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QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial
Erich F. Wedam, MD;
George E. Bigelow, PhD;
Rolley E. Johnson, PharmD;
Paul A. Nuzzo, MA;
Mark C. P. Haigney, MD
Arch Intern Med. 2007;167(22):2469-2475.
Background Levomethadyl acetate, methadone hydrochloride, and buprenorphine hydrochloride are equally effective treatments for opioid dependence. Each blocks the human ether-a-go-go–related gene (hERG)-associated channel in vitro and represents a risk for QT prolongation. To compare the effects of 3 known hERG-associated channel blockers on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid-addicted subjects.
Methods We analyzed 12-lead electrocardiograms collected at baseline and every 4 weeks from 165 opioid-addicted participants in a 17-week randomized double-blind clinical trial of equally effective doses of levomethadyl, methadone, and buprenorphine at a major referral center. Analyses were limited to the 154 patients with a normal baseline QTc = (QT/ R-R) who had at least 1 subsequent in-treatment electrocardiogram. Patients were randomized to receive treatment with levomethadyl, methadone, or buprenorphine (hereinafter, levomethadyl, methadone, and buprenorphine groups, respectively). The prespecified end points were a QTc greater than 470 milliseconds in men (or >490 milliseconds in women), or an increase from baseline in QTc greater than 60 milliseconds.
Results Baseline QTc was similar in the 3 groups. The levomethadyl and methadone groups were significantly more likely to manifest a QTc greater than 470 or 490 milliseconds (28% for the levomethadyl group vs 23% for the methadone group vs 0% for the buprenorphine group; P < .001) or an increase from baseline in QTc greater than 60 milliseconds (21% of the levomethadyl group [odds ratio, 15.8; 95% confidence interval, 3.7-67.1] and 12% of the methadone group [odds ratio, 8.4; 95% confidence interval, 1.9-36.4]) compared with the buprenorphine group (2% of subjects; P < .001). In subjects whose dosage of levomethadyl or methadone remained fixed over at least 8 weeks, the QTc continued to increase progressively over time (P = .08 for the levomethadyl group, P = .01 for the methadone group).
Conclusion Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.
Author Affiliations: Department of Cardiology, National Naval Medical Center, Bethesda, Maryland (Dr Wedam); Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland (Drs Bigelow and Johnson and Mr Nuzzo). Division of Cardiology, Department of Medicine, Uniformed Services University, Bethesda (Dr Haigney). Dr Johnson is now with Reckitt-Benckiser Pharmaceuticals Inc. Mr Nuzzo is now with the Department of Behavioral Sciences, University of Kentucky, Lexington.
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