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QTc Prolongation Among Hospitalized Patients Receiving Methadone—Reply

QTc Prolongation Among Hospitalized Patients Receiving Methadone—Reply In reply We are delighted that our article has captured the attention of our colleagues and we appreciate the comments and additional data. Petrosillo et al describe QT interval prolongation (QTc >0.44 seconds½) in 29 (29%) of 99 HIV-positive injection drug users; similar proportions have been reported by others.1 In our study, 76 (46%) of 167 methadone maintenance patients and 16 (20%) of 80 controls without methadone use presented with a QTc greater than 0.44 seconds½. It is interesting that Petrosillo et al also found a significantly increased risk of QTc prolongation with methadone treatment and a trend for increased risk with the use of cytochrome 3A4 inhibitors. It is important to note, however, that their prospectively examined outpatients differ from the inpatients in our study, notably in that only 29 (29%) of their patients are methadone maintenance patients and in our methadone group only 67 (40%) were HIV positive. The 2 groups of patients are therefore not unequivocally comparable, but both findings underline the possibility of multiple simultaneous risk factors for QT prolongation with methadone treatment. Schmittner and Krantz rightly point out that the article by Krantz et al2 on 17 methadone-treated patients presenting with TdP has not been adequately appreciated in our report. The strength of correlation between methadone dose and QTc is higher in this report: +0.51 for methadone use alone compared with +0.32 for methadone use and 3 additional risk factors. There is variation between the 2 reports that might explain this difference, such as setting, case ascertainment, methadone doses and indication, and age of patients, among others. It is interesting to note that in the article by Krantz et al,2 other risk factors for LQTS, like hypokalemia, were not significantly associated with QT prolongation, although the average daily methadone dose was more than 3 times higher and thus the “repolarization reserve” might be more compromised in their patients. We thank Justo for emphasizing that the correlation between drug-induced LQTS and the risk for TdP is unknown. He reviewed 40 published reports on methadone-induced TdP and found that none of these patients exhibited the 4 risk factors reported in our article. In our study, 2 of 6 patients with TdP exhibited a QTc of less than 0.5 seconds½: 0.48 seconds½ in 1 female and 0.43 seconds½ in 1 male patient. Only this last case can be classified as having a normal QT interval. We agree that methadone treatment has been shown to be of great benefit in most patients. It has taken many years for Krantz and colleagues and our group to describe the frequent QT interval prolongation that can occur with methadone administration.3,4 Because of the rarity of its occurrence, further studies will be necessary to analyze the occurrence of TdP in a subset of patients. The recent identification of common genetic determinants of QT length in the general population5 might open new scientific avenues. Correspondence: Dr Ehret, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205 (georg@jhmi.edu) References 1. Kocheril AGBokhari SABatsford WPSinusas AJ Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997;202810- 2816PubMedGoogle ScholarCrossref 2. Krantz MJKutinsky IBRobertson ADMehler PS Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003;23802- 805PubMedGoogle ScholarCrossref 3. Krantz MJLewkowiez LHays HWoodroffe MARobertson ADMehler PS Torsade de pointes associated with very-high-dose methadone. Ann Intern Med 2002;137501- 504PubMedGoogle ScholarCrossref 4. Bittar PPiguet VKondo-Oestreicher MDesmeules JDayer P Methadone-induced long QTc and “torsade de pointes” [abstract P244]. Swiss Med Forum 2002; ((8 suppl)) 36SGoogle Scholar 5. Arking DEPfeufer APost W et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 2006;38644- 651PubMedGoogle ScholarCrossref http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Archives of Internal Medicine American Medical Association

QTc Prolongation Among Hospitalized Patients Receiving Methadone—Reply

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Publisher
American Medical Association
Copyright
Copyright © 2006 American Medical Association. All Rights Reserved.
ISSN
0003-9926
eISSN
1538-3679
DOI
10.1001/archinte.166.20.2289-b
Publisher site
See Article on Publisher Site

Abstract

In reply We are delighted that our article has captured the attention of our colleagues and we appreciate the comments and additional data. Petrosillo et al describe QT interval prolongation (QTc >0.44 seconds½) in 29 (29%) of 99 HIV-positive injection drug users; similar proportions have been reported by others.1 In our study, 76 (46%) of 167 methadone maintenance patients and 16 (20%) of 80 controls without methadone use presented with a QTc greater than 0.44 seconds½. It is interesting that Petrosillo et al also found a significantly increased risk of QTc prolongation with methadone treatment and a trend for increased risk with the use of cytochrome 3A4 inhibitors. It is important to note, however, that their prospectively examined outpatients differ from the inpatients in our study, notably in that only 29 (29%) of their patients are methadone maintenance patients and in our methadone group only 67 (40%) were HIV positive. The 2 groups of patients are therefore not unequivocally comparable, but both findings underline the possibility of multiple simultaneous risk factors for QT prolongation with methadone treatment. Schmittner and Krantz rightly point out that the article by Krantz et al2 on 17 methadone-treated patients presenting with TdP has not been adequately appreciated in our report. The strength of correlation between methadone dose and QTc is higher in this report: +0.51 for methadone use alone compared with +0.32 for methadone use and 3 additional risk factors. There is variation between the 2 reports that might explain this difference, such as setting, case ascertainment, methadone doses and indication, and age of patients, among others. It is interesting to note that in the article by Krantz et al,2 other risk factors for LQTS, like hypokalemia, were not significantly associated with QT prolongation, although the average daily methadone dose was more than 3 times higher and thus the “repolarization reserve” might be more compromised in their patients. We thank Justo for emphasizing that the correlation between drug-induced LQTS and the risk for TdP is unknown. He reviewed 40 published reports on methadone-induced TdP and found that none of these patients exhibited the 4 risk factors reported in our article. In our study, 2 of 6 patients with TdP exhibited a QTc of less than 0.5 seconds½: 0.48 seconds½ in 1 female and 0.43 seconds½ in 1 male patient. Only this last case can be classified as having a normal QT interval. We agree that methadone treatment has been shown to be of great benefit in most patients. It has taken many years for Krantz and colleagues and our group to describe the frequent QT interval prolongation that can occur with methadone administration.3,4 Because of the rarity of its occurrence, further studies will be necessary to analyze the occurrence of TdP in a subset of patients. The recent identification of common genetic determinants of QT length in the general population5 might open new scientific avenues. Correspondence: Dr Ehret, McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205 (georg@jhmi.edu) References 1. Kocheril AGBokhari SABatsford WPSinusas AJ Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997;202810- 2816PubMedGoogle ScholarCrossref 2. Krantz MJKutinsky IBRobertson ADMehler PS Dose-related effects of methadone on QT prolongation in a series of patients with torsade de pointes. Pharmacotherapy 2003;23802- 805PubMedGoogle ScholarCrossref 3. Krantz MJLewkowiez LHays HWoodroffe MARobertson ADMehler PS Torsade de pointes associated with very-high-dose methadone. Ann Intern Med 2002;137501- 504PubMedGoogle ScholarCrossref 4. Bittar PPiguet VKondo-Oestreicher MDesmeules JDayer P Methadone-induced long QTc and “torsade de pointes” [abstract P244]. Swiss Med Forum 2002; ((8 suppl)) 36SGoogle Scholar 5. Arking DEPfeufer APost W et al. A common genetic variant in the NOS1 regulator NOS1AP modulates cardiac repolarization. Nat Genet 2006;38644- 651PubMedGoogle ScholarCrossref

Journal

Archives of Internal MedicineAmerican Medical Association

Published: Nov 13, 2006

Keywords: methadone,qtc

References