title: Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials.
abstract: OBJECTIVE
  To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80).
  
  
  METHODS
  Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI).
  
  
  RESULTS
  In the first study (n = 44), the maximum upper bounds of the 90% confidence interval (CI) for mean placebo-corrected change from baseline in QTcI across 13 time points over 24 h were: 10.0 msec for BTDS 10 (Day 6) and 13.3 msec for BTDS 40 (Day 13); and 17.0 msec (Day 6) and 15.5 msec (Day 13) for moxifloxacin, respectively.  Similarly, in the second study (n = 66), the upper bound of the 90% CI for mean placebo-corrected change from baseline for QTcI was under 10 msec at all time points for BTDS 10 (maximum upper bound, 5.63 msec), over 10 msec at 5 time points for BTDS 40 (maximum 11.81 msec) and over 10 msec at all 13 time points for BTDS 80 (maximum, 14.14 msec). Naltrexone administered with BTDS eliminated the QTcI prolongation seen with supratherapeutic BTDS doses (BTDS 40, BTDS 80) administered without naltrexone.
  
  
  CONCLUSIONS
  At the therapeutic dose of 10 mcg/h, BTDS has no clinically significant effect on QTc. At supratherapeutic doses of 40 and 80 mcg/h, BTDS treatment produces prolongation of QTcI similar in magnitude to that produced by a 400 mg dose of moxifloxacin. Despite the modest, dose-dependent increase in QTcI noted in these studies, transdermal buprenorphine has not been associated with proarrhythmic effects.
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Harris
authors.affiliation: b eResearch Technology, Inc ., Philadelphia , PA , USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Morganroth
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Ripa
authors.affiliation: c Statistical Resources, Inc ., Philadelphia , PA , USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Thorn
authors.affiliation: a Purdue Pharma L.P ., Stamford , CT , USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Colucci
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D001145:Arrhythmias, Cardiac / Q000139:chemically induced*; D001372:Aza Compounds / Q000009:adverse effects / Q000627:therapeutic use; D002047:Buprenorphine / Q000009:adverse effects* / Q000627:therapeutic use; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D024841:Fluoroquinolones / Q000009:adverse effects* / Q000627:therapeutic use; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D009271:Naltrexone / Q000009:adverse effects* / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy*; D014481:United States; D055815:Young Adult
chemical_list: D001372:Aza Compounds; D024841:Fluoroquinolones; D002047:Buprenorphine; D009271:Naltrexone; D000077266:Moxifloxacin
keywords: Buprenorphine; QT interval; QT/QTc prolongation cardiovascular risk; QTcI; cardiac safety