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.
Design: 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).
Participants: Twenty nondependent, opioid-experienced volunteers.
Methods: Subjects in the solution experiment received sublingual buprenorphine solution in single ascending doses of 4, 8, 16 and 32mg. Subjects in the tablet experiment received sublingual tablets combining buprenorphine 4, 8 and 16mg with naloxone at a 4: 1 ratio or buprenorphine 16mg 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 32mg solution, buprenorphine 16mg tablet and buprenorphine/naloxone 16/4mg tablet were only 54 ± 16%, 70 ± 25% and 72 ± 17%, respectively, of that of the 4mg 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 32mg solution dose, even though acceptability of the 4mg dose was greatest. Naloxone did not change the bioavailability or effects of the buprenorphine 16mg tablet.
Conclusion: Less than dose-proportional increases in plasma buprenorphine concentrations may contribute to the observed plateau for most pharmacodynamic effects as the dose is increased.
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Acknowledgements
This study was supported by US Public Health Service grants DA12393 and DA00053 and contract no. N01DA-4-8306 from the National Institute on Drug Abuse, National Institutes of Health, and carried out in part in the General Clinical Research Center at the University of California, San Francisco, with support of the Division of Research Resources, National Institutes of Health (RR-00079).
The authors thank Tina Melby, Emilio Fernandez, Alan Dearborn, and the staff of the Drug Dependence Research Center and the UCSF General Clinical Research Center for assistance in conducting the study; Susette Welm, Alan Bostrom, Robert Jimison, and Gina Sequeira for data analysis and presentation; and Kaye Welch for editorial assistance. There are no potential conflicts of interest that the authors may have that are directly relevant to the contents of this manuscript.
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Harris, D.S., Mendelson, J.E., Lin, E.T. et al. Pharmacokinetics and Subjective Effects of Sublingual Buprenorphine, Alone or in Combination with Naloxone. Clin Pharmacokinet 43, 329–340 (2004). https://doi.org/10.2165/00003088-200443050-00005
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DOI: https://doi.org/10.2165/00003088-200443050-00005