an extra favouring factor (bradycardia) reduced that difference.