Methadone, QTc interval prolongation and torsade de pointes: Case reports offer the best understanding of this problem (original) (raw)
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The Successful Use of Parenteral Methadone in a Patient with a Prolonged QTc Interval
Journal of Pain and Symptom Management, 2007
Recent case reports have raised concerns about the potential for methadone to prolong the QTc interval (QT corrected for heart rate) and predispose patients to torsade de pointes (TdP), a life-threatening arrhythmia. We present a case report that describes the successful use of parenteral and oral methadone in a patient with uncontrolled cancer pain and a history of QTc prolongation. We describe an approach to the use of methadone in this patient and review both case reports and recent prospective studies that have evaluated the risk of TdP and the long-term outcome with respect to the development of TdP in patients receiving methadone for chronic pain or addiction. J Pain Symptom Manage 2007;34:566e569.
QTc interval prolongation associated with intravenous methadone
Pain, 2003
Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (I HERG ) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments I HERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (^standard error) per patient in QTc intervals on and off methadone was 41.7 (^7.8) ms, p , 0:0001. Mean difference in QTc intervals on and off morphine was 9.0 (^6.1) ms, p ¼ 0:15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant ðp , 0:0001Þ. Methadone and chlorobutanol independently block I HERG in a concentration-dependent manner with IC 50 values of 20^2 mM and 4.4^0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block I HERG . Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation. q
Addiction, 2012
Aims The aim of this study was to investigate the frequency of corrected QT interval (QTc) prolongation in a methadone maintenance therapy (MMT) population, and to examine potential associations between this QTc interval and methadone dose as well as concurrent use of opiates, cocaine and benzodiazepines. Design Cross-sectional study of patients attending a specialist drug treatment clinic from July 2008 to January 2009. Setting Single-centre inner-city specialist drug treatment clinic, Ireland. Participants A total of 180 patients on stable MMT attending for daily methadone doses, over a 6-month period, where a total of 376 patients were attending during the study period. Measurements All patients agreeing to participate in the study underwent 12-lead electrocardiograms and QTc analysis, as well as analysis of urine toxicology screen results for opiates, benzodiazepines and cocaine. ECGs were carried out prior to methadone dose being received, regardless of time of day (trough ECG). Findings The average age was 32.6 Ϯ 7.1 years, with mean [standard deviation (SD)] methadone dose 80.4 Ϯ 27.5 mg. The mean (SD) QTc was 420.9 Ϯ 21.1 ms, range 368-495 ms. Patients who had a positive toxicology screen for opiates were receiving significantly lower doses of methadone (77.8 Ϯ 23.5 mg versus 85.0 Ϯ 21.4 mg, P = 0.04). No significant association was noted between QTc interval prolongation and presence of cocaine metabolites in the urine (P = 0.13) or methadone dose (P = 0.33). 8.8% of patients had evidence of prolonged QTc interval (8.3% male QTc Ն 450 ms and 0.5% female QTc Ն 470 ms), with 11.1% (n = 20) having QTc intervals > 450 ms. Conclusions Drug-induced corrected QT interval prolongation is evident (ranging from 8.8-11.1%, depending on definition applied) in patients receiving relatively low daily doses of methadone therapy, with no evidence of a dose-response relationship. The presence of cocaine metabolites in urine does not appear to be associated with increased corrected QT interval. Increased awareness of cardiac safety guidelines, including relevant clinical and family history, baseline and trough dose ECG monitoring, should be incorporated into methadone maintenance therapy protocols.
Prevalence of long QTc interval in methadone maintenance patients
Drug and Alcohol Dependence, 2009
Background: There is a concern about cardiac rhythm disorders related to QTc interval prolongation induced by methadone. A cross-sectional study was designed to evaluate the prevalence of long QTc (LQTc) interval in patients in methadone maintenance treatment (MMT) and risk factors for LQTc. Methods: The study population included 109 subjects (74 males, median age 43 years). Socio-demographic and toxicological variables were recorded, as well as concomitant use of drugs related with QT prolongation, history of heart diseases, and corrected QT interval by heart rate (QTc) in the ECG. Plasma concentrations of (R)-methadone and (S)-methadone enantiomers were determined in 69 subjects. Results: Ten patients (9.2%) presented a QTc above 440 ms but a QTc above 500 ms was observed in only 2 (1.8%). Patients with QTc above 440 ms compared with the remaining subjects were older (median [25th-75th percentile range]: 49 [39-56] years vs. 37 [33-43]; Wilcoxon's W = 217.5, p = 0.002) and took a higher daily dose of methadone (median [25th-75th percentile range]: 120 [66-228] mg/day vs. 60 [40-110] mg/day; W = 298.5, p = 0.037). Methadone dose correlated with QTc interval (Pearson's r 2 = 0.291, p = 0.002). Patients with and without long QTc showed no differences in plasma concentrations of (R)-methadone and (S)-methadone enantiomers.
Methadone-associated Q-T interval prolongation and torsades de pointes
American Journal of Health-System Pharmacy, 2009
Purpose. The association of methadone with Q-T interval prolongation and torsades de pointes (TdP) is reviewed, and recommendations for preventing Q-T interval prolongation in methadone users are provided. Summary. Abnormalities in voltagegated potassium channels have been shown to lead to prolonged action potentials that are expressed as long Q-T intervals, and methadone has been found to interact with the voltage-gated potassium channels of the myocardium. While cardiac arrhythmias in methadone users have been reported for several decades, specific reports of methadone-associated Q-T interval prolongation and TdP did not appear in the literature until the early part of the 21st century. Because not every patient experiences Q-T interval prolongation with methadone, recent research has elucidated risk factors that predispose patients to this adverse effect, including female sex, hypokalemia, high-dose methadone, drug interactions, underlying cardiac conditions, unrecognized congenital long Q-T interval syndrome, and predisposing DNA polymorphisms. Given
Dose-Dependent Effects of Methadone on QT interval in Patients under Methadone Maintenance Treatment
Asia Pacific Journal of Medical Toxicology, 2013
Background: The role of methadone in QTc prolongation, Torsades de Pointes (TdP) arrhythmia and sudden cardiac death has been debated. Because of widespread use of methadone in methadone maintenance treatment (MMT) centers, we aimed to study dose-related effects of methadone on QTc prolongation. Methods: In a comparative observational study, 90 patients who were under MMT were evaluated. Patients were divided into three groups according to methadone daily dose (G1: 0-59 mg, G2: 60-109 mg, G3: 110-150 mg). Twelve-lead electrocardiograms (ECG) were performed at baseline and two months later, after reaching the maximum daily dose of methadone. The QTc were calculated for each patient. Comparison of mean QTc and mean QTc prolongation between baseline and follow up ECGs were analyzed. Results: In total, mean (SD) age was 32.4 (8.5). TdP was not detected in any patients. Mean QTc was 405.2 (17.0) and 418.5 (23.1) msec before and two months after MMT respectively. There was a significant d...
Addiction, 2007
To determine and evaluate QTc intervals in electrocardiograms (ECGs) of former heroin addicts, currently in methadone maintenance treatment (MMT), as previous reports suggest that methadone may prolong QTc intervals, thus possibly increasing the risk for Torsade de pointes (TdP). Design Cross-sectional study. Setting Between January 2003 and September 2004, patients on a steady dose of methadone for at least 2 weeks were studied. Participants This study is a subset of 153 patients, of whom 151 patients participated in a study of high methadone doses and serum levels. A total of 138 patients in MMT for a minimum of 100 days up to 10.7 years, receiving 40-290 mg/day methadone dose, participated. Measurements Patients had an ECG at the time when blood was drawn for determination of serum methadone levels at around 24 hours after the last oral methadone dose. Corrected-QT intervals (QTc) were calculated using the Bazett formula. Findings Of 138 patients studied, 98 (71%) were male. Mean QTc interval was 418.3 Ϯ 32.8 milliseconds (ms). Mean methadone dose was 170.9 Ϯ 50.3 mg/day and mean serum methadone level was 708.2 Ϯ 363.1 ng/ml. Methadone dose and serum levels did not correlate with QTc. Three patients had QTc intervals above 500 ms ('prolonged'). After 2 Ϯ 0.4 years of follow-up, two patients died; they were two of three patients with very prolonged QTc. Causes of death were not attributed to cardiac origin. An additional 19 patients had QTc intervals of between 450 and 499 ms ('possibly prolonged'). None of these QTc Ն 450 ms patients had any cardiac problems. Methadone doses of all 22 patients were > 120 mg/day. Conclusions Methadone maintenance is generally safe; however, the possible toxicity of high dose (> 120 mg/day) should be monitored for QTc.
Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone
Archives of Internal Medicine, 2006
Background: Drug-induced long QT syndrome is a serious adverse drug reaction. Methadone prolongs the QT interval in vitro in a dose-dependent manner. In the inpatient setting, the frequency of QT interval prolongation with methadone treatment, its dose dependence, and the importance of cofactors such as drug-drug interactions remain unknown.