SummarySynopsis: Butorphanol tartrate1,2is a totally synthetic strong analgesic with both narcotic agonist and antagonist properties. When 1 or a few doses of butorphanol and other strong analgesic drugs such as morphine, pethidine or pentazocine were administered to patients with acute (in most cases postoperative) pain in a series of comparative studies, the analgesia produced was usually comparable in all aspects. Studies of analgesic efficacy and safety in patients with acute myocardial infarct pain have not been done. Only a small number of patients with chronic pain have received repeated doses of butorphanol over extended periods, and its relative efficacy, safety and tolerability when used in this manner needs further investigation. In other areas of use, 1 or 2 doses of butorphanol (1 or 2mg) were at least as effective and safe as 40 or 80mg of pethidine when used to relieve pain during active labour, but further studies utilising neurobehavioural evaluations of the newborns for several days should be undertaken to confirm the apparent lack of adverse effects on the infant. In a few well designed anaesthesia studies butorphanol appeared to be comparable to morphine or pethidine when used as a pre-anaesthetic medication or as a component of ‘balanced’ anaesthesia.Side effects with butorphanol have been typical of those usually associated with strong analgesics, sedation and nausea being the most frequent. As with other morphine-like agents, respiratory depression can occur, but unlike morphine (and in common with some other partial agonists-antagonists) the dose-response curve for this effect is plateau-like or bell-shaped, ‘higher’ doses (probably above about 1 to 2mg in healthy subjects) producing a lesser effect than ‘lower’ doses. Butorphanol-induced respiratory depression was reversible in healthy subjects with moderate doses (up to 0.8mg) of naloxone. Psychotomimetic reactions have been reported in some patients receiving butorphanol, and in some cases have been tentatively associated with butorphanol antagonism of previously chronically administered narcotics. However, this relationship is not well established, and the relative incidence of such reactions with butorphanol as compared with other drugs with both narcotic agonist and antagonist activity, such as pentazocine or nalorphine, needs clarification.Studies in animal models and in a few volunteers have suggested that butorphanol may have a lower dependence liability than narcotic drugs such as morphine or pethidine. If this is indeed the case it will offer an important advantage over these agents, but as with other drugs of this type only widespread use over several years will determine with any certainty the relative abuse and dependence potential of butorphanol.Pharmacodynamic Studies: As occurs with other partial narcotic agonists-antagonists, butorphanol tartrate was a much more potent analgesic in some standard animal antinociceptive tests than in others. In other animal tests for typical opiate-like effects, butorphanol often exhibited a bell-shaped dose-response curve, ‘higher’ doses producing a lesser effect than ‘lower’ doses, as is seen with some other drugs with both narcotic agonist and antagonist properties such as buprenorphine and pentazocine.In man subcutaneous butorphanol was about 3 to 5 times as potent as morphine and 15 to 25 times as potent as pentazocine in tests for the production of opiate-like subjective effects and myosis. Similarly, in a potency assay study in cancer patients with postoperative pain, intramuscular butorphanol was approximately 3.5 to 5 times as potent as morphine sulphate on a weight-for-weight basis. This is a slightly lower relative potency than that reported in most therapeutic trials (about 7 times as potent as morphine), possibly due to the previous narcotic experience of most of these cancer patients.In animal tests for narcotic antagonist activity, oral or parenteral butorphanol was about equipotent with nalorphine (and about 5 to 50 times less potent than naloxone), but in studies in morphine-dependent volunteers 4mg of subcutaneous butorphanol produced a less pronounced abstinence syndrome than 3mg of nalorphine.Indeed, administered alone, butorphanol also produces respiratory depression, usual therapeutic doses apparently resulting in a similar degree of depression of respiratory function as that seen with morphine. Unlike morphine, however (but as occurs with some other partial agonists-antagonists) respiratory depression with butorphanol is not dose related, probably reaching a peak at a dose of about 1 to 2mg in healthy subjects beyond which further dose increases produce a lesser effect. As with other drugs with both agonist and antagonist properties, the dose of naloxone required to reverse butorphanol's effects in animal experimental studies was higher than that required to antagonise complete narcotic agonists. However, in healthy subjects it was possible to completely reverse butorphanol induced (usual analgesic doses) respiratory depression with a moderate dose of naloxone (up to 0.8mg), in contrast to reported findings with another new agent with both agonist and antagonist properties, buprenorphine, which was only partially reversed by much higher doses (2.4 to 16mg) of naloxone. Adequate studies of the extent and reversibility of butorphanol's respiratory depressant activity in ‘poor risk’ patients such as those with congestive heart failure or acute myocardial infarctions have not been reported. In studies in patients with cardiovascular disease undergoing diagnostic cardiac catheterisation some haemodynamic differences between butorphanol and equianalgesic doses of morphine were observed. Butorphanol markedly increased pulmonary pressures, and in 1 study may have slightly improved the pump performance of the heart and left ventricular function. However, the number of patients in such investigations was relatively small, and the reproducibility and possible clinical significance of these findings needs to be examined in further well designed studies in patients with heart disease.Preliminary studies in animal models and in a few volunteers suggest that the dependence liability of butorphanol may be lower than that of the traditional morphine-like analgesic drugs. However, as with all strong analgesics (and other centrally acting drugs) the abuse and addiction potential of butorphanol will only become clear after widespread use over a period of several years.Pharmacokinetic Studies: Following oral or intramuscular administration of radiolabelled butorphanol to healthy subjects, absorption was essentially complete, with peak plasma levels occurring at about 1 to 1.5 or 0.5 to 1 hours, respectively. However, oral bioavailability was limited to about 17% compared with intravenous administration, due to extensive first-pass metabolism.Distribution in animals was mainly to excretory organs and fatty or highly perfused tissues. When administered intramuscularly to women in labour butorphanol readily passed into the fetus, neonatal serum containing 0.4 to 1.4 times the maternal serum levels of butorphanol and 0.5 to 0.9 times the maternal butorphanol glucuronide serum concentrations.Butorphanol is extensively metabolised in man, mainly to hydroxybutorphanol. Neither this compound nor a minor (10%) metabolite, norbutorphanol, appear to have analgesic activity. Excretion occurs primarily in the urine (about 70%), although some biliary elimination (about 11 to 14%) of a parenteral dose has been reported. The elimination half-life in healthy subjects is about 2.5 to 3.5 hours.Therapeutic Trials: Butorphanol has been studied primarily in a series of double-blind comparisons with other strong analgesics in patients with moderate to severe postoperative pain. In postoperative patients, as well as in some other areas of study, the doses of drugs used were often below or at the lower end of the usual therapeutic range; and in some instances the dose ratios compared tended to favour butorphanol, on the basis of calculated relative potencies. Thus, further studies comparing somewhat higher equianalgesic doses of butorphanol with the standard comparison drugs would help to clarify the relative efficacies of these agents. Nevertheless, butorphanol has been shown to be an effective analgesic drug. In comparative studies parenteral (usually intramuscular) butorphanol tartrate appeared to be about 7 times as potent as morphine sulphate, about 40 times as potent as pethidine hydrochloride and about 20 times as potent as pentazocine lactate (pentazocine dose expressed as the base) on a weight-for-weight basis. The analgesia produced by 1 or a few doses of butorphanol and that produced by the comparison drugs appeared to be qualitatively similar. In all studies the onset of analgesia was similar for the drugs compared (peak effect about 0.5 to 1 hour after intramuscular injection) and butorphanol was at least as long acting (usually about 3 to 4 hours) as the reference agents.In studies in women with moderate to severe pain during active labour, 1 or 2 intramuscular or intravenous doses of butorphanol (1 or 2mg) were at least as effective as relatively low doses (40 or 80mg) of pethidine. There were no significant differences in fetal or newborn status between the 2 drug groups, but further studies utilising neurobehavioural evaluations of the newborns for several days following delivery are needed to confirm the lack of adverse effects on the infant when the drug is used in this manner.Studies of oral administration have demonstrated analgesic activity with doses of 4 to 16mg of butorphanol. 8 or 16mg oral doses produced a peak analgesic effect similar to that seen with 60mg of codeine when given for a few days to patients with acute musculoskeletal or episiotomy pain, but butorphanol appeared to be longer acting and was thus often statistically superior to codeine at 4 to 6 hours after administration of a dose. Similarly, a single 8mg dose of oral butorphanol was more effective than 50mg of pentazocine (usual oral dose 50 to 100mg) at several evaluation times in postoperative patients, and appeared to be longer acting.Only a small number of patients with chronic pain have received intramuscular or oral butorphanol over an extended period, and a statement of its relative analgesic efficacy in this situation must await further well designed studies, preferably comparing butorphanol with other strong analgesics.In studies of other areas of potential use in addition to plain analgesia, butorphanol has been employed as a pre-anaesthetic medication and as a component of ‘balanced’ anaesthesia, and was comparable to pethidine or morphine in such trials. There are no published studies of butorphanol's analgesic efficacy or safety in patients with acute myocardial infarctions.Side Effects: The profile and overall incidence of side effects which have been reported in studies in patients with acute pain with butorphanol are similar to those seen with other strong analgesics. Sedation, which might be considered a desirable effect in some pre- and postoperative patients, has occurred in about 30 to 40% of patients, nausea in about 4% and vomiting in 1 to 2%. Other effects typical of morphine-like drugs, such as dizziness, confusion, headache and sweating have also been reported (usually in about 1 to 2% of patients) with both butorphanol and the comparison drugs. Blood pressure changes (usually hypotension but infrequently increased blood pressure) have occasionally occurred. Changes in respiratory patterns including Cheyne-Stokes respiration, shallow respiration and bradypnoea have been seen in a few patients, but respiratory depression has not been a clinically significant problem with analgesic doses in patients studied to date, most of whom were basically healthy patients who would not be considered to be ‘poor risks’.The incidence of some typical narcotic-like adverse effects (such as lightheadedness, unusual dreams, feelings of fright) has been higher in cancer patients considered to be at least partially dependent on narcotics than in postoperative patients with no previous chronic narcotic experience. It has been suggested that this may be due to the production of a ‘minimal withdrawal syndrome’ as a result of butorphanol's narcotic antagonist activity. Similarly, other psychotomimetic reactions (feelings of floating or unreality, depersonalisation, hallucinations, euphoria) which have been reported in some patients receiving butorphanol, have in some cases been tentatively associated with butorphanol antagonism of previously administered narcotics, but this has not been clearly established. The relative incidence of such effects in non-dependent and narcotic-dependent patients with butorphanol compared with other strong analgesics will likely be clearly established only after the drug has been in use for some time.Only a small group of patients with chronic pain have received repeated intramuscular or oral doses of butorphanol over an extended period. Treatment was discontinued due to side effects (sedation, nausea, confusion, dizziness, rash) in 18 of 63 patients receiving repeated injections (usually 2 or 4mg) for up to 34 weeks. In a small number of patients who received oral treatment over a 6 to 8 month period, no drug related changes in laboratory or physical examination findings occurred. However, further studies in which larger numbers of patients are treated for extended periods are needed to more clearly determine the drug's tolerability and safety when used in the treatment of chronic pain.Dosage and Administration: The usual recommended dose of butorphanol is 2mg intramuscularly (range 1 to 4mg) or 1mg intravenously (range 0.5 to 2mg), repeated every 3 to 4 hours, as necessary. If oral administration is used, the usual recommended single dose is 4 or 8mg, although up to 16mg may be used in more severe pain.Precautions which would be observed while administering other strong analgesics (e.g. careful observation of ‘poor risk’ patients, avoidance of activities requiring particular alertness) should be exercised with butorphanol until the patients' response to treatment has been determined.