Electrocardiographic effects of lofexidine and methadone coadministration: secondary findings from a safety study.
OBJECTIVE
To determine the electrocardiographic effects of coadministration of lofexidine and methadone.


METHODS
Prospective, double-blind study.


METHODS
Outpatient drug treatment research clinic.


METHODS
Fourteen adults (mean +/- SD age 34.9 +/- 5.3 yrs) with physical dependence on opioids.


METHODS
Participants were stabilized on methadone maintenance therapy, reaching a target dose of 80 mg/day. After 3 weeks of methadone stabilization, participants received lofexidine 0.4 mg or placebo once/day, each for 1 week, administered at the same time as methadone. From weeks 3-8, all subjects received lofexidine, with the dose escalated each week in 0.2-mg increments so that by week 8, participants were receiving lofexidine 1.6 mg/day. Electrocardiograms (ECGs) were obtained at baseline (before methadone), after stabilization with methadone, and after lofexidine coadministration during peak plasma lofexidine levels.


RESULTS
Prespecified outcome measures of mean and maximal changes in heart rate, and PR, QRS, and QTc intervals were obtained after stabilization with methadone and after lofexidine 0.4 mg coadministration. Repeated-measures regression showed no significant changes in heart rate or PR, QRS, or QTc interval after methadone stabilization, but a significant decrease in heart rate (mean +/- SD -8.0 +/- 7.3 beats/min, p=0.0006) after starting lofexidine. When data were analyzed by using maximal ECG response, again, no significant changes were noted during methadone induction compared with baseline, but significant changes did occur in all four ECG parameters when lofexidine was coadministered: decreased heart rate (mean +/- SD -9.6 +/- 5.8 beats/min, p<0.0001) and increased PR interval (+11.1 +/- 19.8 msec, p=0.026), QRS interval (+3.7 +/- 4.3 msec, p=0.002), and QTc interval (+21.9 +/- 40.8 msec, p=0.018). In three female participants, the change in QTc interval from baseline was clinically significant (> 40 msec).


CONCLUSIONS
Our preliminary data suggest that coadministration of lofexidine and methadone induces QTc interval prolongation. This drug combination should be prescribed cautiously, with ECG monitoring. Furthermore, because the participants with the largest changes in QTc interval in our study were female, women may be at highest risk.
Schmittner
John
J
Clinical Pharmacology and Therapeutics Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
Schroeder
Jennifer R
JR
Epstein
David H
DH
Krantz
Mori J
MJ
Eid
Nicole C
NC
Preston
Kenzie L
KL
D000328:Adult; D003000:Clonidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D006801:Humans; D008297:Male; D008691:Methadone / Q000008:administration & dosage* / Q000009:adverse effects*; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000009:adverse effects*; D009293:Opioid-Related Disorders / Q000188:drug therapy; D010865:Pilot Projects; D012307:Risk Factors; D012727:Sex Characteristics
D009292:Narcotic Antagonists; D003000:Clonidine; D008691:Methadone; C025655:lofexidine