Oral methadone therapy is an effective and increasingly popular treatment for opioid dependency and chronic pain. Although it is not typically considered pro-dysrhythmic, we present the unique case of a 52-year-old HIV-positive woman without underlying cardiac disease who developed QTc prolongation and pulseless Torsades secondary to high dose methadone therapy

Brooks, Daniel E

Katz, Kenneth D, MD

Routhier, Denise D

English

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Lehigh Valley Health Network LVHN Scholarly Works Toxicology Division QTc prolongation and torsades de pointes associated with methadone therapy. Denise D Routhier Kenneth D. Katz MD Lehigh Valley Health Network, kenneth_d.katz@lvhn.org Daniel E Brooks Follow this and additional works at: https://scholarlyworks.lvhn.org/toxicology  Part of the Medicine and Health Sciences Commons Published In/Presented At Routhier DD, Katz KD, Brooks DE. QTc prolongation and torsades de pointes associated with methadone therapy. J Emerg Med. 2007 Apr;32(3):275-8. doi: 10.1016/j.jemermed.2006.07.027. Epub 2007 Feb 2. This Article is brought to you for free and open access by LVHN Scholarly Works. It has been accepted for inclusion in LVHN Scholarly Works by an authorized administrator. For more information, please contact LibraryServices@lvhn.org. doi:10.1016/j.jemermed.2006.07.027ClinicalCommunicationsQTc PROLONGATION AND TORSADES DE POINTES ASSOCIATED WITHMETHADONE THERAPYDenise D. Routhier, MD,* Kenneth D. Katz, MD,*† and Daniel E. Brooks, MD*†*Department of Emergency Medicine, and †Division of Medical Toxicology, University of Pittsburgh Medical Center,Presbyterian Hospital, Pittsburgh, PennsylvaniaReprint Address: Kenneth D. Katz, MD, UPMC Presbyterian Hospital, 200 Lothrop Street, Suite D-L45, Pittsburgh, PA 15213e Abstract—Oral methadone therapy is an effective andincreasingly popular treatment for opioid dependency andchronic pain. Although it is not typically considered pro-dysrhythmic, we present the unique case of a 52-year-oldHIV-positive woman without underlying cardiac disease whodeveloped QTc prolongation and pulseless Torsades second-ary to high dose methadone therapy. © 2007 Elsevier Inc.e Keywords—methadone; QTc prolongation; Torsades dePointes; HIV; dysrhythmiaINTRODUCTIONMethadone is commonly used for opioid dependency andchronic pain, often at high daily doses. Though not con-sidered a pro-dysrhythmic drug, there are reports of patientstaking methadone (typically higher than 100 mg/day) whodevelop prolongation of the QT interval and Torsades dePointes (TdP) (1). We report a case of a patient withmethadone-induced QTc prolongation and TdP.CASE REPORTA 52-year-old woman with a past medical history sig-nificant for human immunodeficiency virus (HIV), Hep-atitis B and C, opioid dependency, and anxiety presentedto the Emergency Department (ED) with fever and syn-cope. She complained of tactile fever, frontal headache,and a syncopal episode the night before presentation.Vital signs on presentation were: temperature 40.2°C(104.3°F), heart rate 86 beats/min, respiratory rate 20breaths/min, blood pressure 142/72 mm Hg; her physicalexamination had no significant findings. Her prescribedmedications included: methadone (145 mg daily), acy-clovir, zidovudine, lamivudine, amoxicillin, ranitidineand alprazolam. While in the ED, the patient experiencedventricular ectopy with a self-terminating run of TdPwith a prolonged QTc of 517 milliseconds (ms). Shecomplained of nausea and lightheadedness during thisepisode, but remained hemodynamically stable. Labora-tory data: Na 140 mEq/L, K 3.2 mEq/L, Cl 102mEq/L, CO2 31 mEq/L, BUN 19 mg/dL, Cr 1.1 mg/dL,Glucose 98 mg/dL, Ca 9.4 mg/dL, Mg 1.3 mEq/L,PO4 1.3 mg/dL, WBC 5.5 K/uL, Hgb 9.5 g/dL, Hct 28.1,Plt 190 K/uL. Urine drug screen was positive for co-caine, methadone, and benzodiazepines. She was treatedwith 2 g i.v. magnesium and 100 mg i.v. lidocaine andexperienced no further dysrhythmias in the ED. Bloodand urine cultures were obtained, lumbar puncture per-formed, and ceftriaxone was administered.On hospital day 2, the patient experienced pulselesspolymorphic ventricular tachycardia (Figure 1). Cardio-pulmonary resuscitation was performed and the patientwas successfully cardioverted with 200 Joules. At thetime of arrest, her QTc was 618 ms and serum electro-lytes were normal. Troponin after the arrest peaked at0.28 ng/mL. A transthoracic echocardiogram was per-RECEIVED: 3 June 2005; FINAL SUBMISSION RECEIVED: 10 March 2006;ACCEPTED: 5 July 2006The Journal of Emergency Medicine, Vol. 32, No. 3, pp. 275–278, 2007Copyright © 2007 Elsevier Inc.Printed in the USA. All rights reserved0736-4679/07 $–see front matter275Downloaded for Anonymous User (n/a) at Lehigh Valley Health Network from ClinicalKey.com by Elsevier on June 27, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.formed, which revealed: a nondilatated left ventricle withhypokinesis involving the anterior and inferior septumand inferior wall, ejection fraction 50% to 55%, mildmitral regurgitation, mild to moderate tricuspid regurgi-tation, and no vegetations. Blood cultures grew Strepto-coccus viridans of unidentifiable origin, and she com-pleted a 2-week course of Ceftriaxone and Vancomycin.No further cardiac testing was performed. No other causefor the QTc prolongation or dysrhythmia was elucidated.The patient was still receiving 145 mg methadone dailyat the time of her arrest. However, her methadone dose wasthen gradually reduced to 80 mg daily, and subsequentelectrocardiograms (ECG) revealed narrowing of the QTcinterval (503 ms) on hospital day 4. The QTc was normal atthe time of discharge of hospital day 19 (454 ms).DISCUSSIONThis case demonstrates QTc prolongation and TdP sub-sequent to high-dose methadone therapy. As in this andmost cases of drug-induced Torsades, there is a conflu-ence of potential factors, including underlying cardiac,hepatic, electrolyte abnormalities or other medicationsthat may contribute to dysrhythmia development (2).Methadone may cause TdP by blockade of the rapid com-ponent of the delayed rectifier potassium current (IKr), acommon mechanism of drug-induced QT prolongation andTorsades (3). Methadone also shares a chemical structuresimilar to verapamil and may induce bradycardia throughcalcium channel blockade (4). It has demonstrated nega-tive chronotropic effects in vitro and, therefore, maycause bradycardia and early after-depolarizations withthe potential to deteriorate into Torsades (3,5). In HIV-positive patients there exists potential for underlyingdilatated cardiomyopathy or myocarditis, which may fur-ther predispose to dysrhythmias. However, this patientdemonstrated normal ECGs both before methadone wasprescribed and after reduction of high-dose methadonetherapy (Figure 2), and her echocardiogram revealed nor-mal ejection fraction with only mild hypokinesis thought tobe secondary to arrest-induced myocardial stunning.Methadone seems to exhibit a dose-dependent effecton QTc prolongation but only at high doses. Krantz et al.reported a series of 17 patients who had Torsades whileon high dose methadone (400 mg daily). Multiple linearregression indicated that only daily methadone dose waspredictive of the QTc interval (3). Martel et al. followedserial ECGs during methadone induction of 132 patients,revealing a statistically significant QTc prolongation. Pa-tients receiving higher doses (110–150 mg) had the longestprolongations (6). Kornick et al. studied i.v. methadoneboth clinically and in vitro and demonstrated: 1) a statisti-cally significant increasing QTc interval with increas-ing methadone doses, and 2) concentration-dependentblockade of methadone on cardiac potassium channels(7). As methadone’s usage for opiod dependency andchronic pain increases, there is a trend to prescribe highdose therapy (8). Consequently, there may be a higherincidence of QTc prolongation and TdP in this patientpopulation.A potential contributing factor for the development ofTdP is the concomitant use of cocaine. Although ourpatient’s urine drug screen was positive for cocaine, shedemonstrated no evidence of sympathomimetic toxicityupon presentation. In low concentrations, cocaine, likemethadone, selectively blocks IKr, causing prolongationof the action potential and QTc interval. Isolated casereports have described TdP in recreational cocaine users.However, all patients had evidence of prolonged QTcafter abstinence from cocaine (9).Examination of the patient’s prescribed medicationregimen did not reveal any other drug known to causeQTc prolongation or significant CYP3A4 interaction.The patient was prescribed zidovudine and lamivudine(NRTIs); however, there is no current association be-tween antiretrovirals and long QT (1). Methadone ismetabolized by CYP3A4, and NRTIs neither induce norinhibit this enzyme system. Studies have failed to showany increase in serum methadone concentration withconcurrent NRTI use (10). The patient was prescribedalprazolam, which shares CYP3A4 metabolism and maytheoretically competitively inhibit methadone metabo-Figure 1. Torsades rhythm strip at the time of pulseless cardiac arrest.276 D. D. Routhier et al.Downloaded for Anonymous User (n/a) at Lehigh Valley Health Network from ClinicalKey.com by Elsevier on June 27, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.lism. However, this phenomenon has neither been dem-onstrated in vitro nor in vivo (11).Other possible etiologic factors implicated in Torsadesinclude electrolyte abnormalities and liver dysfunction (adecreased ability to metabolize pro-dysrhythmic drugs). Inthis case, the serum K and Mg concentrations wereinitially low on presentation, which may have contrib-uted to the patient’s dysrhythmia, however, they werenormal at the time of the arrest. Despite a known historyof viral hepatitis, liver function tests were normal with-Figure 2. ECG (a) before methadone therapy, QTc interval 407 ms; (b) during methadone therapy, QTc 618 ms; (c) after reductionof methadone dose, QTc 454 ms.Methadone and Torsades 277Downloaded for Anonymous User (n/a) at Lehigh Valley Health Network from ClinicalKey.com by Elsevier on June 27, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.out evidence of synthetic dysfunction. Additionally, theQTc clearly decreased in a temporal fashion with thedecrease in methadone dosage.CONCLUSIONThis case report suggests the ability of methadone toinduce QTc prolongation and Torsades de Pointes in anapparent dose-dependent manner. Physicians should beaware of methadone’s potential cardiotoxicity, particu-larly when considering its increased use and dosing foropioid dependency and chronic pain. Additionally, itmay be prudent to obtain ECGs in methadone users whoare prescribed additional medications known to inhibitmethadone metabolism or effect.REFERENCES1. Gil M, Sala M, Anguera I, et al. QT prolongation and Torsades dePointes in patients infected with human immunodeficiency virusand treated with methadone. Am J Cardiol 2003;92:995–7.2. Krantz M, Lewkowiez L, Hays H, et al. Torsade de pointesassociated with very-high-dose methadone. Ann Intern Med 2002;137:501–4.3. Krantz M, Kutinsky I, Robertson A, Mehler P. Dose-related effectsof methadone on QT prolongation in a series of patients withtorsade de pointes. Pharmacotherapy 2003;23:802–5.4. Lakshmi A, Ajjan M, Culclasure T. Methadone-induced bradycar-dia. J Emerg Med 2005;29:73–5.5. Roden D. Drug-induced prolongation of the QT interval. N EnglJ Med 2004;350:1013–22.6. Martel B, Arnsten J, Ray B, Gourevitch M. The impact of meth-adone induction on cardiac conduction in opiate users. Ann InternMed 2003;139:154–5.7. Kornick C, Kilborn M, Santiago-Palma J, et al. QTc intervalprolongation associated with intravenous methadone. Pain 2003;105:499–506.8. D’Aunno T, Folz-Murphy N, Lin X. Changes in methadone treat-ment practices: results from a panel study. Am J Drug AlcoholAbuse 1999;25:681–99.9. Bauman J, DiDomenico R. Cocaine-induced channelopathies:emerging evidence on the multiple mechanisms of sudden death.J Cardiovasc Pharmacol Ther 2002;7:195–202.10. Gourevitch M, Friedland G. Interactions between methadone andmedications used to treat HIV infection: a review. Mt Sinai J Med2000;67:429–36.11. Leavitt S. Methadone-drug interactions. Addiction treatment fo-rum 2005. Available at. http://www.atforum.com/SiteRoot/pages/addiction_resources/Drug_Interactions.pdf.Figure 2. (continued).278 D. D. Routhier et al.Downloaded for Anonymous User (n/a) at Lehigh Valley Health Network from ClinicalKey.com by Elsevier on June 27, 2022. For personal use only. No other uses without permission. Copyright ©2022. Elsevier Inc. All rights reserved.

QTc prolongation and torsades de pointes associated with methadone therapy.

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QTc prolongation and torsades de pointes associated with methadone therapy.

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