CLINICAL-PHARMACOLOGY OF BUPRENORPHINE - CEILING EFFECTS AT HIGH-DOSES

Objective: The purpose of this study was to characterize the acute eff ects of buprenorphine, an opioid partial mu-agonist, across a wide ran ge of doses in comparison to methadone. Method: Healthy adult male vol unteers, who had experience with but were not physically dependent on opioids, participated while residing on a closed research unit. Four s ubjects received buprenorphine (0, 1, 2, 4, 8, 16, and 32 mg sublingua lly and five subjects received methadone (0, 15, 30, 45, and 60 mg ora lly) in ascending order at 1-week intervals. Physiologic, subjective, and behavioral measures were monitored for 96 hours after drug adminis tration. Results: Both drugs produced typical opioid agonist effects ( positive mood, sedation, respiratory depression, and miosis), some of which persisted for 24 to 48 hours. A plateau was observed for the dos e effects of buprenorphine on subjective measures and respiratory depr ession. Pharmacokinetic data revealed that plasma concentrations of bu prenorphine were linearly related to dose, indicating no limits on sub lingual absorption in this dose range. Conclusions: This study shows a plateau on buprenorphine effects, consistent with its partial agonist classification, and that single doses of buprenorphine up to 70 times the recommended analgesic dose are well tolerated by nondependent hum ans.