title: Effects of a higher-bioavailability buprenorphine/naloxone sublingual tablet versus buprenorphine/naloxone film for the treatment of opioid dependence during induction and stabilization: a multicenter, randomized trial.
abstract: OBJECTIVE
  Sublingual buprenorphine and combination buprenorphine/naloxone (BNX) are effective options for the treatment of opioid dependence. A BNX sublingual tablet approved by the US Food and Drug Administration for the induction and maintenance treatment of opioid-dependence in adults was developed as a higher-bioavailability formulation, allowing for a 30% lesser dose of buprenorphine with bioequivalent systemic exposure compared with another BNX sublingual tablet formulation. No data were previously available comparing the higher-bioavailability BNX sublingual tablet to generic buprenorphine or BNX sublingual film; we therefore evaluated treatment retention during induction and stabilization with the higher-bioavailability BNX sublingual tablet versus generic buprenorphine or BNX sublingual film.
  
  
  METHODS
  This multicenter, prospective, randomized, parallel-group noninferiority trial was conducted at 43 centers in the United States. Eligible patients were adults aged 18 to 65 years who met the criteria for opioid dependence and had at least mild withdrawal symptoms. On days 1 and 2, patients received blinded, fixed-dose induction with the higher-bioavailability BNX sublingual tablet or generic buprenorphine. On days 3 to 14, patients induced with BNX received open-label, titrated doses of the BNX tablet for stabilization; patients induced with buprenorphine received sublingual BNX film. Co-primary end points were treatment retention on days 3 and 15; noninferiority was concluded if the lower limit of the 95% CI of the between-group difference in treatment retention was ≥-10%. Tolerability was assessed throughout the study period.
  
  
  RESULTS
  A total of 758 opioid-dependent patients were included in the study (BNX sublingual tablet, 383 patients; generic buprenorphine, 375). Day-3 retention rates were 93.9% (309/329) and 92.6% (302/326) with the BNX tablet and buprenorphine, respectively (between-group difference 95% CI, -2.6 to 5.1). Day-15 retention rates were 83.0% (273/329) and 82.5% (269/326) with the BNX tablet and BNX film, respectively (between-group difference 95% CI, -5.3 to 6.3). No unexpected tolerability issues were identified; the safety profile of the BNX sublingual tablet was similar to those of generic buprenorphine and BNX film.
  
  
  CONCLUSIONS
  Based on the findings from this study in patients with opioid dependence, the higher-bioavailability BNX sublingual tablet formulation was noninferior to both generic buprenorphine (induction) and BNX film (stabilization). These findings suggest that BNX sublingual tablets are an efficacious and well-tolerated option for induction and early stabilization treatment of opioid dependence. ClinicalTrials.gov identifier: NCT01908842.
authors.affiliation: University of Virginia, Charlottesville, Virginia. Electronic address: EWG2N@hscmail.mcc.virginia.edu.
authors.forename: Erik W
authors.initials: EW
authors.lastname: Gunderson
authors.affiliation: Orexo AB, Uppsala, Sweden.
authors.forename: Peter
authors.initials: P
authors.lastname: Hjelmström
authors.affiliation: Orexo US, Inc, Morristown, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Sumner
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D000069479:Buprenorphine, Naloxone Drug Combination / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009293:Opioid-Related Disorders / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies; D013607:Tablets; D014481:United States
chemical_list: D000701:Analgesics, Opioid; D000069479:Buprenorphine, Naloxone Drug Combination; D009292:Narcotic Antagonists; D013607:Tablets
keywords: buprenorphine; buprenorphine/naloxone combination; induction therapy; maintenance therapy; treatment retention