Evaluations on New Drugs

Drugs 16: 473-505 (1978) © ADIS Press 1978

Butorphanol: A Review of its Pharmacological Properties and Therapeutic Efficacy R.C. Heel, R.N. Brogden, T.M. Speight and GS. Avery Australasian Drug Information Services, Auckland Various sections of the manuscript reviewed by: A, Del Pizzo. Department of Anesthesiology, Columbus Cuneo Cabrini Medical Center, Chicago, Illinois, U.S.A.; A.B. Dobkin, Department of Anesthesiology, State University of New York, Upstate Medical Center, Syracuse, New York, U.S.A.; JM. Gibbs, Department of Anaesthesia, Christchurch Clinical School. Christchurch, New Zealand; C. Glynn, Department of Anaesthesia and Intensive Care, Flinders Medical Center, Bedford Park, Australia; DR. Jasinski, National Institute on Drug Abuse Addiction Research Center, Lexington, Kentucky, U.S.A.; T. Kallos, Miami, Florida, U.S.A.; M. Lippmann, Department of Anesthesiology, School of Medicine, University of California, Harbor General Hospital, Torrance, Califomia, U.S.A.; L.E. Mather, Department of Anaesthesia and Intensive Care, Flinders Medical Center, Bedford Park, Australia; DA. McQuillan, Auckland, New Zealand; M.S. Mok, Department of Anesthesiology, School of Medicine, University of California, Harbor General Hospital. Torrance, California, U.S.A.; SN. Steen, Department of Anesthesiology, School of Medicine, University of Califomia, Harbor General Hospital, Torrance, California, U.S.A.; L. Stehling, Department of Anesthesiology, State University of New York, Upstate Medical Center, Syracuse, New York, U.S.A.; RES. Young, Institute of Medical Research Inc., Columbus, Ohio, U.S.A.; H.L. Zauder, Department of Anesthesiology, State University of New York, Upstate Medical Center, Syracuse, New York, U.S.A.

Table ofContents Summary I. Pharmacodynamic Studies I .1 Narcotic Agonist Activity 1.1.1 Animal Tests 1.1.2 Tests for Opiate Effects and Analgesic Potency in Man 1.2 Narcotic Antagonist Activity 1.3 Respiratory Effects 1.3.1 Animal Studies 1.3.2 Studies in Healthy Volunteers I .3.3 Patients Undergoing Cardiac Catheterisation 1.3.4 Anaesthetised Patients 1.4 Haemodynamic Effects 1.5 Reversing Butorphanol's Effects 1.6 Dependence Liability 1.7 Safety Studies 1.8 Toxicology Studies 1.8.1 Acute Toxicity Studies

474 478 479 479 480 480 481 481 481 481 481 482 483 485 485 485 485

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474

1.8.2 Multiple Dose Toxicity Studies 1.8.3 Reproduction Studies 1.8.4 Tests for Carcinogenic Activity 2. Pharmacokinetic Studies 2.1 Absorption 2.2 Distribution 2.2.1 Animal Studies 2.2.2 Human Maternal-fetal Transfer during Labour 2.2.3 Protein Binding 2.3 Elimination 2.3.1 Metabolism 2.3.2 Excretion 3. Therapeutic Trials 3.1 Open Studies of Analgesic Efficacy 3.1.1 Intramuscular Use in Patients with Acute Postoperative Pain 3.1.2 Intramuscular Use in Patients with Chronic Pain 3.2 Controlled Studies of Analgesic Efficacy 3.2.1 Comparisons with a Placebo 3.2.2 Comparisons with Morphine 3.2.3 Comparisons with Pethidine (Meperidine) 3.2.4 Comparisons with Pentazocine 3.2.5 Comparisons with Codeine 3.2.6 Comparison with Paracetamol (Acetaminophen) 3.3 Use as a Pre-anaesthetic Medication 3.3.1 Open Studies 3.3.2 Comparison with Pethidine (Meperidine) 3.4 Use in 'Balanced' Anaesthesia 3.4.1 Open Studies 3.4.2 Comparison with Morphine 3.4.3 Comparison with Pethidine (Meperidine) 4. Side Effects 4.1 Short Term Administration 4.2 Longer Term Administration 5. The Place of Butorphanol in TheraPy........................................................................................ 6. Dosage and Administration 7. Overdosage References

Summary

486 486 486 486 487 487 487 487 487 487 487 488 488 489 489 489 492 492 492 492 495 495 496 497 497 497 498 498 498 498 499 499 500 50 I 502 502 502

Synopsis: Butorphanol tartrate 1 •2 is 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 I 'Dorphanol', 'Stadol' (Bristol Laboratories). 2 Throughout this review 'butorphanol' refers to butorphanol tartrate and all butorphanol doses are expressed as the tartrate unless stated otherwise. Doses of other drugs are expressed according to common usage (e.g. morphine as the sulphate, pethidine and naloxone as the hydrochlorides, pentazocine as the base, etc.).

Butorphanol: A Review

475

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 (J 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 pat(ents 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 ofsuch 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 I 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

Butorphanol: A Review

476

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 I 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 I to 1.5 or 0.5 to I 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 II 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 s.tudies 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 I 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 I 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, I or 2 intramuscular or intravenous doses of butorphanol (lor 2mg) were at least as effective as relatively low doses (40 or 80mg) of pethidine. There were no significant differences in fetal or

Butorphanol: A Review

477

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 50rng 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 I to 2 %. Other effects typical of morphine-like drugs, such as dizziness, confusion, headache and sweating have also been reported (usually in about I 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.

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Butorphanol: A Review

Dosage and Administration: The usual recommended dose of butorphanol is 2mg intramuscularly (range I to 4rng) or Img 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.

1. Pharmacodynamic Studies Butorphanol, ( - )-17-(cyclobutylmethyl) morphinan-3, 14-diol, is a totally synthetic compound of the nalorphine-cyclazocine series of narcotic agonistantagonist drugs (fig. I). In animal tests for analgesic activity, the relative weight-for-weight potency of butorphanol compared with morphine and pentazocine varied, depending on the test model used and the route of administration, but in an analgesic potency assay in postoperative cancer patients intramuscular butorphanol was about 3.5 to 5 times as potent as morphine sulphate. As occurs with other partial narcotic agonists-antagonists, the production of opiate-like effects with butorphanol was not dose related in some tests, higher doses producing lesser effects than a lower dose. In tests for narcotic antagonist activity in animal models, butorphanol was more potent on a weight-

for-weight basis than pentazocine, about equipotent with nalorphine and less potent than naloxone. However, in morphine-dependent volunteers, it was slightly less potent than nalorphine in precipitating withdrawal. Indeed, administered alone butorphanol does depress respiratory function; but in contrast to the dose related respiratory depression seen with morphine, this effect reaches a 'ceiling' beyond which higher doses of butorphanol do not produce further depression. Thus, in healthy volunteers 'higher' doses of intravenous butorphanol (O.06mg/kg) produced less respiratory depression than approximately equianalgesic doses of pethidine (2mg/kg) or morphine (O.30mg/kg); but in patients with heart disease receiving lower equianalgesic doses, butorphanol (O.025mg/kg) produced similar respiratory depression to that which occurred with morphine (O.125mg/kg).

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Butorphanol: A Review

In healthy subjects, analgesic doses of butorphanol do not produce significant haemodynamic effects. In patients with heart disease however, butorphanol produced a marked rise in pulmonary pressure indices, and moderate rises in indices of the pump perform.ance of the heart and of left ventricular function (in contrast to morphine which often slightlyilecreased these indices). In animal model tests, butorphanol appeared to have a lower dependence liability than morphine, pentazocine or dextropropoxyphene. In a direct addiction study in 6 former narcotic addicts, chronic high dose administration resulted in 'liking' scores which reflected indifference or a slight dislike in contrast to moderate 'liking' usually seen with morphine. Abrupt withdrawal produced some abstinence symptoms similar to those seen during both opiate and nalorphine withdrawal.

1.1 Narcotic Agonist Activity 1.1.1 Animal Tests In studies of antinociceptive activity in animals, the relative weight-for-weight potency of butorphanol, as compared with other strong analgesics, has varied among different test models and routes of administration. Thus, subcutaneous butorphanol was about 5 times as potent as morphine and 73 times as potent as pentazocine in the phenylquinone writhing test in mice, but when the drugs were given orally butorphanol was about one-half as potent as morphine and 6 times as potent as pentazocine (Caruso et aI., 1978; Pircio et al., 1976). In other animal test models (rat tail flick, mouse hot plate, dog skin twitch), subcutaneous butorphanol was about equipotent with pentazocine but was less potent (2 to 89 times) than morphine. The activity ofbutorphanol (which is a laevo-rotary isomer) was much higher than that of its dextro-rotary isomer in all such tests. As with morphine and pentazocine, tolerance to the analgesic effect of butorphanol developed in mice receiving multiples of the initial median effective dose (EDsJ for 4 days, the ED so after this period being 3 to

479

5 times that in non-tolerant mice (Caruso et al., 1978). In a test for inhibition of mouse gastrointestinal motility, subcutaneous butorphanol was one-tenth and one-third as potent as morphine and pentazocine, respectively (Caruso et al., 1978). In contrast, in anaesthetised dogs equianalgesic intravenous doses of butorphanol (0.025mg/kg) and morphine (O.lmg/kg) had spasmogenic effects, increasing duodenal activity; but the maximum effect obtained with butorphanol was only about 13 % of that with morphine (Roebel et al., 1977). Butorphanol did not produce any significant changes in bile flow through the terminal bile duct in this study while morphine produced a dose related significant (p < 0.0 I) reduction in bile flow. In tests for central nervous system effects, a high dose ofbutorphanol (J 9mg/kg, expressed as the base, subcutaneously; about 380 times the analgesic dose) decreased motor coordination of mice by about 50 % (Pircio et aI., 1976). Similarly high doses (J 00 times the analgesic dose) inhibited tonic extension of the hind leg during induced seizures in mice (like pentazocine but unlike nalorphine which was inactive) but did not prevent death due to convulsions. I to 5mg/kg (as the base) subcutaneously produced mild to moderate depression in monkeys, with no discernible dose-response relationship. When dogs were injected intravenously with morphine 2mg/kg, excitement and sham rage associated with a 77 % increase in blood histamine levels occurred, followed by typical sedation, but an approximately equianalgesic dose of butorphanol

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485

Butorphanol: A Review

1.6 Dependence Liability Defmitive statements on the dependence liability and abuse potential of butorphanol cannot be made until the drug has had much wider use for a longer period of time. In animal model tests for physical .dependence liability (naloxone induced mouse jumping, abstinence suppression in morphine dependent mice and monkeys, suppression of body weight loss during morphine withdrawal in rats) butorphanol appeared to have a lower dependence potential than morphine, pentazocine or dextropropoxyphene (Caruso et al., 1978; Swain et al., 1973). In a direct dependence study in 6 former narcotic addicts, subcutaneous butorphanol was administered in increasing doses over a 35-day period to a stabilisation dose of 48mg daily (approximately equivalent to 240mg of morphine) by day 14 (Jasinski et al., 1976). Subjects appeared drowsy and sedated, and reported several symptoms usually associated with opiates (constipation, nausea, difficulty urinating), but frequently identified the drug as a barbiturate. Subjects 'liking' scores indicated indifference or a slight dislike for the drug compared with slight to moderate 'liking' scores obtained for morphine (30 to 240mg/day) in other subjects in similar tests. Administration of naloxone 4mg or nalorphine 40mg during the fourth week of treatment produced typical opiate-like withdrawal symptoms. After 35 days of treatment, double-blind substitution of saline for butorphanol produced withdrawal symptoms within 24 hours which increased in severity until 48 hours. Symptoms resembled those seen with opiate withdrawal but included feeling electric shocks and itching in some subjects, which are usually associated with nalorphine withdrawal.

1.7 Safety Studies In a study in rats to determine the local tolerability of repeated (3 to 6 weeks) twice daily intramuscular injections, butorphanol (0.18 or 0.3 6mg / dose) was

better tolerated than pentazocine (3.6 or 7. 2mg / dose) [Oh, 1977]. Fibrotic nodules and myopathic changes in injected or adjacent muscles occurred more frequently (fibrotic nodules 44 %; myopathic changes, injected muscle 63%, adjacent muscle 38%) in pentazocine-treated rats than in those receiving butorphanol (0 %, 13 % and 0 %, respectively) or saline (0 %, 13 % and 0 %, respectively). In a placebo controlled study in 120 volunteers, daily oral doses of 8 to 64mg of butorphanol administered for 28 consecutive days were well tolerated (Vargas-Arreola et al., 1977). Changes in vital sign measurements and laboratory values during treatment were slight and the incidence of such changes did not differ statistically between drug-treated and placebo-treated groups. Side effects such as drowsiness, nausea or dizziness occurred more freqUlmtly (40 to 67 %) with 8, 12 or 16mg doses than with 2 or 4mg doses (25 to 35%), but within these 2 'higher' and 'lower' dosage groups the incidence of such effects was not obviously dose related. Similarly, an unpublished report of longer term (up to 8 months) oral administration (up to 64mg daily, usually 32mg or less) to 268 patients with chronic pain, showed no changes in laboratory data or physical examination findings considered to be drug related (Caruso, 1978). However, the majority of such patients were treated for 1 month or less, only 24 patients receiving the drug for 6 to 8 months.

1.8 Toxicology Studies The toxicology studies conducted with butorphanol have been reported by Caruso et al. (I 978). 1.8.1 Acute Toxicity Studies The median lethal dose (LD50) of butorphanol in mice by the intravenous, subcutaneous and oral routes was 40 to 57mg/kg, 299 to 432mg/kg and 395 to 527mg/kg, respectively. The corresponding figures for rats were 17 to 20mg/kg, 622 to 852mg/kg and 570 to 756mg/kg. In dogs the LD50 following intravenous, intramuscular or oral ad-

486

Butorphanol: A Review

ministration was 10 to 15mg/kg, 17 to 29mg/kg and greater than 50mg/kg, respectively. Similarly, the oral LD50 in monkeys was more than 50mg/kg. 1.8.2 Multiple Dose Toxicity Studies A number of multiple dose toxicity studies have been performed in rats receiving daily (6 days per week) subcutaneous doses of 2.5 or 10mg/kg for I month, 0.5, 2.5 or 5mg/kg for 3 months and 0.4, 2 or 4mg/kg for 6 months, or daily oral doses of I to 16mg/kg for 3 to 12 months. Subcutaneous administration resulted in lower average food intake and body weight gains than in control groups. A syndrome of nervousness developed, beginning about 2 to 3 weeks after beginning subcutaneous injections, which became more pronounced after each dosing, but the duration of this reaction in the high dose group decreased by the end of the 6-month study from more than 5 hours to 3 to 4 hours after each dose. A mild decrease in white blood cell counts occurred in male rats in the high dose group of the 6month study. Irritation occurred more frequently (incidence not stated) at the injection site in drug-treated than in control rats. No drug related effects were observed during oral administration. In studies in monkeys (in which all doses are expressed in terms of butorphanol base), daily intravenous doses of 0.5 or Img/kg for 14 days, intramuscular doses of 0.15,0.75 or 1.5mg/kg for 6 months, and oral doses of 0.5 to 8mg/kg for 3 to 12 months were administered. Dose related slight to moderate weight losses occurred in the intravenous study. Sedation persisting for 3 to 4 hours after dosing in low dose groups or 5 hours in high dose groups was observed during the 6-month intramuscular study. In the latter stages of the study, the period of sedation was reduced to about I hour. No other apparent drug related changes in monkeys were observed with the exception of occasional irritation at intramuscular injection sites. 1.8.3 Reproduction Studies Most standard reproduction studies in rats, mice and rabbits have not shown any effect of butorphanol

on fertility, gestation or parturition. The survival rate of newborns in some studies was lower (about 70 to 80 %) than in controls (99 %), probably due to drug induced nervousness in the mothers resulting in decreased care of the newborns. A very high oral dose (t 60mg/kg/day) reduced the pregnancy rate in rats (79 % versus 100 % in controls) and the mean pup and litter rates, but no dysmorphogenic effects occurred. 1.8.4 Tests/or Carcinogenic Activity In 200 rats receiving I or 2mg/kg ofbutorphanol per day orally for 78 weeks, no neoplasms occurred that were not observed with a similar frequency in the control group. All non-neoplastic changes that were observed (details not given) were considered incidental to ageing and to be unrelated to drug administration.

2. Pharmacokinetic Studies Absorption after oral or intramuscular administration of butorphanol to healthy subjects is essentially complete, peak plasma levels occurring at 0.5 to I (intramuscular) or I to 1.5 (oral) hours, but oral bioavailability is limited (about I 7 % compared with intravenous administration) as a result of fIrst pass metabolism. Distribution in animals is primarily to excretory organs, and highly perfused and fatty tissues. Following administration during active labour in a human study, neonatal serum on delivery contained 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. The extent of butorphanol excretion in the milk of lactating mothers has not been studied. Butorphanol is extensively metabolised to inactive compounds in man, primarily to hydroxybutorphanol, and subsequently excreted mainly in the urine (about 70 %). However, some biliary elimination does occur, accounting for II to 14 % of a paren-

487

Butorphanol: A Review

teral dose. The elimination half-life of butorphanol in healthy subjects appears to be about 2.5 to 3.5 hours.

2.1 Absorption Following intravenous administratioI1of 1mg of tritium-labelled butorphanol to volunteers, a peak plasma level of 1.5ng ofbutorphanol per ml was observed, using radiochromatographic high pressure liquid chromatography procedures for analysis (Caruso et al., 1978). Similar studies following an intramuscular dose of 2mg and an oral dose of 8mg showed peak plasma levels of 2.2ng/ml (at 0.5 to 1 hour) and 0.7ng/ml at I to 1.5 hours, respectively. However, when a radioimmunoassay procedure was employed, the same doses produced peak levels of 1.7ng/ml (at 0.7 hours; intramuscular route) and 0.35ng/ml (at 1.7 hours; oral route) [Pittman and Smyth, 1975]. Tritium recovery studies indicated complete absorption after intramuscular and oral doses, but both methods of assay showed limited systemic oral bioavailability (17 % using radiochromatographic assay, 5 % using radioimmunoassay), due to fIrst-pass metabolism (see section 2.3.1).

dose remained in the liver and carcass of the rat and 7 to 8 % in the monkey. 2.2.2 Human Maternal-fetal Transfer during Labour

Following I or 2 intramuscular doses of butorphanol (I or 2mg) to 6 women during active labour, 1.5 to 3.5 hours before delivery, the neonatal serum concentrations (determined just after delivery by a radioimmunoassay specifIc for butorphanol and butorphanol glucuronide) were 004 to 104 times the maternal serum levels ofbutorphanol, and 0.5 to 0.9 times the maternal butorphanol glucuronide serum concentrations (Caruso et al., 1978; Maduska and Hajghassemali, 1978). Another circulating butorphanol metabolite, hydroxybutorphanol, was also found in both maternal and newborn serum, but the relative concentrations were not established. 2.2.3 Protein Binding In vitro protein binding studies showed 80 % pro-

tein binding of butorphanol (I to 7ng/ml concentration range) to human serum proteins (Caruso et al., 1978).

2.3 Elimination 2.2 Distribution 2.3.1 Metabolism

Butorphanol is extensively metabolised in man, Total tissue tritium concentrations (butorphanol through hydroxylation, O-dealkylation and conjugaplus metabolites) 6 hours after labelled intravenous tion, less than 5 % of a dose being excreted doses of 1.5 and 5mg/kg to monkeys and rats, indi- unchanged. Over 80 % of an oral dose undergoes cated that excretory tissues were the major organs of fIrst-pass metabolism, primarily to hydroxybutordistribution (Caruso et al., 1978). Tissue tritium con- phanol. The peak plasma levels of this metabolite centrations were 53, 13 and II times the plasma con- were OAng/ml 20 minutes after intravenous (Img) centrations for liver, kidney and intestine, respec- administration, 0.6ng/ml 1.5 hours after intramustively. Some other highly perfused organs, such as cular administration (2mg) and 2.0ng/ml after (time heart, lung, spleen and endocrine tissues, also con- not stated) oral administration, plasma levels then tained higher tritium levels than the plasma (2 to 9 declining slowly over about 8 hours (Caruso et al., times) as did fat tissue (3 times). The tritium con- 1978). Free and conjugated norbutorphanol was a centration in the brain was less than that in plasma 6 minor (I 0 %) metabolite. In analgesic screening tests hours after dosing. After 48 hours, I to 2 % of the in mice these metabolites were inactive. 2.2.1 Animal Studies

Butorphanol: A Review

2.3.2 Excretion In man, urinary excretion of tritium accounted for about 50 % of an administered dose in 24 hours (Caruso et al., 1978). In 72 to 96 hours the cumulative urinary excretion was 62 % of a Img intravenous dose, 72% of a 2mg intramuscular dose and 75 % of an 8mg oral dose. II to 14 % of parenterally administered tritium was excreted in the faeces, indicating some biliary elimination of butorphanol and/ or its metabolites. In volunteer studies using radioimmunoassay procedures, the elimination half-life of butorphanol was about 2.7 hours after a 2mg intravenous or intramuscular dose, and 2.4 to 3.5 hours after an 8mg oral dose (Pittman and Smyth, 1975, 1978).

3. Therapeutic Trials The majority of therapeutic trials with butorphanol have been well designed, and seemingly well executed, double-blind comparative studies with other strong analgesics in patients with moderate to severe postoperative pain. Most comparative studies have made reasonable attempts to minimise the notorious difficulties (due to the subjective nature of pain) encountered in evaluating analgesics, by such measures as randomisation of treatment schedules with checks of the comparability of inter-group pretreatment characteristics, including adequate numbers of patients, using several evaluation parameters, etc. and in a few cases by utilising a placebo control. Most studies of analgesic activity used the same series of standard evaluation scales (pain intensity, pain intensity difference, pain relief, with some reports including pain summation score data) based on patients' descriptions of their pain; and many studies also included I or more observer evaluation scales in an attempt to minimise the effects on study results of interpatient variability of pain perception and pain acceptance. However, many studies used doses of butorphanol and comparison drugs which were below or in the lower part of the usual therapeutic range; and, importantly, in some instances (e.g. Del

488

Pizzo, 1976a; Gilbert et al., I976a) the doses of drugs compared were not equianalgesic, the dose ratios used tending to favour butorphanol. Thus, further studies comparing somewhat higher, equianalgesic doses of butorphanol and comparison drugs would help to clarify the relative efficacies of these agents. Nevertheless, butorphanol has been shown to be an effective analgesic agent. In comparative studies using single or a few parenteral doses in patients with acute pain, butorphanol tartrate was calculated to be about 7, 40 and 20 times as potent on a weight-for-weight basis as morphine sulphate, pethidine hydrochloride and pentazocine lactate, respectivelY. In most such studies the onset time (peak effect 0.5 to I hour after intramuscular injection) and the duration of effect (usually about 3 to 4 hours) have been similar for butorphanol and the comparison drugs, the latter being dose related. In women in active labour, I or 2 doses of intramuscular or intravenous butorphanol (I or 2mg) were at least as effective as 40 or 80mg of pethidine, with no significant differences in the status of the newborns occurring between the drug groups. However, in patients with acute ureteral colic a higher intramuscular dose (4mg) of butorphanol was significantly (p < 0.05) superior to 80mg of pethidine at several evaluation times after an intramuscular dose. Oral administration of several doses over I to 3 days to patients with acute episiotomy or musculoskeletal pain has usually shown 8 or 16mg of butorphanol to be similar in peak activity to 60mg of codeine (or on some evaluation scales to be more active), and to be longer acting and thus often statistically superior to codeine 4 to 6 hours after drug administration. In other oral studies, a single 8mg dose of butorphanol was more effective than 50mg of pentazocine at several evaluation times in patients with postoperative pain, and a combination of 4mg of butorphanol with 650mg of acetaminophen was more active and longer lasting than either drug alone. In an open study, and in a double-blind comparison with pethidine in another area of potential therapeutic usefulness, 2 or 4mg of butorphanol in-

Butorphanol: A Review

489

Table II. Open studies of intramuscular butorphanol tartrate in the treatment of postoperative pain Author

Patient population (number)

Dose (no. of doses)

Onset of max. effect

Duration of effect

Degree of pain relief'

Dobkin et al. (1976a)

Major surgery (usually abdominal or h~ replacement). severe pain (150)

1mg 1.5mg 2mg (1-5)

0.5h 0.5-1h 0.5-1h

2-3h 3-4h 3-4h

Effect. 79% Partial effect. 14 %

Steg (1978)

Post-surgery adolescents (11-17yrs); usually spinal fusion (27)

0.7-3mg (3-22)

0.5h

-3h

Excellent 37 % Good 52%

Zeedick (1977a)

Uncomplicated surgery; usually abdominal (95)

1mg 2mg (1-31)

0.5-1h 0.5-1h

2-3h 3-4h

Effect. 95% Partial effect. 2 %

Zeedick (1977b)

Moderate to severe post-op pain (41)

4mg (1-32)

0.5-1h

4+h

Excellent 93 % Good 7%

1 Effect = effective. Indicates that pain was controlled initially and the patient continued on butorphanol until a parenteral analgesic was no longer needed. Partial effect = partially effective. Indicates that pain was controlled initially but subsequently relief decreased and another parenteral analgesic drug was used.

tramuscularly was a satisfactory pre-anaesthetic medication, more patients (23 to 25 %) showing marked sedation with butorphanol than with 80mg of pethidine (I 4 %). 1.5 to 4mg of butorphanol intravenously has also been used as an induction aid in 'balanced' anaesthesia, and an initial dose of 2mg of butorphanol appears to be comparable to 10mg of morphine or 80mg of pethidine (all followed by incremental doses as required) when used in this manner.

3.1 Open Studies of Analgesic Efficacy 3.1.1 Intramuscular Use in Patients with Acute Postoperative Pain Intramuscular administration of several I to 4mg doses of butorphanol tartrate has provided satisfactory pain relief in about 90 % of postsurgical (usually abdominal surgery, spinal fusion or total hip replacement) patients with moderate to severe pain (table 11).

The onset of pain relief was rapid, the maximum effect occurring 0.5 to I hour after injection. The duration of effect appeared to be dose related, Img providing relief for 2 to 3 hours, 1.5 to 2mg for 3 to 4 hours and 4mg for more than 4 hours. Butorphanol was usually well tolerated, although severe urinary retention occurred on several occasions in a group of adolescent patients (Steg, 1978; see section 4.

n.

3.1.2 Intramuscular Use in Patients with Chronic Pain Intramuscular butorphanol has been used for up to 8 months for the treatment of moderate to severe chronic pain associated with malignancy (29 patients) or due to neuropathy (19 patients) or orthopaedic conditions (15 patients) [Kliman et aI., 1977]. Although most of the patients had received strong analgesics prior to entering the study, none were physically dependent on narcotics. Patients received I to 8mg (usually 2 or 4mg) every 3 to 4 hours, most receiving

Table III. Summary of comparisons of butorphanol tartrate (B) with morphine sulphate (M) and pethidine hydrochloride (Pd) in postoperative patients Author

Patient population (number)

Study design'

Dose-route (number of doses)

Results 2 pain intensity score

Comments pain intensity difference

pain relief

overall effectiveness 3 total

Comparisons with morphine Del Pizzo Varied surgery; (1976a) mod. -severe pain

Db,r. between

BO,5, 1 and 2mgIV(1) M2.5and5mg IV(1)

B 1,2mg ";> M5mg BO.5mg ";> M2.5mg

BO.5mg = M 2.5mg B2mg > M 5mg = B lmg

BO.5mg 2.5mg Bl,2mg 5mg

Dobkin et al. (1974)

Major surgery; mod.-severe pain (120)

Db,r, between

BO.73 and 1.46mgIM(1) M5and lOmg IM(1)

B= M

B= M

B= M

Lippmann et al. Major surgery; (1976, 1977b) mod.-severe pain (100)

Db,r, between

BO.5-2mg IM(1-4) M 2.5-10mg IM(1-3)

Tavakoli et al. (1976)

Db, r, between

B 0.73, 1.46, 2.92mg 1M (1) M5,10mg

Db,r, between

BO.5-2mg IM(1-28) Pd 20-80mg IM(1-31)

Major surgery; mod.-severe

pain(127)

Comparisons with pethidine Comunale and Varied surgery; mod.-severe Filtzer( 1977) pain(91)

Galloway et al. (1977)

Major surgery; mod.-severe

pain (126)

Db,r, between

BO.5-2mg IV(l) Pd20-4Omg IV(l)

B lmg = M5mg B2mg = M 10mg

partial

>M

of peak effect

B=M (M

-a::r

duration of relief

B= M (4 + h)

Ql

g. ~

» ffi'
B 0.5mg, Pd 20mg; B 2mg ";> Pd 40mg

onset

OJ

c:

S

4 2 2

B = Pd

!= lh)

B=M (about 1.5h4 )

Relative potency: B = 5 x M

B= M 2h)

Relative potency:

B = Pd (- 4-5h)

Duration of action dose-related for B Relative potency:

(>

B~7xM

B~40xPd

B = Pd (