title: Pharmacokinetics and subjective effects of sublingual buprenorphine, alone or in combination with naloxone: lack of dose proportionality.
abstract: OBJECTIVE
  Buprenorphine and buprenorphine/naloxone combinations are effective pharmacotherapies for opioid dependence, but doses are considerably greater than analgesic doses. Because dose-related buprenorphine opioid agonist effects may plateau at higher doses, we evaluated the pharmacokinetics and pharmacodynamics of expected therapeutic doses.
  
  
  METHODS
  The first experiment examined a range of sublingual buprenorphine solution doses with an ascending dose design (n = 12). The second experiment examined a range of doses of sublingual buprenorphine/naloxone tablets along with one dose of buprenorphine alone tablets with a balanced crossover design (n = 8).
  
  
  METHODS
  Twenty nondependent, opioid-experienced volunteers.
  
  
  METHODS
  Subjects in the solution experiment received sublingual buprenorphine solution in single ascending doses of 4, 8, 16 and 32 mg. Subjects in the tablet experiment received sublingual tablets combining buprenorphine 4, 8 and 16 mg with naloxone at a 4 : 1 ratio or buprenorphine 16 mg alone, given as single doses. Plasma buprenorphine, norbuprenorphine and naloxone concentrations and pharmacodynamic effects were measured for 48-72 hours after administration.
  
  
  RESULTS
  Buprenorphine concentrations increased with dose, but not proportionally. Dose-adjusted areas under the concentration-time curve for buprenorphine 32 mg solution, buprenorphine 1 6 mg tablet and buprenorphine/naloxone 16/4 mg tablet were only 54 +/- 16%, 70 +/- 25% and 72 +/- 17%, respectively, of that of the 4 mg dose of sublingual solution or tablet. No differences were found between dose strengths for most subjective and physiological effects. Pupil constriction at 48 hours after administration of solution did, however, increase with dose. Subjects reported greater intoxication with the 32 mg solution dose, even though acceptability of the 4 mg dose was greatest. Naloxone did not change the bioavailability or effects of the buprenorphine 16 mg tablet.
  
  
  CONCLUSIONS
  Less than dose-proportional increases in plasma buprenorphine concentrations may contribute to the observed plateau for most pharmacodynamic effects as the dose is increased.
authors.affiliation: Drug Dependence Research Center, Langley Porter Psychiatric Institute, University of California, San Francisco, San Francisco, California 94143-0984, USA.
authors.forename: Debra S
authors.initials: DS
authors.lastname: Harris
authors.forename: John E
authors.initials: JE
authors.lastname: Mendelson
authors.forename: Emil T
authors.initials: ET
authors.lastname: Lin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Upton
authors.forename: Reese T
authors.initials: RT
authors.lastname: Jones
mesh_terms: D000286:Administration, Sublingual; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000097:blood / Q000494:pharmacology*; D019540:Area Under Curve; D001682:Biological Availability; D002047:Buprenorphine / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D002047:Buprenorphine