Intensive Care Med (2004) 30:1690–1691 DOI 10.1007/s00134-004-2335-0 (HR 90/min, day 12) while the QRS com- plex always remained less than 12 ms. The patient was becoming progressively more agitated and as this was interpreted as probable methadone withdrawal, meth- adone was reintroduced on day 12 at a dose of 130 mg per day. On the next day the QTc interval started gradually increas- ing. It rose to 552 ms (HR 83/min) on the next day (day 13) and reached 581 ms (HR 91/min) on day 19. Given the poor prognosis, further resuscitation efforts were deemed futile, and the patient died 2 days later from ventilator associated pneumonia. Methadone is a synthetic opioid widely used for the treatment of narcotic addic- tion. Tolerance may develop, and the daily maintenance dose must be increased in patients treated by oral methadone for sev- eral years. Until recently there was little evidence of the effect of methadone on the human heart. Kornick et al. [5] found in patients treated by intravenous methadone for cancer pain that there is an approxi- mately linear relationship between QTc interval prolongation and the log-dose of methadone. In these patients the presence of chlorbutanol in the commercial solution was considered a possible contributing fac- tor. However, the authors were demonstra- ted that methadone alone blocked cardiac human ether a-go-go related gene (HERG) K + channels in vitro in comparable concen- trations to those observed in the patients receiving intravenous methadone for chronic pain management. A prospective study conducted in 132 drug-addicted patients beginning oral methadone main- tenance treatment observed a significant increase in the QTc interval between base- line and follow-up [4]. Men and patients receiving higher methadone doses (110–150 mg) had the greatest prolonga- tion. Gil et al. [1] recently found that four patients infected with the human immunodeficiency virus developed syn- cope and prolongation of the QT interval while receiving high doses of methadone (>200 mg/day); shortening of the QT inter- val occurred when methadone doses were reduced. Among the other drugs or substances taken by our patient, fluoxetine, olanzap- ine, and cocaine can also cause QT interval prolongation and may be associated with torsades de pointes. The hallmark of co- caine intoxication is wide complex arrhyth- mia which was absent in our patient [6]. Fluoxetine can cause QTc prolongation in toxic doses. Three clinical studies involv- ing 350 patients treated with fluoxetine showed no significant changes in the QTc interval. There is a single case report of QTc prolongation in a patient taking 40 mg fluoxetine daily which resolved after fluox- etine was stopped. Our patient was taking half of that dose and had therapeutic flu- oxetine levels on admission. Additionally the QTc prolongation reappeared despite the discontinuation of fluoxetine [7, 8]. Therapeutic olanzapine and trazodone have mild and clinically nonsignificant effects on QTc prolongation [9, 10]. The QTc interval showed a dose-re- sponse relationship consistent with the administration of methadone; it gradually decreased when methadone was stopped and became immediately prolonged after methadone was reinstituted. Our patient had a normal QTc interval 4 years prior to the event while he was taking the same amount of methadone (404 ms vs. 576 ms postresuscitation). The delayed effect of methadone on the QTc interval and ques- tionable compliance of the patient can probably explain this difference. Although cocaine may have contributed to our patient’s cardiac arrest, we believe that this effect took place on an already com- promised heart secondary to the document- ed QTc prolongation induced by metha- done. This effect was reported to the local drug safety center. In conclusion, in addition to the experi- mental evidence supporting the concept that methadone prolongs the QTc interval through a dose-dependent mechanism, there is an increasing number of reports suggesting that this effect can also occur in humans. Consequently the QT interval should be carefully monitored especially when the dose of methadone is increased or when the patient is given other medica- tions which could also affect the QT inter- val [11]. References 1. Gil M, Sala M, Anguera I, Chapinal O, Cervantes M, Guma JR, Segura F (2003) QT prolongation and torsades de pointes in patients infected with human immunodeficiency virus and treated with methadone. Am J Cardiol 92:995–997 2. Lipski J, Stimmel B, Donoso E (1973) The effect of heroin and multiple drug abuse on the electrocardiogram. Am J Heart 86:663–668 3. Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS (2002) Torsade de pointes associat- ed with very-high-dose methadone. Ann Intern Med 137:501–504 4. Martell BA, Arnsten JH, Ray B, Gourevitch MN (2003) The impact of methadone induction on cardiac conduction in opiate users. Ann Intern Med 139:154–155 CORRESPONDENCE J. A. Decerf B. Gressens C. Brohet A. Liolios P. Hantson Can methadone prolong the QT interval? Accepted: 10 May 2004 Published online: 8 June 2004 © Springer-Verlag 2004 Sir: The cardiac safety of high doses of methadone has been questioned in recent publications describing the impact of meth- adone on cardiac conduction [1, 2, 3, 4]. We present a case of prolonged QTc inter- val in a patient treated with methadone for several years. A 37-year-old man was found in cardiac arrest (asystole) and was successfully resuscitated. He had been receiving methadone maintenance treatment for more than 8 years at a daily oral dose of 130 mg; it is not known how compliant the patient was during these years. Elec- trocardiography (ECG) performed in 2000 while the patient was on methadone re- vealed sinus bradycardia (49/min) with a normal QRS interval and a normal QTc interval of 404 ms. The patient was also taking fluoxetine (20 mg/day), trazodone (10 mg/day), and olanzapine (5 mg/day). According to his wife, he had used co- caine (“sniffing”) a few hours before the cardiac arrest, but he was not seen taking an excessive dose of methadone. Toxico- logical screening showed therapeutic serum levels of fluoxetine, trazodone, and olanzapine, and the presence in the patient’s serum of two cocaine metabo- lites [benzoylecgonine (0.263 μg/ml), methylecgonine (0.012 μg/ml)] and meth- adone (0.229 μg/ml). Postresuscitation ECG showed sinus rhythm (90/min) with a QRS complex less than 100 ms and a QTc interval of 576 ms; there were no findings consistent with ischemia. No electrolyte abnormalities were noted. The patient developed anoxic encephalopathy with a poor prognosis for neurological re- covery. The only medication the patient was receiving was low doses of propofol for fighting the ventilator. ECG changes were monitored daily. Methadone and its metabolites were still detected in the blood until day 7 and in the urine until day 11. Cocaine metabolites were detected in the serum until day 4. The QTc inter- val gradually decreased from 600 ms (heart rate, HR, 72/min, day 2) to 485 ms