Buprenorphrine: demonstration of physical dependence liability.

This study was designed to assess the dependence-producing capacity of the opiate partial agonist, buprenorphine. Rats chronically treated with buprenorphine for 4 days showed only very weak signs of withdrawal upon cessation of buprenorphine treatment or upon challenge with naloxone, although complete tolerance had developed to the drug at this time. However, more intense withdrawal could be induced when buprenorphine treatment was followed by substitution treatment with morphine. Even one injection of morphine given 12 h after the last buprenorphine treatment enabled the precipitation of withdrawal with naloxone. Naloxone could not precipitate signs of withdrawal in naive rats treated with this dose of morphine. Thus, contrary to some claims in the literature, buprenorphine, like other opiate agonists and partial agonists, induces dependence. The fact that only few signs of withdrawal are seen in direct dependence tests, probably reflects the slow dissociation of the drug from the receptor - which probably limits the intensity of withdrawal by preventing the rapid uncovery of the receptor upon discontinuance of treatment with the drug or upon injection of an antagonist. In addition, the maximum degree of dependence induced by buprenorphine - in comparison to pure agonists is limited, like that of other partial agonists.