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 (IHERG) 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 microM 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.
authors.affiliation: Pain and Palliative Care Service, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Pharmacology, Georgetown University Medical Center, Washington, DC, USA Department of Pharmacy, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Cardiology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA Department of Medicine, University of Arizona Health Sciences Center, Tucson, AZ, USA.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Kornick
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kilborn
authors.forename: Juan
authors.initials: J
authors.lastname: Santiago-Palma
authors.forename: Glenn
authors.initials: G
authors.lastname: Schulman
authors.forename: Howard T
authors.initials: HT
authors.lastname: Thaler
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Keefe
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Katchman
authors.forename: John C
authors.initials: JC
authors.lastname: Pezzullo
authors.forename: Steven N
authors.initials: SN
authors.lastname: Ebert
authors.forename: Raymond L
authors.initials: RL
authors.lastname: Woosley
authors.forename: Richard
authors.initials: R
authors.lastname: Payne
authors.forename: Paolo L
authors.initials: PL
authors.lastname: Manfredi
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D016014:Linear Models; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology; D008297:Male; D008691:Methadone / Q000008:administration & dosage* / Q000009:adverse effects*; D010146:Pain / Q000188:drug therapy
chemical_list: D008691:Methadone