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Pharmacokinetics and Pharmacodynamics of Multiple Sublingual Buprenorphine Tablets in Dose-Escalation Trials

From the Division of Psychiatry, Boston University School of Medicine, Boston, Massachusetts (Dr D. A. Ciraulo, Dr Knapp, Dr Sarid-Segal, Ms A. M. Ciraulo); Boston Veterans Affairs Healthcare System, Boston, Massachusetts (Dr D. A. Ciraulo, Dr Sarid-Segal); the Department of Behavioral Neuroscience, Oregon Health Sciences University, Portland (Dr Hitzemann); Cincinnati Addiction Research Center, University of Cincinnati and Cincinnati VA Medical Center, Cincinnati, Ohio (Dr Somoza); the Department of Psychiatry, New York University School of Medicine and VA New York Harbor Healthcare, New York, New York (Dr Rotrosen); Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (Dr Greenblatt); and the National Institute on Drug Abuse, Bethesda, Maryland (Dr Chiang).

In this investigation, the pharmacokinetic and pharmacodynamic properties were determined of multiple doses of sublingual tablets containing either buprenorphine alone or buprenorphine and naloxone. Subjects were experienced opiate users who received escalating doses (4-24 mg) of buprenorphine either alone or in combination with naloxone. Peak concentration (Cmax) and area under the concentration-time curves (AUCs) increased for both buprenorphine and naloxone with escalating doses. Significant differences were found across the range of doses administered for dose-adjusted Cmax for both tablet formulations and for the dose-adjusted AUCs for the buprenorphine-naloxone tablets. For both formulations, the maximal buprenorphine-induced decreases in respiratory rate and pupil diameter did not vary significantly across doses. Several of the subjective effects of buprenorphine did not increase as the dose of buprenorphine administered was increased. These findings are consistent with the ceiling effect associated with the partial agonist actions of buprenorphine. They also indicate a lack of dose proportionality for buprenorphine sublingual tablets, at least during the times at which levels of this agent are highest.

Key Words: Opioid dependence • partial agonist • naloxone • sublingual

Address for reprints: Domenic A. Ciraulo, Boston University School of Medicine, Doctors Office Building, Suite 914, 720 Harrison Avenue, Boston, MA 02118.

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