QT-interval effects of methadone, levomethadyl, and buprenorphine in a randomized trial.
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/ radical 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).


CONCLUSIONS
Buprenorphine is associated with less QTc prolongation than levomethadyl or methadone and may be a safe alternative.
Wedam
Erich F
EF
Division of Cardiology, Department of Medicine, Uniformed Services University of the Health Sciences, A3060, USUHS, Bethesda, MD 20814, USA.
Bigelow
George E
GE
Johnson
Rolley E
RE
Nuzzo
Paul A
PA
Haigney
Mark C P
MC
D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage*; D002047:Buprenorphine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008691:Methadone / Q000008:administration & dosage*; D008692:Methadyl Acetate / Q000008:administration & dosage*; D009293:Opioid-Related Disorders / Q000503:physiopathology / Q000534:rehabilitation*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D000701:Analgesics, Opioid; D002047:Buprenorphine; D008692:Methadyl Acetate; D008691:Methadone