title: Effect of Buprenorphine Implants on Illicit Opioid Use Among Abstinent Adults With Opioid Dependence Treated With Sublingual Buprenorphine: A Randomized Clinical Trial.
abstract: OBJECTIVE
  The effectiveness of buprenorphine treatment of opioid dependence is limited by suboptimal medication adherence, abuse, and diversion.
  
  
  OBJECTIVE
  To determine whether 6-month buprenorphine implants are noninferior to daily sublingual buprenorphine as maintenance treatment for opioid-dependent patients with stable abstinence.
  
  
  METHODS
  Outpatient, randomized, active-controlled, 24-week, double-blind, double-dummy study conducted at 21 US sites from June 26, 2014, through May 18, 2015. Outpatients were prescribed daily sublingual buprenorphine for 6 months or more, were abstinent while taking 8 mg/d or less of sublingual buprenorphine for 90 days or longer, and were determined to be clinically stable by their physician.
  
  
  METHODS
  Participants were randomized to receive sublingual buprenorphine plus 4 placebo implants or sublingual placebo plus four 80-mg buprenorphine hydrochloride implants (expected efficacy, 24 weeks).
  
  
  METHODS
  The primary end point was between-group difference in proportion of responders (≥4 of 6 months without opioid-positive urine test result [monthly and 4 times randomly] and self-report). The noninferiority established for the lower bound of the 95% confidence interval was greater than -0.20 (P < .025). Secondary end points included cumulative percentage of negative opioid urine results, abstinence, and time to first illicit opioid use. Safety was assessed by adverse event reporting.
  
  
  RESULTS
  Of 177 participants (mean age, 39 years; 40.9% female), 90 were randomized to sublingual buprenorphine with placebo implants and 87 to buprenorphine implants with sublingual placebo; 165 of 177 (93.2%) completed the trial. Eighty-one of 84 (96.4%) receiving buprenorphine implants and 78 of 89 (87.6%) receiving sublingual buprenorphine were responders, an 8.8% difference (1-sided 97.5% CI, 0.009 to ∞; P < .001 for noninferiority). Over 6 months, 72 of 84 (85.7%) receiving buprenorphine implants and 64 of 89 (71.9%) receiving sublingual buprenorphine maintained opioid abstinence (hazard ratio, 13.8; 95% CI, 0.018-0.258; P = .03). Non-implant-related and implant-related adverse events occurred in 48.3% and 23% of the buprenorphine implant group and in 52.8% and 13.5% of participants in the sublingual buprenorphine group, respectively.
  
  
  CONCLUSIONS
  Among adults with opioid dependence maintaining abstinence with a stable dose of sublingual buprenorphine, the use of buprenorphine implants compared with continued sublingual buprenorphine did not result in an inferior likelihood of remaining a responder. However, the study population had an exceptionally high response rate in the control group, and further studies are needed in broader populations to assess the efficacy in other settings.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT02180659.
authors.affiliation: Center for Addictive Disorders, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Rosenthal
authors.affiliation: University of Kentucky College of Medicine, Center on Drug and Alcohol Research, Lexington.
authors.forename: Michelle R
authors.initials: MR
authors.lastname: Lofwall
authors.affiliation: Braeburn Pharmaceuticals, Princeton, New Jersey.
authors.forename: Sonnie
authors.initials: S
authors.lastname: Kim
authors.affiliation: TCM Groups Inc, Berkeley Heights, New Jersey.
authors.forename: Michael
authors.initials: M
authors.lastname: Chen
authors.affiliation: Titan Pharmaceuticals, South San Francisco, California.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Beebe
authors.affiliation: Friends Research Institute Inc, Baltimore, Maryland.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Vocci
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D000701:Analgesics, Opioid / Q000097:blood; D002047:Buprenorphine / Q000008:administration & dosage*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004343:Drug Implants; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009292:Narcotic Antagonists / Q000008:administration & dosage*; D009293:Opioid-Related Disorders / Q000188:drug therapy*; D057566:Self Report
chemical_list: D000701:Analgesics, Opioid; D004343:Drug Implants; D009292:Narcotic Antagonists; D002047:Buprenorphine