title: Electrocardiographic effects of lofexidine and methadone coadministration: secondary findings from a safety study.
abstract: 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.
authors.affiliation: 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.
authors.forename: John
authors.initials: J
authors.lastname: Schmittner
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Schroeder
authors.forename: David H
authors.initials: DH
authors.lastname: Epstein
authors.forename: Mori J
authors.initials: MJ
authors.lastname: Krantz
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Eid
authors.forename: Kenzie L
authors.initials: KL
authors.lastname: Preston
mesh_terms: 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
chemical_list: D009292:Narcotic Antagonists; D003000:Clonidine; D008691:Methadone; C025655:lofexidine