Huttner, A.

Lüthi, B.

Mueller, N.

Speck, R.

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BRIEF REPORTMethadone-induced Torsade de pointesafter stopping lopinavir–ritonavirB. Lüthi & A. Huttner & R. F. Speck & N. J. MuellerPublished online: 18 April 2007# Springer-Verlag 2007Various drugs can cause prolongation of the QT interval in anECG, and in rare cases this is followed by the development ofpotentially fatal Torsade de pointes (TdP) [1]. Since 2001,reports to the drug authorities in Europe and the USA haveraised concerns that methadone may prolong the QT intervaland thereby cause fatal arrhythmias. QT prolongation inducedby methadone is dose-dependent. Patients treated for opioiddependence with methadone often receive concomitantmedications for psychiatric disorders and infections (e.g.HIV), which allows great potential for drug–drug interactions.Described here is a case in which interruption of antiretroviraltreatment triggered TdP by elevating the level of methadonein the patient’s blood.A 53-year-old HIV-positive female patient presented inDecember 2005 with a 2-month history of weakness, weightloss (8 kg) and fatigue. She had contracted HIV in 1992.Since July 2004 she had been on a combination antiretroviraltherapy (cART) consisting of tenofovir (245 mg once daily),didanosine (250 mg once daily), fos-amprenavir (700 mgtwice daily) and lopinavir–ritonavir (400 mg/100 mg twicedaily). Other medications included methadone (75 mg twicedaily) and methylphenidate (20 mg twice daily) for opioiddependence, and oxazepam (50 mg once daily) andparoxetin (30 mg once daily) for an anxiety disorder.Physical examination was unremarkable. Routine laboratorystudies revealed a slightly elevated alanine aminotransferaselevel of 56 IU/l (normal <52 IU/l) and an increased lactatevalue of 2.9 mmol/l (normal range 0.6–2.4 mmol/l). In 2001,hepatitis C serology had been positive with an undetectablelevel of HCV-RNA; at this presentation it was 472,000 IU/mland of genotype 1B. The HIV viral load was undetectable ata CD4+ cell count of 212 cells per μl.In January 2006, the patient was seen again because ofabdominal discomfort. Her lactate level had increased to5.1 mmol/l. A presumptive diagnosis of symptomatichyperlactatemia was made and cART was discontinued.Five days later she experienced symptomatic improvementwith resolution of her abdominal pain. The lactate level haddecreased to 3.3 mmol/l. Eight days after stopping cART,the patient complained of palpitations and an ECG wasperformed; this revealed a corrected QT interval of 654 ms(normal <450 ms in women). Electrolyte blood levels werelow (potassium 3.2 mmol/l, phosphate 0.46 mmol/l,magnesium 0.77 mmol/l). The patient was admitted to theICU on the same day and she developed TdP requiringelectromechanical conversion and intubation for 48 h(Fig. 1). All oral medications were stopped and morphinewas substituted for methadone. Potassium levels were keptabove 5.0 mmol/l. Subsequent ECGs showed gradualnormalization of the corrected QT interval, reaching avalue of 420 ms after 4 days. After cART with tipranavir–ritonavir, nevirapine, tenofovir and lamivudine was re-sumed in February of 2006, the patient developed ascitesand had to be hospitalized again. Liver biopsy revealed afully cirrhotic liver. Despite discontinuation of cART andthe initiation of supportive therapy, the patient died ofcomplications related to liver failure.Long QT syndrome (LQTS) is characterized by aprolonged QT interval in the ECG as well as a patient’spropensity to develop syncope and experience suddencardiac death due to the polymorphic ventricular arrhythmiacalled TdP. The QT interval is predominantly determinedEur J Clin Microbiol Infect Dis (2007) 26:367–369DOI 10.1007/s10096-007-0293-5B. Lüthi :A. Huttner :R. F. Speck :N. J. Mueller (*)Department of Internal Medicine,Division of Infectious Diseases and Hospital Epidemiology,University Hospital of Zurich,Raemistrasse 100/RAE U 74,8091 Zurich, Switzerlande-mail: Nicolas.Mueller@usz.chby the duration of the action potential of ventricular cells.Genetic or acquired factors that alter the balance betweeninward and outward currents during the action potentialsignificantly prolong its duration. Most drugs known toprolong the QT interval block a specific type of cardiacpotassium channel expressed by the human ether-a-go-go-related gene involved in the repolarization phase of the cardiacaction potential; they thus lengthen the QT interval [2]. LQTShas long been a well-known complication of anti-arrhythmicdrug treatment [3]. However, a growing list of non-anti-arrhythmic drugs has been reported to cause LQTS.Various other clinical factors have been identified that addto the risk of developing TdP, which is the most severe formof LQTS [4]. The most common is female gender (71% ofcases); others include heart diseases, hypokalemia, potentialdrug interactions associated with the administration of twoor more drugs prolonging the QT interval and high druglevels due to impaired metabolism or excessive dosage.Methadone is a synthetic opioid frequently used in drugmaintenance programs for heroin addicts. This patientpopulation is characterized by high comorbidity, whichoften leads to the administration of additional antiviral aswell as antibiotic drugs. Uncontrolled substance abuse isfrequent, as is antipsychotic treatment. Methadone and itsderivate levacetyl–methadone are the most potent inhibitorsof the delayed potassium ion current in human cells amongthe opioid agonists, and both prolong the QT interval [5].Methadone is mainly metabolised by the isoenzymeCYP3A4 and, to a lesser extent, by the isoenzyme CYP2D6of the hepatic cytochrome-P450-system [6]. These path-ways are also utilized by numerous antibiotics, antivirals,antihistamines, and antidepressants, all of which influencethe metabolism of methadone.The association between methadone and TdP arrhythmiaswas described for the first time in a case series of 17 patients in2002 [7]. The mean dose of methadone at the time of TdPtachycardia was very high (397±283 mg/day); six patientshad been prescribed a higher methadone dosage in the monthprior to the development of TdP. A study by Sticherling et al.[8] reported five patients with TdP who were receivingmethadone in a drug maintenance program. All of the patientshad additional factors that influenced the QT time, namely,the consumption of other QT-prolonging drugs, cocaine use,taking of substances that increase the methadone level byvirtue of CYP3A4 inhibition (e.g. ciprofloxacin or cocaine),or very low potassium levels. Our patient received only150 mg of methadone daily and no new drugs had beenintroduced in the month prior to the final presentation.Three of the drugs taken by our patient (methadone,paroxetine and methylphenidate) are known to prolong theQT interval. The fact that she had been on the same dosageof these three drugs for at least the preceding year withoutany symptoms prompted us to seek additional factors thatmight have triggered QT prolongation.None of the antiretroviral drugs used by our patient are onthe list of drugs that can prolong the QT interval (www.qtdrugs.org). Gil et al. [9] mention that among the HIV-infected patients treated with methadone, drug interactionshave increased with the introduction of cART due to theinhibitory and/or inducing effects on cytochrome P450. Themost frequently observed interaction is a decrease inthe levels of methadone circulating in patients taking non-nucleoside reverse transcriptase inhibitors, and, less frequently,protease inhibitors. These drugs are occasionally stoppedwithout any parallel decrease of the methadone doses. Twostudies have examined the clinical and pharmacokineticinteractions between methadone and the protease inhibitorslopinavir and ritonavir [10, 11]. Ritonavir has been shown toinhibit CYP3A4, thereby slowing the pharmacokineticmetabolism of lopinavir and producing lopinavir levels thatexceed the inhibitory concentrations for HIV [12]. Althoughit would be expected that the simultaneous administration ofmethadone with lopinavir–ritonavir would increase metha-done concentrations, since it is mainly metabolized byCYP3A4, the opposite effect was demonstrated in bothstudies. In eight HIV-positive patients on methadone mainte-nance therapy, a 36% reduction in the area under the plasmaconcentration time curve was observed for methadone afterLPV/r was introduced, and no coincident symptoms of opioidwithdrawal were seen [10]. McCance-Katz et al. [11] showeda similar pharmacokinetic effect in 15 healthy individualsreceiving LPV/r in addition to methadone-maintenancetherapy, i.e., significant reductions in the area under theconcentration time curve for methadone and a significantincrease in opiate withdrawal symptoms. The researchersconcluded that LPV/r leads to a net in vivo induction ofmetabolic clearance of methadone involving CYP3A4 andCYP2D6 and, possibly, intestinal glycoprotein P450.We assume that the discontinuation of lopinavir–ritona-vir in the case of our patient increased the level ofFig. 1 Rhythm strip from the day of admission showing Torsade de pointes. QTc-time was 654 ms (corrected with the Bazett formula).Hemodynamic instability necessitated multiple cardioversions368 Eur J Clin Microbiol Infect Dis (2007) 26:367–369methadone in the blood thus precipitating the QT prolon-gation and near-fatal TdP. This is supported by theunusually high methadone level of 2640 nmol/l detectedon the day of admission. Additional risk factors for thedevelopment of TdP in this case were hypokalemia,hypomagnesemia and female gender. Although a directeffect of antiretroviral drugs on the QT interval has notbeen demonstrated thus far, drug–drug interactions betweenmethadone and antiretroviral medications have to be takeninto consideration, not only when adding a new drug butalso when stopping drugs that have the potential to inducedrug metabolism. In the case described here, variouscommon risk factors for TdP were present, such as femalegender and electrolyte disturbances. Our patient was alsotreated with various QT-prolonging drugs. In this case,discontinuation of the protease inhibitor LPV/r led to anincrease in the concentration of methadone since there wasa lack of methadone metabolism induction.References1. Viskin S, Justo D, Halkin A, Zeltser D (2003) Long QT syndromecaused by noncardiac drugs. Prog Cardiovasc Dis 45:415–4272. Abriel H, Schlapfer J, Keller DI, Gavillet B, Buclin T, Biollaz J,Stoller R, Kappenberger L (2004) Molecular and clinicaldeterminants of drug-induced long QT syndrome: an iatrogenicchannelopathy. Swiss Med Wkly 134:685–6943. Tartini R, Kappenberger L, Steinbrunn W, Meyer UA (1982)Dangerous interaction between amiodarone and quinidine. Lancet1:1327–13294. Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S(2003) Torsade de pointes due to noncardiac drugs: most patientshave easily identifiable risk factors. Medicine (Baltimore) 82:282–2905. Katchman AN, McGroary KA, Kilborn MJ, Kornick CA,Manfredi PL, Woosley RL, Ebert SN (2002) Influence of opioidagonists on cardiac human ether-a-go-go-related gene K(+)currents. J Pharmacol Exp Ther 303:688–6946. Wang JS, DeVane CL (2003) Involvement of CYP3A4, CYP2C8,and CYP2D6 in the metabolism of (R)- and (S)-methadone invitro. Drug Metab Dispos 31:742–7477. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, RobertsonAD, Mehler PS (2002) Torsade de pointes associated with very-high-dose methadone. Ann Intern Med 137:501–5048. Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S(2005) Methadone-induced Torsade de pointes tachycardias.Swiss Med Wkly 135:282–2859. Gil M, Sala M, Anguera I, Chapinal O, Cervantes M, Guma JR,Segura F (2003) QT prolongation and Torsades de pointes inpatients infected with human immunodeficiency virus and treatedwith methadone. Am J Cardiol 92:995–99710. Clarke S, Mulcahy F, Bergin C, Reynolds H, Boyle N, Barry M,Back DJ (2002) Absence of opioid withdrawal symptoms in patientsreceiving methadone and the protease inhibitor lopinavir–ritonavir.Clin Infect Dis 34:1143–114511. McCance-Katz EF, Rainey PM, Friedland G, Jatlow P (2003)The protease inhibitor lopinavir–ritonavir may produce opiatewithdrawal in methadone-maintained patients. Clin Infect Dis37:476–48212. Lea AP, Faulds D (1996) Ritonavir. Drugs 52:541–546, discussion547–548Eur J Clin Microbiol Infect Dis (2007) 26:367–369 369

Methadone-induced Torsade de pointes after stopping lopinavir-ritonavir

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Methadone-induced Torsade de pointes after stopping lopinavir-ritonavir

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