Synopsis: Buprenorphine1, a derivative of the morphine alkaloid thebaine, is a strong analgesic with marked narcotic antagonist activity. In studies in relatively small groups of postoperative patients with moderate to severe pain, one or a few doses of buprenorphine parenterally (by intramuscular or slow intravenous injection) or sublingually2 were at least as effective as standard doses of other strong analgesics such as morphine, pethidine or pentazocine, and buprenorphine was longer acting than these agents. Only a small number of patients with chronic pain have received repeated doses, but in such patients there was no need for increased doses during several weeks to months of treatment. Buprenorphine appears to produce side effects which are similar to those seen with other morphine- like compounds, including respiratory depression. There is apparently no completely reliable specific antagonist for buprenorphine’s respiratory depressant effect, since even very high doses of the antagonist drug naloxone may produce only a partial reversal. The respiratory stimulant drug doxapram has overcome respiratory depression in volunteers and in a few patients in a clinical setting, but such studies have not been done in an overdose situation. Animal studies and a direct addiction study in a few volunteers suggest that the dependence liability of buprenorphine may be lower than that of other older morphine- like drugs. However, a slowly emerging abstinence syndrome did occur on withdrawal after very high doses administered for 1 to 2 months. A definitive statement on the drug’s dependence liability and abuse potential cannot be made until it has had much wider use for a longer period of time. In most in vitro and in vivo animal studies buprenorphine has also shown the ability to antagonise the effects of single doses of morphine, and to precipitate abstinence in animals dependent on morphine. Although in several such tests a ‘ceiling effect’ of antagonist activity occurred with higher doses not producing an increased response, in others (precipitation of abstinence in morphine dependent monkeys) such an effect was not observed. In man, the narcotic antagonist activity of buprenorphine has been demonstrated through precipitation of abstinence in narcotic dependent subjects and by reversal of fentanyl anaesthesia. The respiratory depressant activity of single equianalgesic doses of buprenorphine and morphine appears to be similar. Although a ‘ceiling effect’ for buprenorphine induced respiratory depression has been demonstrated in animals, it is presently unclear whether or not this occurs in man, but within the therapeutic dose range respiratory depression is dose related. The onset of peak respiratory depressant effect is slower after intramuscular buprenorphine than after morphine (3 hours versus 1 hour) and the duration of such an effect, although not clearly determined, is longer. In therapeutic trials published to date respiratory depression with buprenorphine has not been a problem, but such studies have usually involved single doses in fit patients undergoing surgery. The respiratory depressant effects in ‘poor risk’ patients or following repeated doses need further study. There appears to be no completely reliable specific antagonist for buprenorphine induced respiratory depression, since even very high doses of naloxone may produce only partial reversal. However, the respiratory stimulant drug doxapram has reversed respiratory depression due to buprenorphine in a few healthy volunteers and in a few patients in a clinical setting. Haemodynamic changes in healthy volunteers after intramuscular (0.15 to 0.6mg), sublingual (0.4 or 0.8mg) or oral (1 to 4mg) doses of buprenorphine have been limited to a dose related reduction in heart rate (up to 25%) and a small decrease in systolic blood pressure (about 10%), as occurred with morphine. Similar dose related effects occurred in anaesthetised patients undergoing surgery and in a few patients with myocardial infarctions, although in the latter group the heart rate remained relatively unchanged. In animal distribution studies the liver and brain contained the highest levels of radioactivity. In pregnant rats, radioactivity readily reached the placenta after oral or parenteral doses. In man, N-dealkylbuprenorphine and conjugates of this and the parent drug are the only metabolites so far identified. The pharmacological activity of these metabolites has not been studied. Excretion occurred primarily in the faeces (71% and 68% of radioactivity after 15μg/kg orally and 2μg/kg intravenously, respectively) which contained mainly unchanged buprenorphine, while urinary excretion products (15% and 27% of radioactivity after oral and intramuscular administration) were conjugates of buprenorphine and N-dealkylbuprenorphine. In a small number of patients with chronic pain, usually due to cancer, sublingual buprenorphine (up to 0.8mg 4-hourly) provided adequate pain relief for periods of up to several months but side effects (usually nausea or vomiting) required discontinuing treatment in about 1/3 to 1/2 of the ambulant patients treated in this way. Following analgesic anaesthesia, usually with fentanyl, in about 180 patients buprenorphine (usually 0.4 to 0.8mg intravenously) has been used to reverse some of the anaesthetic effects while producing continued analgesia which lasted about 8 to 12 hours after a single dose. The antagonist activity, however, was frequently more short lived, declining rapidly after 90 to 120 minutes; and a second dose of buprenorphine was often required at this time to prevent re-emergence of anaesthetic effects. Moderate to marked drowsiness has been reported in about 40 to 45 % of patients (up to 75% in some studies), but all such patients were easily arousable on stimulation. Nausea and/or vomiting occurred in about 15% of patients. Other minor side effects typical of strong analgesics such as dizziness, sweating, headache, or confusion have been reported with a widely varying incidence. Euphoria has been reported on rare occasions. Respiratory depression, as determined by laboratory measurements of respiratory function, does occur with buprenorphine, the extent of such depression being similar to that seen with other opioid drugs administered in usual clinical doses; but this has not been a problem in clinical studies to date which were usually conducted in fit patients. The effect of buprenorphine on respiration in ‘poor risk’ patients such as those with respiratory disease or congestive heart failure has not been determined. However, it appears that buprenorphine would have the same potential problems as morphine in this patient group. Administration of buprenorphine to patients already receiving large doses of narcotic drugs should be undertaken with caution until the response is established, since its antagonist activity could conceivably precipitate abstinence in this situation.