QTc interval prolongation associated with intravenous methadone Journal Article


Authors: Kornick, C. A.; Kilborn, M. J.; Santiago-Palma, J.; Schulman, G.; Thaler, H. T.; Keefe, D.; Katchman, A. N.; Pezzullo, J. C.; Ebert, S. N.; Woosley, R. L.; Payne, R.; Manfredi, P. L.
Article Title: QTc interval prolongation associated with intravenous methadone
Abstract: 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 IHERG 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=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20±2 μM and 4.4±0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. 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. © 2003 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
Keywords: controlled study; major clinical study; clinical trial; side effect; linear models; controlled clinical trial; pain; cell line; cancer pain; dose-response relationship, drug; evaluation; methadone; infusions, intravenous; electrocardiography; electrocardiogram; arrhythmias; torsade des pointes; kidney cell; qt interval; chlorbutol; long qt syndrome; humans; human; male; female; priority journal; article; chlorobutanol; herg potassium current; qt; potassium current
Journal Title: Pain
Volume: 105
Issue: 3
ISSN: 0304-3959
Publisher: Elsevier Science BV  
Date Published: 2003-10-01
Start Page: 499
End Page: 506
Language: English
DOI: 10.1016/s0304-3959(03)00205-7
PUBMED: 14527710
PROVIDER: scopus
DOI/URL:
Notes: Export Date: 12 September 2014 -- Source: Scopus
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MSK Authors
  1. Deborah Keefe
    36 Keefe
  2. Craig A Kornick
    12 Kornick
  3. Richard Payne
    55 Payne
  4. Howard T Thaler
    227 Thaler