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 sublingually2were 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.
Pharmacodynamic Studies: In animal tests and in man, buprenorphine has displayed both typical narcotic agonist and antagonist properties. Agonist effects often exhibited a bell-shaped dose-response curve, as occurs with pentazocine, and subjective opiate-like effects reached a maximum at a dose of about 1mg (subcutaneously) in man. The onset of agonist effects in man was slower (peak effects about 6 hours after subcutaneous or intramuscular injection) but the duration of such effects was longer (about 72 hours) than with morphine (about 3 to 4 hours and 24 to 48 hours, respectively). Dose finding tests of analgesic activity in postoperative or cancer patients (some with previous narcotic ‘experience’) showed buprenorphine to be about 25 times as potent as morphine, although in therapeutic trials in postoperative patients this potency ratio was often higher.
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 models buprenorphine appeared to have a lower dependence liability than the opioid agonists morphine and codeine or the partial antagonist pentazocine, but the extent to which such results can be extrapolated to man is uncertain. In a single direct addiction study in 5 volunteers, very high (8mg daily) intramuscular doses of buprenorphine administered for 1 to 2 months produced a very slowly emerging abstinence syndrome on withdrawal. Thus, while results to date are encouraging, definitive statements on the dependence liability of the drug cannot be made until it has been much more widely used, particularly in patients with chronic pain receiving repeated doses over an extended time period.
Pharmacokinetic Studies: There is little information available on the pharmacokinetic properties of buprenorphine in man. In primates and in 2 volunteers absorption occurred rapidly after intramuscular administration of a labelled dose (2μg/kg) and more slowly after an oral (15μg/kg) dose (peak plasma radioactivity in man at less than 7 minutes and about 2 hours, respectively). Detectable blood radioactivity persisted for more than 24 hours after oral ingestion compared with about 7 hours after intramuscular injection. The absorption pattern after sublingual administration has not been studied.
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.
Therapeutic Trials: Most studies of buprenorphine have been single dose trials in small groups of postoperative patients. In such studies a dose of 0.2 to 0.6mg of buprenorphine parenterally (intramuscular or intravenous injection) or 0.4 to 0.8mg sublingually was at least as effective as usual analgesic doses of morphine, pentazocine or pethidine for 1 to 2 hours after drug administration, and was often superior to the comparison drug at subsequent evaluation periods, indicating a longer duration of analgesic effect (about 6 to 8 hours in many studies). Buprenorphine has not been studied in therapeutic trials in patients with pain due to acute myocardial infarction.
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.
Side Effects: The overall profile of side effects which occur with buprenorphine appears similar to that for other morphine-like analgesics. Most patients studied to date have received a single dose while recovering from surgery. Whether the incidence of side effects would be increased in ambulatory patients, as occurs with other morphine-like agents, cannot be clearly determined from present studies but it is reasonable to expect that this would occur. Only a small number of patients with chronic pain have received repeated doses of buprenorphine over a long period, and the incidence and nature of side effects with this type of administration needs further clarification.
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.
Dosage and Administration: Buprenorphine is presently generally available only for parenteral use. The recommended dosage is 0.3 to 0.6mg by intramuscular or slow intravenous injection, repeated every 6 to 8 hours as needed.
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.