Buprenorphine

Evaluations on New Drugs

Drugs 17: 81-110 0012-6667/79/0200-0081/$07.50/0 © AD IS Press Australasia Pty Ltd. All rights reserved.

Buprenorphine: A Review of its Pharmacological Properties and Therapeutic Efficacy

R.C. Heel, R.N. Brogden, T.M. Speight and G.S. Avery Australasian Drug Information Services, Auckland

Various sections of the manuscript reviewed by: B. Berkowitz, Roche Institute of Molecular Pharmacology, Nutley, New Jersey, USA; A.B. Dobkin. State University of New York, Upstate Medical Center, Syracuse, New York, USA; ME. Dodson, University of Manchester, The Royal Infirmary, Manchester, England; J.M. Gibbs, Department of Anaesthesia, Christchurch Clinical School, New Zealand; C.J. Glynn, Department of Anaesthesia and Intensive Care, F~nders Medi-cal Center, Bedford Park, Australia; B.C. Hovell, Department of Anaesthesia, Hull Royal Infirm-ary, Hull, England; D.R. Jasinski, Naticmallnstitute on Drug Abuse Research Center, Lexington, Kentucky, USA; W.B. Loan, Queen's University of Belfast, Belfast, N. Ireland; L.E. Mather, Department of Anaesthesia and Intensive Care, Flinders Medical Center, Bedford Park, Australia; DA. McQuillan, Department of Anaesthesia, National Women's Hospital, Auckland, New Zea-land; G. Rolly, Department of Anaesthesiology, University of Gent, Belgium.

Table a/Contents

Summary ..................................................... .................................................................................. 82 I. Pharmacodynamic Studies ................. ................... ..................... ............. .................... ................ 85

1.1 Narcotic Agonist Activity .................................................................................................. 86 1.1.1 Animal Screening Studies .......................................................................................... 86 1.1.2 In Vitro Tests ............................................................................................................ 88 1.1.3 Studies in Man .......................................................................................................... 89

1.2 Narcotic Antagonist Activity .............................................................................................. 89 1.3 Respiratory Effects ................................ .......................................... .................................. 90

1.3.1 Animal Studies .......................................................................................................... 90 1.3.2 Studies in Healthy Volunteers .................................................................................. 90 1.3.3 Studies in Anaesthetised Patients .............................................................................. 91 1.3.4 Studies in Postoperative Patients .............................................................................. 91

1.4 Cardiovascular Effects ........................................................................................................ 91 1.4.1 Animal Studies .............................. ............................................................................ 91 1.4.2 Studies in Healthy Volunteers ............................ .............................................. ........ 92 1.4.3 Surgical or Myocardial Infarct Patients .......................................... .......................... 92

1.5 Reversibility of Buprenorphine's Effects by Narcotic Antagonists .................................... 92 1.5.1 Animal Studies .......................................................................................................... 92 1.5.2 Reversibility of Respiratory Depression in Man ........................................................ 94

Buprenorphine: A Review

Summary

1.6 Dependence Liability Studies ............................................................................................. . 1.6.1 Animal Model Studies of Physical Dependence Liability ......................................... . 1.6.2 Psychic Dependence Studies in Monkeys ................................................................. . 1.6.3 Studies in Man ......................................................................................................... .

1.7 Toxicology Studies ............................................................................................................. . 1.7.1 Acute Toxicity

82

94 94 94 94 95 95

1.7.2 Subacute and Chronic Toxicity .................................................................................. 95 1.7.3 Fertility, Perinatal and Postnatal Studies and Dysmorphological Effects .................. 95

2. Pharmacokinetic Studies .................................................................................................... ........ 95 2.1 Absorption ................................................................................................... ...................... 96 2.2 Distribution ........................................................................................................................ 96

2.2.1 Protein Binding ............................................................................................. 97 2.3 Elimination ...................................................................................................... 97

2.3.1 Metabolism ...................................................................................................... 97 2.3.2 Excretion ............................................................................. ........................... 97

3. Therapeutic Trials .................................................................................... ................................. 97 3.1 Open Studies ......................................................................................... .......................... 98

3.1.1 Intramuscular Administration .................................................................................. . 98 3.1.2 Sublingual Administration in Chronic Pain .............................................................. 98 3.1.3 Use in Anaesthesia .................... .. ............................................................................. 99

3.2 Comparative Studies .......................................................................................................... 102 3.2.1 Comparisons with Morphine .................................................................................... 102 3.2.2 Comparisons with Pentazocine ................................................................................. 102 3.2.3 Comparisons with Pethidine ...................................................................................... 103 3.2.4 Comparison with Dextropropoxyphene plus Paracetamol ...................... 104

4. The Place of Buprenorphine in Therapy .................................................................................... 104 5. Side Effects .................................................................................................................... 104

5.1 Studies Using One or a Few Doses ................................................................................. .. 5.2 Chronic Administration .................................................................... ..

105 106

6. Dosage and Administration ....................................................................................................... 106 7. Overdosage ................................................................................................................................ 106 References ............................................................................................................................ 107

Synopsis: Buprenorphine l , 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 ofbuprenorphine paren-terally (by intramuscular or slow intravenous injection) or sublingually2 were at least as effec-tive 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 respira-tory 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.

'Temgesic' (Reckitt & Colman). 2 Buprenorphine is presently generally available only for parenteral use.

Buprenorphine: A Review 83

A nimal 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 I mg (subcutaneously) in man. The onset of agonist effects in man was slower (peak effects about 6 hours after subcutaneous or intramuscular in-jection) 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 an-tagonise the effects of single doses of morphine, and to precipitate abstinence in animals de-pendent on morphine. Although in several such tests a 'ceiling effect' of antagonist activity oc-curred 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 res-piratory 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 rel-ated. The onset of peak respiratory depressant effect is slower after intramuscular buprenorphine than after morphine (3 hours versus I hour) and the duration of such an effect, although not clearly determined, is longer. In therapeutic trials published to date res-piratory 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 buprenorphinl> induced respiratory de-pression, since even very high doses of naloxone may produce only partial reversal. How-ever, 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.

Haemodynarnic changes in healthy volunteers after intramuscular (0.15 to 0.6mg), sublingual (0.4 or 0.8mg) or oral (I 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 ofbuprenorphine administered for I 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 pro-perties of buprenorphine in man. In primates and in 2 volunteers absorption occurred rapidly after intramuscular administration of a labelled dose (2pg/kg) and more slowly after an oral (15pg/kg) dose (peak plasma radioactivity in man at less than 7 minu~ and about 2 hours, respectively). Detectable blood radioactivity persisted for more than 24 hours after oral inges-tion 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 radioac-tivity. 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 15pg/kg orally and 2pg/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-dealkyl-buprenorphine.

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 0.8rng sublingually was at least as effective as usual analgesic doses of morphine, pentazocine or pethidine for I 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 administra-tion 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 I 5 % 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 func-tion, 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 paren-teral use. The recommended dosage is 0.3 to 0.6mg by intramuscular or slow intravenous in-jection, 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.

1. Pharmacodynamic Studies

Buprenorphine is a highly lipophilic ring-C-bridged oripavine derivative of thebaine (fig. I). In animal screening tests it has displayed both typical narcotic agonist (usually at 'lower' doses) and an-tagonist (usually at 'higher' doses) activity, the former response often exhibiting a bell-shaped dose-response curve in which higher doses were less active as agonists than lower doses, as occurs with pentazocine (Brogden et aI., 1973).

In studies of agonist activity in man, buprenorphine produced typical dose related opiate actions up to a maximum dose of about 1 mg (sub-cutaneously) beyond which lesser subjective effects

a

occurred. Such effects were of slower onset but of longer duration than those seen with morphine. In studies of analgesic activity in postoperative or cancer patients, parenteral buprenorphine was about 25 times as potent as morphine (although in therapeutic trials the potency ratio was higher) with marked analgesia occurring at a dose of 0.3 to O.4mg in-tramuscularly. In these studies, the time-effect curves of morphine and buprenorphine were similar when equianalgesic doses were used.

Higher doses of buprenorphine (O.S or 1.6mg, in-tramuscularly) acted as a narcotic antagonist in 2 patients dependent on narcotics, the antagonist ac-tivity apparently being dose related. A very high dose (Smg daily) given chronically blocked the effects of

b

HO-C-CH3 I

/., CH 3 CH3 CH 3

Fig. 1. Structural formulae of morphine (a) and buprenorphine (b).


single high doses (up to 120mg) of morphine in 5 volunteers.

Although in man buprenorphine appears to have a slower onset and longer duration of respiratory depression than morphine, equianalgesic doses appear to produce about the same degree of respiratory depression overall. Very high doses of naloxone only partially reversed buprenorphine induced respiratory depression in man and other buprenorphine induced effects in animals.

Haemodynamic effects of buprenorphine have usually been relatively slight, and limited to small decreases in heart rate, blood pressure and right ven-tricular work, with compensatory increases in stroke volume.

In a direct addiction study in volunteers made de-pendent on buprenorphine, withdrawal led to a very slowly emerging abstinence syndrome, maximum withdrawal symptoms occurring 14 days after stop-ping the drug.

1.1 Narcotic Agonist Activity

1.1.1 Animal Screening Studies In a number of animal screening tests buprenor-

phine has displayed typical narcotic agonist activity, often with a curvilinear dose-response curve in which 'higher' doses produced a lesser effect than 'lower' doses. In such tests, a summary of some of which follows, buprenorphine was more potent than morphine or pentazocine on a weight-for-weight basis.

Antinociceptive Activity: In a number of standard animal "antinociceptive tests, buprenorphine was more potent (on a weight·for-weight basis) than other reference agents tested (table I), and was longer-acting than morphine (fig. 2). In the phenylquinone" anti-writhing test in mice, tolerance to buprenorphine developed slowly with repeated injections and cross tolerance between buprenorphine and morphine could be demonstrated (unpublished data, Reckitt & Colman).

100

80

60

* ... 40 u Q)

~ Q)

"K 20 Q) u "u o c ... c « 0

86

... 1---....... Buprenorphine

...... ~-..... Morphine

23456789 Time (hours)

Fig. 2. Duration of antinociceptive action of buprenorphine 0.046mg/kg s.c. and morphine 1.0mg/kg in the rat tail pressure test. Doses administered are the previously estimated ED50's (Cowan et al.. 1977b).

Like pentazocine, in some antinociceptive tests buprenorphine showed a bell-shaped dose-response curve, 'larger' doses having less activity than 'smaller' doses, with the maximum response occurring at less than complete analgesia (fig. 3); but in other such tests (e.g. rat tail pressure test; Cowan et aI., I 977b) it produced a consistent complete analgesia with 'high-er' doses (0.10 to 1 OOmg/kg). The antinociceptive ac-tivity of a range of doses of buprenorphine in rats was not influenced by lowered brain catecholamine levels (produced by intraventricular 5-hydroxydopamine) or lowered 5-hydroxytryptamine levels (produced by midbrain raphe lesion; Cowan et aI., 1974), in con-trast to findings in a single-dose morphine study in which midbrain lesions decreased and 5-hydroxy-dopamine increased that drug's antinociceptive ac-tivity (Samanin and Bernasconi, 1972, quoted in Cowan et aI., 1974).


Table I. The antinociceptive activity of buprenorphine and some reference drugs in animal tests

Author

Atkinson and Cowan (1974)

Cowan (1974) [see also Lewis, 1974)2

Cowan et al. (1977b)2

Lewis and Cowan (1972)2

Matsuki et al. (1977)

Michne et al. (1974)

Pircio et al. (1975)

Test

Yeast-induced motor impairment (rat hind paw)

Mouse writhing Rat tail pressure

Mouse tail flick Rat tail flick Rat tail pressure

Mouse writhing

Rat tail pressure

Mouse acetic acid stretching

Mouse hot plate

Mouse writhing

Arthritic rat vocalisation

Route of administration

sc

sc or ip sc or ip

ip ip ip

po

sc

po

sc

po

sc

po

sc po

sc

sc

Results'

b = 0.12, m= 1.93, p = 6.79

b = 0.033, m = 0.64 b = 0.024, m = 1.8

b = 2.4, m = 3.8 p > 30 b = 1.6, m = 9.5, p>30 b = 0.016, m = 0.66, p = 8.8 b = 0.35, m = 3.6, p = 35

b = 0.030, m = 0.64, p = 3.0 b = 0.19, m = 2.0, p =31.3 b = 0.005, m = 1.7, p = 17 b = 0.048, m = 17, p = 90

b = 0.02, m = 0.33, p = 5.04 b = 0.40, m "'c 1.37, p = 37.3 m:b:p = 1:140-200:0.1-0.23

m:b:p = 1:16-28: <0.053

b = 0.058

b = 0.005, m = 0.22, buto = 0.012, n = 0.18

Numbers given refer to the ED50 in mg/kg unless otherwise stated; b = buprenorphine, m = morphine, p = pentazocine, buto = butorphanol. n = naloxone.

2 In some tests in these studies buprenorphine produced a bell-shaped dose-response curve. See text. 3 Results reported as relative potency.

Behavioural Effects: 0.1 to 3mg/kg of buprenorphine produced initial immobility in rats, the maximum effect occurring at a dose of 0.30mg/kg (Cowan et ai., 1977b), followed by in-creased locomotor activity and stereotyped actions at 4 to 5 hours after dosing (Cowan et ai., I 977a).

Guinea pigs were very sensitive to buprenorphine in-duced catalepsy (EDso 0.007 to I mg subcutaneously) [Cowan et ai., I 977a; Lewis and Cowan, 1972], but higher doses in primates (0.08 to 10mg/kg sub-cutaneously or intravenously) produced only mild signs of CNS depression (Swain and Seevers, 1975).


100

?R 80

... u 60 .2! a; CIl .~ 40 "-CIl U ·u 20 0 c . ;::; c « 0

.03 .10 .30 3 10 30 Dose (mg/kg sc)

Fig. 3. Dose-response curves obtained with buprenorphine in the rat tail flick test using water at 45°C (.) or 55°C (0) as the stimulus (Cowan et al .• 1977b).

Buprenorphine, morphine and pentazocine in-creased ipsilateral turning in rats with lesions in the left substantia nigra, while higher doses reduced d-amphetamine induced turning in the same animal model (Cowan et aI., I 975b). All 3 drugs reduced the incidence of apomorphine induced circling in rats but slightly potentiated apomorphine stereotypy (sniffmg, licking, gnawing), suggesting that these agents have a similar effect on dopaminergic neurotransmission (Cowan et aI., 1975a). Indeed, Cowan et al. (J 976) reported that behaviour modifying doses of buprenorphine appeared to increase the turnover of dopamine, but not that of noradrenaline or 5-hy-droxytryptamine, in the forebrain of rats. However, other authors (Costall and Naylor, 1975) have sug-gested that 5-hydroxytryptamine does playa role in the regulation of behavioural effects of morphine-like agents, including buprenorphine.

Other Tests: In the non-tolerant, non-dependent chronic spinal dog, both buprenorphine and mor-phine depressed flexor and skin twitch reflexes and depressed body temperature (Martin et aI., 1975, I 976a), buprenorphine's effects reaching a maximum

88

at a dose of about 0.016mg/kg intravenously, higher doses producing a lesser effect. Buprenorphine was about 1/25 as potent as morphine in miotic effect in these animals.

Similarly, in tests for slowing of gastrointestinal activity in rats buprenorphine exhibited a bell-shaped dose-response curve, lower doses (0.0 I to 1.0mg/kg subcutaneously) causing progressive slowing while higher doses (10 and 30mg/kg) were inactive (Cowan et aI., 1 977a,c) .

In morphine-dependent rats neither buprenor-phine (J Omg/kg intraperitoneally) nor pentazocine were substitutes for morphine (Dewey et ai., 1975a,b; Harris, 1976). However, in maximally abstinent morphine dependent chronic spinal dogs bu-prenorphine partially suppressed abstinence (while precipitating it in stabilised animals; see section 1.2), although the dose-response curve slope was less steep for abstinence suppression with buprenorphine than with morphine or dextropropoxyphene (Martin et ai., 1975, 1 976b).

Buprenorphine was a potent antitussive agent in guinea pigs after oral administration, suppressing the cough reflex in this species for as long as 8 to 1 2 hours (Cowan et ai., 1 977a).

Like morphine, buprenorphine also suppressed urine output in animal studies, although buprenorphine was less active than morphine in this respect when approximately equianalgesic doses were used (Cowan et aI., 1 977a).

1.1.2 In Vitro Tests In isolated animal preparations (guinea pig ileum,

mouse vas deferens) the rates of onset and offset of narcotic-like actions of buprenorphine (623 seconds and greater than 90 minutes, respectively) were much greater than with morphine (23 and 32 seconds), methadone (91 and 619 seconds) or other narcotic agents (Kosterlitz et aI., 1975). In such tests, the rates of onset and offset were inversely related to lipid solubility, in contrast to in vivo findings in which a direct relationship existed (Herz and Teschemacher, 1971, quoted in Kosterlitz et aI., 1975).


1.1.3 Studies in Man

General Narcotic Effects: Single intramuscular (J mg) or subcutaneous (0.2 to 0.8mg) doses of buprenorphine in healthy subjects produced typical dose related morphine-like subjective effects, as well as miosis and emesis, which were of slower onset (peak effect for miosis about 6 hours versus 3 to 4 hours with morphine) but longer duration (about 72 hours) than those seen with morphine (about 24 to 48 hours; Jasinski et aI., 1976, 1977, 1978). With buprenorphine a plateau of morphine-like subjective effects appeared to occur at a dose of about I mg sub-cutaneously, I. 2mg producing a lesser response than 0.6mg. A number of unpublished studies in healthy volunteers have similarly observed characteristic nar-cotic-like autonomic and central nervous system effects following buprenorphine administration (un-published data, Reckitt & Colman).

Analgesic Activity: In studies in small groups (5 or 6 subjects) of healthy volunteers, intravenous (J .3)Jg/kg to 200)Jg), intramuscular (J and 2)Jg/kg), oral (20 and 40)Jg/kg) and sublingual (400)Jg) buprenorphine increased the pain threshold as measured by thermal skin stimulation (unpublished data, Reckitt & Colman).

In a dose-finding study in 40 postoperative patients (details of surgical procedure not given), a single intramuscular dose of 0.3 mg of buprenorphine relieved pain for up to 6 hours (Dobkin, 1977). High-er doses (up to 0.6mg) did not provide significantly greater pain relief than 0.3 or O.4mg.

In I 5 patients with acute myocardial infarction, 0.3mg of buprenorphine intravenously produced rapid pain relief with only mild discomfort remaining I 0 minutes after administration. The duration of relief varied (data not provided) but was similar to that with 5mg of diamorphine (Hampton, 1977). When 8 patients received either intravenous pethidine (3 patients) or buprenorphine (5 patients) via a patient-operated demand apparatus after upper ab-dominal surgery, the mean dose of pethidine to buprenorphine used was 2000: I (Sechzer, 1971,

89

quoted in Rosen, 1977), a higher relative potency ratio than has been reported in therapeutic trials using standard administration methods (see section 3.2.3).

Houde et aI. (J 976, 1977) reported that in-tramuscular buprenorphine was about 28 times as potent as morphine in analgesic effect (O.4mg of buprenorphine about equivalent to 10mg of morphine) in a crossover study in 128 postoperative patients (details of surgery not provided) and 8 patients with chronic cancer pain (some with previous narcotic experience). In this study the time-effect curves of the 2 drugs were similar when equi-analgesic doses were used (fIg. 4), although in thera-peutic trials buprenorphine often appeared to be longer acting than morphine, pethidine or pentazocine (see section 3).

1.2 Narcotic Antagonist Activity

In in vitro opiate receptor binding studies buprenorphine behaved like a narcotic antagonist,

2 Jr-.....

/ "-

]! / "'-~ I "-c: I ~ ~1 "-

I "-'0-.. I "-

----/ -...... V '()

2 3 4 5 6 Hours

Fig. 4. Time effect curves (based on hourly pain scores in 96 postoperative and 8 cancer patients) for buprenorphine O.36mg 1M (0) and morphine sulphate 11.3mg 1M (.) [Houde at al., 19761.


binding patterns in rat brain homogenates indicating the presence of saturable binding sites, with an in-crease in sodium ion concentration producing an in-crease in binding (Hambrook and Rance, 1976); an effect typical of opiate antagonists (Simon et ai., 1975). The rate of dissociation from binding sites was very slow and independent of sodium ion concentra-tion, as is also typical of antagonists.

Although in some in vivo rodent tests (rat tail pressure; Cowan, 1974) buprenorphine did not an-tagonise the effects of morphine, in others (e.g. mouse tail flick, mouse jumping, mouse writhing) it was about as potent as naloxone or nalorphine in ant-agonist activity (e.g. Cowan, 1974, 1976; Lewis and Cowan, 1972; Michne et ai., 1977), although the peak effect occurred later with buprenorphine (2 hours versus 0.5 hours). In drug naive rats, a very high dose of buprenorphine OOmg subcutaneously) markedly reversed morphine induced slowing of gastrointestinal transit time, although a lower dose (0.001 mg/kg) enhanced this effect (Cowan et ai., 1 977c). In morphine dependent rats, 'higher' doses (0.1 to 3mg/kg) facilitated gastrointestinal transit, probably indicating the development of abstinence (although other abstinence symptoms did not develop in rats) [Cowan, 1978], since these doses slowed gastrointestinal transit in drug naive rats (see section 1.1. I).

In stabilised morphine dependent chronic spinal dogs buprenorphine precipitated abstinence. It was about one-seventh as potent as naloxone (routes of ad-ministration not stated) in this effect, the dose-res-ponse curve slope for buprenorphine being less steep over the range of 0.02 to 0.08mg/kg with a 'ceiling effect' occurring at about 0.08mg/kg (Martin et ai., 1975, 1 976b). However, in monkeys dependent on morphine the 'ceiling effect' did not occur, a low dose (0.03mg/kg subcutaneously) of buprenorphine pro-ducing a mild abstinence syndrome (Cowan, 1974) and a much higher dose (0.32mg/kg) precipitating severe long-lasting abstinence (Swain and Seevers, 1975).

A similar dose-response occurred in 2 patients de-pendent on unspecified narcotics, in one of whom

90

O.8mg ofbuprenorphine intramuscularly precipitated mild abstinence while 1.6mg in the other produced moderately severe withdrawal symptoms (Houde et aI., 1976). In 5 patients who had received chronic (about I 8 days) high dose (gradually increasing doses up to 8mg intramuscularly daily by day 14) buprenorphine treatment, the effects of single doses of 15 to 120mg of morphine were blocked, such blockade persisting for more than 29 hours after the last dose of buprenorphine (Jasinski et ai., 1978).

The antagonist activity of buprenorphine has also been demonstrated following fentanyl or sufentanyl (fentathienyl) anaesthesia, where buprenorphine has been used to reverse anaesthetic effects (see section 3.1.3).

1.3 Respiratory Effects

J .3.1 A nirnal Studies In some animal tests, buprenorphine (like

morphine) decreased the respiratory rate and in-creased arterial PaC02 while decreasing arterial Paol (Cowan et ai., 1977a; Lewis and Cowan, 1972); but unlike morphine which produced a clear cut dose-res-ponse relationship in these tests, the respiratory depressant effects of buprenorphine were not ob-viously dose related and reached a 'ceiling' at about O.lmg/kg beyond which further dose increases pro-duced the same (or a lesser) degree of depression. In newborn rabbits subjected to anoxia following drug administration, buprenorphine appeared to produce less respiratory depression than approximately equianalgesic doses of pethidine or fentanyl, or 3 pethidine metabolites (Stephen and Cooper, 1977).

1.3.2 Studies in Healthy Volunteers In healthy volunteers there have been diverging

reports as to the extent of respiratory depression pro-duced by buprenorphine, and the characteristics of the dose-response curve for this action. Although some authors (Leeron et aI., 1976; Orwin, 1977b) have suggested that the respiatory depressant activity of buprenorphine appears to reach a 'ceiling' at a dose of


about 0.6 to 1.2mg (intramuscularly or intra-venously), this was not confirmed in 5 healthy sub-jects who received single intramuscular doses of 0.15, 0.3,0.6 and 1.2mg (unpublished data, Reckitt & Col-man). In this study, a linear relationship in the dose-response occurred over the administered dosage range, although the respiratory effects were not con-sidered to be of clinical concern.

Similarly, while 1 unpublished study (Budd, per-sonal communication, quoted in Orwin, 1 977b) has suggested that intravenous doses of 3 to 4mg of buprenorphine caused no 'clinically significant' res-piratory effects, other authors (e.g. Baster et aI., 1976, 1977; Elliott, unpublished data, Reckitt & Col-man; Orwin I 977a,b; Orwin et aI., 1976a) have reported statistically significant respiratory depres-sion which appeared to be dose related, following lower doses. Thus, Baster et al. (I976, 1977) reported that intravenous doses of 0.05 to 0.2mg produced markedly greater depression of the respiratory res-ponse to carbon dioxide stimulus than about equianalgesic doses of morphine (2.5 to 5mg). How-ever, Orwin and colleagues (Orwin, I 977a,b; Orwin et aI., 1976a,c) found no significant difference bet-ween the 2 drugs (approximately equianaigesic in-tramuscular doses) in the overall extent of respiratory depression produced, although buprenorphine had a slower onset (peak effect 3 hours after administra-tion) and longer duration (greater effect a 7 hours post-administration) of respiratory depressant effect than morphine (peak effect at I hour). At the times of maximum effect the relative respiratory depressant potency of buprenorphine compared with morphine was about 44 to I (Orwin, I 977b).

The significant (p < 0.001) decrease in minute volume which occurred I hour after intravenous buprenorphine (0.3mg) was rapidly (but temporarily) antagonised by intravenous injection of a single dose of the respiratory stimulant doxapram (0.5 or 1 mg/kg; Orwin I 977a,b); and such antagonism tended to be maintained with an infusion of dox-apram (225mg over 2 hours). Very high doses of naloxone produced only partial reversal of respiratory depression (see section 1.5).

91

As occurred with parenteral administration, sublingual (0.1 to O. 8mg) and oral (I to 4mg) doses of buprenorphine also decreased the respiratory res-ponse to carbon dioxide, both for more than 6 hours after administration (Orwin, I 977b).

1.3.3 Studies in Anaesthetised Patients In 40 spontaneously breathing anaesthetised

patients intramuscular doses of 3 and 4J.lg/kg of buprenorphine decreased both the respiratory rate and volume (to 80 % and 70 % respectively of baseline measurements with 4J.lg/kg) [Devaux et al., 1976].

However, when higher doses of buprenorphine (usually 0.4 to 0.8mg intravenously) were used to antagonise fentanyl or sufentanyl (fentathienyl) anaesthesia (De Castro and Parmentier, 1975, 1976; see section 3.1.3), 'normal' respiratory volume and rhythm (details not given) were rapidly achieved, sometimes following a short period of hyperventila-tion and tachypnoea. Occasionally, 'morphine-like' respiration (slow, deep respirations with periods of apnoea) re-occurred I to 2 hours after initial buprenorphine administration, requiring a second dose of buprenorphine or administration of naloxone.

1.3.4 Studies in Postoperative Patients Unpublished studies in 13 patients who had un-

dergone aorto-femoral bypass surgery (Wust, 1976; 2.2 or 4J.lg/kg) and 12 patients who had undergone neurosurgery (Huse, 1976; 5-12J.lg/kg) showed that single intravenous doses of buprenorphine produced a tendency toward respiratory acidosis and small decreases in respiratory rate ( I 5 % ) and minute volume (16%).

I .4 Cardiovascular Effects

1.4.1 Animal Studies In studies in rats and dogs buprenorphine usually

decreased heart rate but had little effect on arterial blood pressure (Cowan et aI., I 977a; Lewis and Cowan, 1972). Low intravenous doses (0.01 to


3mg/kg) appeared to sensitise the hearts of anaes-thetised dogs to adrenaline and noradrenaline, but whether this was due to respiratory depressant effect (i.e. a rise in Paco~ or to a direct effect of buprenorphine on the heart is unclear.

1.4.2 Studies in Healthy Volunteers In volunteers both intramuscular buprenorphine

(0.15 to 0.6mg) and morphine (5 to 12.5mg) pro-duced similar significant reductions in heart rate (buprenorphine 0.3mg, maximum reduction 16%; morphine 12.5mg, maximum reduction 15%) [Orwin, 1977b; Orwin et aI., 1976a]. Similarly, equianalgesic intramuscular doses produced about the same decrease (approximately 5 to 10 %) in systolic blood pressure with only minor decreases in diastolic pressure.

Following sublingual doses of 0.4 or 0.8mg in volunteers, heart rate and stroke volume were decreased, but these changes were accompanied by a compensatory increase in stroke volume, so that the mean arterial pressure was usually maintained or only slightly reduced (Orwin, I 977b). Changes in systolic time intervals reflecting the haemodynamic changes were also recorded. Similarly, after an oral dose of I to 4mg a dose related decrease in heart rate occurred (maximum reduction of 23 %, 5 hours after the 4mg dose) but decreases in blood pressure were alike with each dose (about a I 0 % decrease in systolic pressure; slight decrease in diastolic).

1.4.3 Surgical or Myocardial Infarct Patients Although some authors (Malcolm and Coltart,

1977; Rosenfeldt et aI., 1978) have reported no marked changes in cardiovascular parameters other than a 5 to 10% reduction in heart rate following a 5 or 6pg/kg intravenous bolus of buprenorphine in patients after open heart surgery, Devaux et aI. (1976) found that lower intramuscular doses did produce several haemodynamic changes in 40 anaesthetised (pentothiobarbitone followed by nitrous oxide/ oxygen) patients breathing spontaneously while undergoing abdominal surgery. Thus, while a 1.5pg/kg dose was not haemodynamically active, 2,

92

3 and 4pg/kg doses produced dose related decreases in systolic and diastolic pressures (10 to 25 %), oxygen consumption (up to 40 % decrease), left ven-tricular work (up to 19 % decrease) and heart rate (up to 24 % decrease), as well as a compensatory increase in stroke volume.

Like findings were reported in 13 patients who received 2.2pg/kg of buprenorphine by rapid intra-venous injection following aorto-femoral bypass surgery, mean arterial pressure decreasing slightly (about 4 %), and central venous pressure, cardiac in-dex, stroke index and left ventricular work decreasing by about 12 to 17% (Wust, 1976). However, no marked change in heart rate occurred in these patients. Similarly, in 5 patients with acute myocar-dial infarctions, 0.3mg of buprenorphine intra-venously caused small decreases in systemic and pulmonary artery blood pressures, but had little effect on heart rate (Hampton, 1977; fig. 5).

1.5 Reversibility of Buprenorphine's Effects by Narcotic Antagonists

1.5.1 Animal Studies Buprenorphine appears to form a stable complex

with the opiate receptor, dissociating from stereo-specific binding sites in rat brain very slowly (Hambrook and Rance, 1976). Administration of a narcotic antagonist prior to or concurrently with buprenorphine (drugs given intravenously) markedly reduced the level of stereo-specific binding of buprenorphine in rat brain (measured 30 minutes after buprenorphine administration); but when the antagonist was given I 5 minutes after buprenorphine a much smaller reduction in binding occurred (Rance and Dickens, 1978).

Similarly, the antinociceptive activity of buprenor-phine in rats was markedly reduced when a narcotic antagonist was administered concurrentiy, but much higher doses ( 1 0 times) of antagonist were required to reverse the effects of established buprenorphine (Cowan et aI., I 977b). In rabbits, administration of


+4 6.HR Or-_~

6. BP

-4

o -4 -8

systolic (mmHgl -12

-16 -20

-4

93

6. BP diastolic (mmHgl

+~~ :1~ ~.~---.e-----____ ~.a

6. PA systolic (mmHgl

+~~ ~----•• -----------2~ - •

t:.. PA diastolic (mmHg)

+4~

-~ ~;:':~~=:~===~~"I'--_-':-_-':---~~~~ -10 0515 30 60 120

Time (minutesl

Fig. 5. Mean changes in systemic and pulmonary artery (PAl blood pressure and heart rate (HR) after buprenorphine in 5 patients with acute myocardial infarction (Hampton. 19771.

naloxone (O.4mg) after buprenorphine (O.6mg intra-venously) did not alter the effects of buprenorphine on the EEG (increased delta and theta activity), but administration of naloxone prior to buprenorphine delayed the onset of or completely prevented buprenorphine effects (Kubicki et aI., 1976, personal communication).

Although a 3mg/kg dose of naloxone ad-ministered 5 minutes prior to buprenorphine blocked buprenorphine induced reduction of apomorphine cir-cling in rats (Cowan et aI., 1 975a), much higher prior doses (J 0 to IOOmg/kg) of naloxone only partially

produced by the same dose of buprenorphine (Cowan et aI., 1 977a). When buprenorphine was ad-ministered prior to naloxone (I to 10mg/kg) in morphine dependent mice and rats it prevented the development of abstinence, and was more potent and longer acting in this regard than pentazocine or butorphanol (Jacob et al., 1976). Similarly, in buprenorphine dependent monkeys (Swain and Seevers, 1975) a .high dose (2mg/kg) of naloxone or nalorphine did not produce signs of abstin-ence, although in buprenorphine dependent dogs O.2mg/kg of naloxone produced a mild abstinence

blocked the increased spontaneous locomotor activity syndrome hich emerged more slowly than in


morphine dependency (Martin et aI., 1976b) [see section 1.6].

1.5.2 Reversibility of Respiratory Depression inMan In a study in 5 healthy volunteers, very high intra-

venous doses of naloxone (2.4 to 16 mg) only partially reversed the respiratory depression produced by buprenorphine (Orwin, 1977b; Orwin et aI., I 976b), although this effect was temporarily reversible with a respiratory stimulant drug (see section 1.3.2>. In clinical practice however, both naloxone (usual doses) and respiratory stimulant drugs have been suc-cessfully used in a few patients with respiratory depression, although in a few others the response to such treatment was apparently not completely satisfactory (unpublished data, Reckitt & Colman). Thus, further data are needed to clarify the relative reversibility of buprenorphine induced respiratory depression in man.

1 .6 Dependence Liability Studies

There are two kinds of dependence associated with drugs acting at narcotic receptors - psychic and physical. Psychic dependence is manifested in man as euphorigenic activity leading to drug-seeking behaviour. Physical dependence is demonstrated by physiological changes following withdrawal of the chronically administered drug; drug-seeking behaviour in this situation derives from the need to suppress the discomfort of the abstinence effects. Buprenorphine appears to have a much lower depen-dence liability than morphine, and may be superior to other older morphine-like analgesics in this regard; but only much wider use over a long period of time can clearly determine its relative potential for produc-ing dependence.

1.6.1 Studies of Physical Dependence Liability Using Animal Models In substitution studies in morphine dependent

animals, buprenorphine did not substitute for

94

morphine in rats, although some substitution occur-red in chronic spinal dogs (see section 1.1.1 ), although the slope of the substitution dose-response curve was less than that with agonist analgesic drugs.

In the mouse jumping test (with antagonist challenge) the descending rank order for apparent physical dependence capabilities of the drugs tested was morphine, codeine, pentazocine, buprenorphine (Lewis and Cowan, 1972). Similarly, when the test model of weight loss in rats during drug withdrawal was used, morphine and pentazocine (22 % and 3 to 8 % weight loss in 24 hours, respectively) had a greater apparent dependence liability than buprenorphine (slight weight gain) [unpublished data, Reckitt & Colman]. Although in studies in buprenorphine dependent monkeys, neither ad-ministration of narcotic antagonists (see section 1.5) nor abrupt withdrawal of buprenorphine precipitated abstinence (Cowan, 1974; Lewis and Cowan, 1972; Swain and Seevers, 1975), in dependent chronic spinal dogs both naloxone and drug withdrawal pro-duced a slow emerging, mild abstinence syndrome, the maximum withdrawal effects occurring 2S hours after the last dose (Martin et a\., 1976b).

1.6.2 Psychic Dependence Studies in Monkeys In a study designed to assess psychic dependence

liability using self-administration techniques in monkeys, the dose-response curve for the rate of self-administration with buprenorphine showed a peak below that in codeine controls, similar to that with butorphanol (another partial agonist-antagonist analgesic) and greater than with nalorphine or pen-tazocine (Woods, 1977).

1.6.3 Studies in Man In a direct addiction study in S former narcotic

addicts, buprenorphine was administered sub-cutaneously for 40 to 5.0 days in a daily dose of 8mg, following a 2-week period of gradually increasing doses (Jasinski et al., 1976, 1977, 1978; see also Graham, 1977). Subjects and observers identified buprenorphine as a morphine-like agent. Subsequent administration of naloxone 4 mg (subcutaneously) did


not produce an abstinence syndrome, but substitution of saline for buprenorphine resulted in very slowly emerging signs of withdrawal. Thus, from the third to the tenth day of drug withdrawal only mild signs of abstinence were noted; but on the fourteenth day relatively marked withdrawal effects began, including nausea, vomiting, restlessness, insomnia and diar-rhoea, indicating a very long duration of action of buprenorphine following chronic administration con-sistent with its apparently very slow dissociation from opiate receptor sites (see section 1.5. I). Thus, the maximum abstinence score (Himmelsbach score) which occurred with buprenorphine on day 15 of withdrawal (about 21 or 22), was similar to maxi-mum withdrawal scores seen with codeine, dextro-propoxyphene, nalorphine, pentazocine and butor-phanol (maximum scores of about 15 to 26) during the first few days of their withdrawal. Morphine pro-duced a maximum abstinence score of about 37 in such studies.

1.7 Toxicology Studies

1.7.1 Acute Toxicity The median lethal single doses (LDso's) for

buprenorphine in mice were 24 to 29mg/kg, 90 to 97mg/kg and 260 to 261 mg/kg for intravenous, in-traperitoneal and oral administration, respectively. The corresponding figures in the rat were 3 I to 38mg/kg, 197 to 207mg/kg and more than 600mg/kg (Cowan et aI., I 977a; see also Lewis and Cowan, 1972). The therapeutic index (median lethal dose divided by median effective dose) with in-traperitoneal administration in the rat tail pressure test was 464 for morphine and 12,313 for buprenorphine (Cowan et aI., I 977a).

1.7.2 Subacute and Chronic Toxicity Following oral and subcutaneous administration

for I month and intramuscular administration for 6 months of a range of doses of buprenorphine to rats, a treatment related (but not dose related) decrease in body weight gain occurred but other abnormalities

95

were not observed (unpublished data, Reckitt & Col-man). Similar findings were reported in dogs and monkeys. In baboons intramuscular administration of 0.5 or 5mg/kg/day for 6 months produced some haematological changes associated with inflammation at the injection site but such changes did not occur at a dose of 0.05mg/kg/ day.

1.7.3 Fertility, Perinatal and Postnatal Studies and Dysmorphological Effects Daily intramuscular doses of 0.05 to 5mg/kg of

buprenorphine in rats slightly increased the incidence of intrauterine deaths and neonatal mortality (especially the highest dose), but did not appear to affect mating or fertility (unpublished data, Reckitt & Colman). Surviving pups showed a slightly depressed growth rate but no other abnormalities.

When pregnant rabbits or rats received similar in-tramuscular doses from days 6 to 18 (rabbits) or 6 to 15 (rats) of gestation, there was no evidence of ad-verse effects on the fetuses (unpublished data, Reckitt & Colman)'

2. Pharmacokinetic Studies

There is only limited information available on the pharmacokinetic properties of buprenorphine in man.

In rodent studies both oral and intramuscular ad-ministration were followed by similarly rapid absorp-tion, 100J.lg/kg orally producing peak plasma levels similar to those with 20J.lg/kg intramuscularly. In 2 volunteers however (and in studies in primates), the peak plasma level of radioactivity after an oral labelled dose occurred more slowly (about 2 hours) than after intramuscular administration (less than 7 minutes), and detectable blood levels persisted much longer following oral ingestion (more than 24 hours compared with about 7 hours after intramuscular ad-ministration). There are no studies of absorption pat-terns after sublingual administration. In man, excre-tion was mainly in the faeces as unchanged buprenorphine with a lesser proportion of the dose

Buprel1orphil1e: A Review

excreted in the urine as conjugates of buprenorphine and N-dealkylbuprenorphine.

2.1 Absorption

There are no published data on the absorption of buprenorphine. In unpublished studies (unpublished data, Reckitt & Colman) in rats, both intramuscular and oral administration of radiolabelled bu-prenorphine produced peak blood levels of radioac-tivity within 10 minutes of dosing, followed by a rapid decline and another smaller peak at about 5 to 8 hours. An intramuscular dose of 20pg/kg and an oral dose of I OOpg/kg gave similar peak blood levels of radioactivity. In baboons and monkeys intra-muscular administration (2pg/kg) produced peak blood levels within a few minutes, but after oral ad-ministration peak blood levels did not occur for about 2 or more hours. Similarly, sublingual administra-tion to anaesthetised monkeys produced a peak plateau in blood levels at 2 to 4 hours.

In 2 healthy volunteers, an intramuscular (2pg/kg) dose was followed by a rapid peak in blood level and then a fairly rapid decline (based on

2.6 2.4 2.2

96

measurements of total radioactivity), while an oral dose (I5pg/kg) produced a peak blood level at 2 hours followed by a rapid decline until 6 hours and then a gradual decline over more than 24 hours (fig. 6). When plasma levels of buprenorphine in a few patients were determined using a specific radioim-munoassay method, the peak concentration range after an intramuscular or intravenous dose of O.3mg was 0.5 to 3.6ng/ml and 1.0 to 7.6ng/ml, respec-tively. Sublingual administration to patients (0.6mg) or volunteers (OAmg) produced peak levels of I to 2ng/ml and 0.7 to 4ng/ml, respectively, at about 2 hours after administration.

2.2 Distribution

In the rat, highest levels of radioactivity were found in the liver after both oral and intramuscular administration, but peak levels in this organ occurred faster (10 minutes) after an oral than after an in-tramuscular (40 minutes) dose. Levels in the brain (this organ contained only unchanged buprenorphine) after 20pg/kg intramuscularly were 2 to 3 times higher than after 100pg/kg orally. Similarly, in

.S 2.0 0----,0 Oral 15,.,g/kg (n = 1) I/) 1.8 E 1.6 Ol ro 1.4 > ·s 1.2 c-Ol 1.0 Ol-e: C'l 0.8 :.c~ e-e: 0.6 0-

0.4 e: ttl ~ E 0.2 Q.(/) ::J~ 0 CD Q.

___ Intramuscular 2pg/kg (n = 1)

?" , ' , " I ' , , , \:>---0 --0-----------__________________________________ {) , I I : I I I

0 1 2 3 4 5 6 7 Time (hours)

24

Fig. 6. Plasma radioactivity after administration of radiolabelled buprenorphine to healthy volunteers (unpublished data, Reckitt & Colman).


rhesus monkeys, brain levels were higher after in-tramuscular than after oral administration (2~g/kg and l5~g/kg, respectively), but liver levels were higher after oral dosing (unpublished data, Reckitt & Colman). These findings are consistent with a high first-pass extraction in the liver.

In studies in pregnant rats radioactivity readily reached the placenta following parenteral or oral administration of a labelled dose, and appeared to accumulate in the fetal gastrointestinal lumen, presumably as a result of biliary excretion occurring in the absence of developed entero-hepatic circulation.

2.2.1 PrOTein Binding In in \'itro studies with human plasma proteins

using a concentration ofbuprenorphine (0 to 7ng/mJ) which approximated the therapeutic range, the drug was highly protein bound (about 96 %), primarily to a- and ~-globulin fractions (unpublished data, Reckitt & Colman).

2.3 Elimination

2.3.1 Metabolism In the rat, dog, baboon, rhesus monkey and in

man (number of subjects not stated) the metabolic pattern of buprenorphine appeared to be similar, and in man was not greatly influenced by the route of ad-ministration, although there was a higher proportion of polar metabolites (as compared to unchanged drug) present in the plasma after oral administration than after an intramuscular dose in animal studies (Rance and Shillingford, 1976; unpublished data, Reckitt & Colman). Indeed, studies with rat gut sac prepara-tions have shown that buprenorphine is conjugated with glucuronic acid during passage through the gut wall (Rance and Shillingford, 1976, 1977). In animals radioactivity in the bile (and in some other tissues) was present as glucuronide conjugates of buprenorphine or N-dealkylbuprenorphine, but the central nervous system appeared to contain only unchanged drug, suggesting that the effects of buprenorphine are mediated by interaction of

97

buprenorphine alone with the opiate receptor. Nevertheless, studies examining the pharmacological activity of N-dealkylbuprenorphine would be of interest.

2.3.2 Excretion In animals the majority of an oral or intramuscu-

lar dose was excreted in the faeces (72 % and 56 %, respectively, following an oral and intramuscular dose in rats; 59 % and 48 % in baboons). Biliary ex-cretion was an important route in rats, especially after intramuscular administration (65 % of administered radioactivity within 24 hours). 7 days after dosing only traces of radioactivity remained in body organs (unpublished data, Reckitt & Colman).

In 2 volunteers radioactivity was also excreted mainly in the faeces (71 % after 15~g/kg orally, 68 % after 2~g/kg intramuscularly) with smaller amounts appearing in the urine (1 5 % after an oral dose, 27 % after an intramuscular dose) [unpublished data, Reckitt & Colmanl. In man, the faeces contain mainly unchanged buprenorphine while urinary ex-cretion products are conjugates of buprenorphine and N-dealkylbuprenorphine.

3. Therapeutic Trials

Pain is a subjective matter and its perception and acceptance may vary greatly from I patient to another. SimilarlY, quantitative measurement of pain and pain relief is based on primarily empirical methods, some authors preferring patients' own sub-jective assessments and others using scoring systems involving trained observers. Whatever 'measurement' system is used however, the design of analgesic drug trials should attempt to minimise the effects of in-terindividual variation by such measures as choosing patients who are most likely to require analgesic treatment (e.g. major orthopaedic, abdominal or thoracic surgery, chronic consistent pain), random administration sequences or careful matching of


patient groups, large patient numbers, and so on. Although ethical considerations may perhaps pre-clude the determination of the placebo response in patients in analgesic trials, this response may vary considerably from I patient population to another and even from time to time in the same patients (Houde, 1977).

Most trials with buprenorphine have been well designed, although some have not adequately described the patient population and all studies have involved only small numbers of patients. Some have used trained observers to assess pain and pain relief while others have utilised patient scoring systems. The majority of published trials have been single dose studies in postoperative patients, only a few patients with chronic pain having received multiple doses. In such studies buprenorphine was an effective analgesic when given parenterally (about 0.2 to O.6mg in-tramuscularly or intravenously) or sublingually (0.4 to 0.8mg); most comparative studies showing it to be at least as effective as usual doses of morphine, pen-tazocine or pethidine (meperidine) for I to 2 hours after administration, and subsequently often to be more effective, indicating its long duration of action (about 6 to 8 hours in many studies). The incidence and type of side effects with buprenorphine appear to be comparable to that with other strong analgesics (see section 5).

3. I Open Studies

3.1.1 Intramuscular Administration Intramuscular administration of a single dose of

4J.lg/kg of buprenorphine following major pelvic surgery (150 patients) produced a noticeable analgesic effect within 10 to 20 minutes with a duration of analgesia of at least 5 to 6 hours (Rolly and Ver-sichelen, 1976a,b,c). 71 % of patients considered the overall pain relief provided to be very good, 24 % fairly good and 5 % felt it was insufficient. A slightly larger dose (0.3mg) given once or twice (6 hours apart) after unidentified major surgery, provided 'ade-quate' relief in 26 of 27 patients after the first dose

98

and in all patients after the second dose (Rees-Jones, 1977). A similar percentage of several thousand patients have reportedly experienced adequate or good pain relief 2 hours (92 % of patients) or 4 hours (89 %) after an initial injection of an analgesic dose (dose range not stated) ofbuprenorphine, according to a report on the monitored release of this agent (data on file, Reckitt & Colman). Subsequent injections in those patients requiring more than I dose produced a similar rate of response. The majority of these patients had acute postoperative pain, although a few hundred had pain of malignant, chest or renal origin. These patients achieved adequate relief with about the same frequency as postoperative patients.

In a study in which a single 0.2mg dose was given to 21 consecutive emergency department patients who required an analgesic, the maximum effect was relatively slow in onset, occurring 90 minutes after injection at which time 77 % of patients had no or only slight pain (fig. 7; Delooz and Vercruysse, 1976).

3.1.2 Sublingual Administration in Chronic Pain Preliminary results from several unpublished

studies in small numbers of patients with chronic pain, receiving sublingual buprenorphine (up to 4.8mg/day) for up to several months (but usually for shorter periods), have shown good to complete pain relief in about 2/ 3 of patients with cancer pain (as oc-curred with intramuscular use; section 3.1.2) but in only about 1 /4 of patients with orthopaedic or neuro-logical pain (Robbie, I 977b; Robbie et al., 1 977a,b). Although only a few cancer patients (who were usually hospitalised) discontinued treatment due to side effects, 9 of the 16 ambulant patients with non-malignant pain discontinued treatment due to nausea and vomiting.

In a published study in chronic pain, 14 cancer patients and 8 with chronic pain of other origins received sublingual doses of 0.15mg 6-hourly to 0.8mg 4-hourly for an average duration of treatment of I month (Adriaensen and Van De Walle, 1976). No dosage increases were required after the initial ad-justment period. In one-half of the patients


buprenorphine was judged to be a 'satisfactory' analgesic while in the others it was unsatisfactory due to inadequate pain relief (3 patients) or side effects (8 patients; nausea, vomiting, confusion, sedation, depression; see section 5). Whether or not other drugs such as cytotoxic agents were being concur-rently administered was not stated, but most patients had previously received other strong analgesics. No symptoms of withdrawal were seen on discontinuing treatment with buprenorphine.

100

I 7 I 90 f:

J 80 r-70 ':::= ~}

I / 60 V- /

50 ~ V-~

~ /

40 / 30 ~

V- / V- I'

*- 20 ~ V V

III V-E 10 ~ Q) V-'';; V-Ol 0 n.. 0 15 30 45 Time (minutes)

Pain intensity:

IZ§] E'Za Severe Moderate

99

3.1.3 Use in Anaesthesia

As a Component of 'Balanced' Anaesthesia: Buprenorphine (0.1 to O.6mg intravenously) has been used as a component of anaesthesia in some patients (total number unspecified) in combination with flunitrazepam and nitrous oxide (De Castro and Par-mentier, 1975, 1976; Lecron and Levy, 1976; Lecron et aI., 1975), or 'Althesin' (alphaxalone/alphadolone) and nitrous oxide (Humphrey, 1976), apparently with

t ~ g T V- F

~ V V- ,/ ,/ V- ~

,/ ,/

,/ ,/

"" "" "" 60 " 90

rr 120 " 180

- D Slight None

Fig. 7. The analgesic effect of a single 200"g intramuscular dose of buprenorphine given to 21 consecutive patients seen in an emergency department who required an analgesic (Delooz and Vercruysse, 1976).

Tabl

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Com

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stud

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=m

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>m

8

= m

(se

datio

n.

Sim

ilar

initi

al p

ain

(197

7)

surg

ery

pts

(160

) m

5 o

r IO

rng

1M

betw

een

inte

nsity

and

rel

ief

B 0

.2rn

g >

m 5

mg

naus

ea,

vom

iting

) in

tens

ity in

all

grou

ps

(1 d

ose)

B

O.4

mg;

;' m

10m

g

Dow

ning

et

al.

Cae

saria

n se

ctio

n B

0,6

rng,

m

Db,

r,

Pt s

corin

g of

pai

n B

;;' m

(at

1 &

2h)

B

= m

8

>m

B

dec

reas

ed b

.p,.

In 1

5pts

in a

n op

en

(197

7)

(58)

15

rng

1M (1

dos

e)

betw

een

inte

nsity

and

rel

ief;

B >

m (

at 3

& 4

hr

B &

m d

ecre

ased

st

udy

obse

rver

s he

art r

ate

dura

tion

with

b

0,6m

g =

7h

Hov

ell a

nd

Sele

cted

B

0,3

rng,

m

Db

Trai

ned

obse

rver

s,

B>

m

B =

m (

seda

tion,

W

ard

(IS?

?)

surg

ical

pIS

, 10

mg

rM

asse

ssm

ent

at

naus

ea

(see

als

o m

ost

abdo

min

al

(1 do

se)

rest

and

on

Hov

ell,

1977

b]

surg

ery

(50)

m

ovem

ent

Kay,

197

8 M

ajor

abd

omin

al

B 0

.3m

g IV

D

b, r

, c,

Pt

sco

ring

of

B>

m

B=

m

B>

m

B =

m (

seda

tion,

su

rger

y (5

1)

(1 d

ose)

; m

be

twee

n pa

in in

tens

ity

naus

ea)

10m

g IV

(1 d

osel

McQ

uilla

n C

aesa

rian

sect

ion

B O

Arng

, be

twee

n O

bser

vers

B

> '

Om

nopo

n'

B >

'0

' B

< '0

' N

o se

datio

n w

ith b

(1

976)

(6

0)

'Om

nopo

n'3

asse

ssm

ents

; pt

s 20

mg

IV a

fter

asse

ssm

ents

afte

r de

liver

y; t

hen

48h

b O

.4m

g SL

or

'Om

nopo

n'

15.2

0rng

1M

prn

Oul

letle

(197

6)

Mod

erat

e to

B

0,2

or

0,4m

g D

b, r

, O

bser

ver

scor

ing

B 0

,2 a

nd 0

,4m

g B

>m

B

= m

se

vere

pos

t-1M

11 d

ose)

; be

twee

n =

m 1

0rng

> op

erat

ive

pain

m

5 o

r 10

mg

m 5

m9

1M (1

dos

e)

Com

paris

on w

ith m

orph

ine

(m)

and

pent

azoc

ine

(pz)

D

odso

n et

al.

Sel

ecte

d hy

ster

ec-

Up

to b

2-4~g/kg,

Db,

r,

Obs

erve

r sc

orin

g;

No

stat

, si

g.

B >

m,

Pl

B =

m =

pl

Res

p. r

ate

decr

ease

d (1

977)

to

my

pts

(68)

m

150~g/kg, p

l be

twee

n pt

inte

rvie

ws

at

diffe

renc

es

(dill

ones

s,

by a

ll dr

ugs

3()()~g/kg I

V o

ver

24h

naus

ea)

5 m

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dos

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B ;

;. m

. p

l (vo

mit-

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atio

n)

8

Com

paris

on w

ith p

enta

zoci

ne (p

z)

Buck

ley

(197

6)

Abd

omin

al s

ur-

B 1

5 or

20~

g/kg

D

b, c

o Pa

in s

corin

g at

B

> p

z'

B;>

pz

B;>

pz (

vom

iting

, ge

ry (3

2)

1M (1

dos

e);

rest

and

on

dizz

y, e

upho

ria)

pz 0

.86n

ng/k

g m

ovem

ent;

fo

rced

vita

l cap

a-1M

(1 d

ose)

" ci

ty m

easu

re-

men

t

Mas

son

(197

6)

Pos

tope

rativ

e B

0.4

-0.8

mg

Sl:

p2

Obs

erve

r sc

orin

g B

O.4

mg

~

pz

B =

pz

B ~

pz

, ex

cept

w

ith m

oder

ate

to

50m

g or

al.

each

B

O,8

mg

> pz

fo

r di

zzin

ess

seve

re p

ain

(150

) w

ith a

ltern

ate

whe

re B

> p

z pl

aceb

o (1

dos

e)

Com

paris

on w

ith p

enta

zoci

ne (p

z) a

nd p

ethi

dine

(pd)

H

ovel

l (19

76,

Pos

tope

rativ

e B

2-8~g/kg 1

M,

Db,

Pt

ass

essm

ent

B 2~g/kg ~

pz

B~pz~pd

1977

a,b)

(1

72)

pz

betw

een

usin

g no

min

al

~pd

exce

pt s

edat

inn

600~g/kg 1

M,

pd

scal

e, a

t re

st a

nd

B 4~g

/kg

whe

re 8

8~g/kg

(1 do

se)

1 mg/

kg 1

M on

mov

ing

>p

d

;;, pz

, pd

B

8~g/kg

;;, pz

>

pd

Com

paris

on w

ith p

ethi

dine

(pd)

G

ibbs

and

El

ectiv

e ab

dom

inal

B

4 o

r 8~g/kg

Db,

P

t an

d ob

serv

er

B4~g/kg =

pd

B =

pd

B =

pd

B <

pd (

seda

tion)

Jo

hnso

n su

rger

y (7

1)

1M (1

dos

e);

betw

een

scor

ing;

pt

1mg/

kg;

B

B ~

pd

(na

usea

) (1

978)

El

ectiv

e gy

nae-

pd 1

or

2mg/

kg

inte

rvie

ws

8~g/

kg =

pd

colo

gica

l sur

gery

1M

(1 d

ose)

2m

g/kg

(8

9)

B 4~g

/kg'

;; p

d lm

g/kg

; B

8~g/kg <

pd 2

mg/

kg

Kam

el a

nd

Gyn

aeco

logi

cal

B 5~g

/kg,

pd

Bet

wee

n Pt

ass

essm

ent

B>

pd

from

2

B =

pd

B

> p

d B

<:

pd

Ged

des

surg

ery

lmg/

kg

hour

s on

war

d (1

977.

19

78)

(60)

IV

(1 d

ose)

1 D

b ~

doub

le-b

lind;

r ~

ra

ndom

; be

twee

n ~

betw

een

patie

nt c

ompa

rison

, c ~

incl

uded

con

trol g

roup

rec

eivi

ng n

o tre

atm

ent;

Co =

C

ross

over

des

ign.

2

See

text

for

fur

ther

dis

cuss

ion.

3

'Om

l'lopo

n' c

onta

ins

tota

l opi

um a

lkalO

Ids

equi

vale

nt t

o 50

% a

nhyd

rous

mor

phin

e.

4 V

ery

high

dos

es o

f bup

reno

rphi

ne c

ompa

red

with

mod

erat

ely

high

dos

e o

f pe

ntaz

ocin

e.

CD

B s

ig.

incr

ease

d c:

PaC

0 2

~ " g -0

::T

5'

~ » ::IJ ~ :IE

Gro

ups

wel

l mat

ched

See

text

Bot

h ca

used

som

e ch

ange

s in

b.p

., h.

r. an

d re

spira

tion

§


satisfactory results (although the induction time was long - about 15 minutes) in some studies.

To Reverse Anaesthetic Effects: The same authors, and others (Hovell, 1976; Samayoa de Leon, 1976), have reported that intravenous (or in some cases in-tramuscular) administration of buprenorphine (usually 0.4 to 0.8mg; occasionally 0.1 to 0.2mg) about 1 to 4 hours after induction of fentanyl or su-fentanyl (fentathienyl) anaesthesia (20 I patients in total) reversed most anaesthetic effects, but appeared to produce continued analgesia for about 4 to 12 hours. The antagonist activity was not noticeable for 15 to 20 minutes after administration and decreased rapidly after 90 to 120 minutes, a second dose of buprenorphine or administration of naloxone often being required at this time to prevent re-emergence of anaesthetic effects.

Data in both these areas of use is very limited, and no definite conclusions can be drawn at present regarding buprenorphine's relative efficacy when used as a component of anaesthesia or to reverse anaesthetic effects.

3.2 Comparative Studies

3.2.1 Comparisons with Morphine In single dose comparative trials as a postoperative

analgesic (usually following abdominal surgery), 0.2 to 0.6mg of buprenorphine intramuscularly was at least as effective overall as 5 to 15mg of morphine (table 11), and was often judged more effective than morphine at evaluation periods several hours after ad-ministration, suggesting that it has a longer duration of action. Indeed, several authors have reported that buprenorphine provided longer relief from pain (mean of 5.6, 6.3 and 7 hours with 0.2, 0.4 and 0.6mg intramuscularly, respectively) than occurred with morphine (mean of 4.2 and 4.8 hours with 5 and 10mg, respectively) [Dobkin et al., 1977; Down-ing et aI., 1977]. The time to onset of analgesic action of the 2 drugs after intramuscular administration ap-peared to be similar (Dobkin et aI., 1977).

102

In a single dose study in which an intravenous dose of buprenorphine (0.3mg) or morphine (10mg) was given to postoperative patients as soon as they could open their eyes on command, buprenorphine was significantly (p < 0.05) more effective than morphine in preventing the onset of pain and was longer acting over the 5-hour observation period (Kay, 1978; table II).

In a comparative study of multiple dose (up to 5 doses of buprenorphine) administration (McQuillan, 1976), an initial dose of O.4mg of buprenorphine in-travenously followed by O.4mg sublingually as needed was compared with 20mg of 'Omnopon'* in-travenously followed by 15-20mg intramuscularly when necessary, in 60 patients who had undergone a caesarian section. Buprenorphine was clearly prefer-red by patients and was superior on the basis of ob-servers' as~essments of pain and discomfort. Fewer buprenorphine patients (19) needed more than I addi-tional dose after the initial administration than 'Om-nopon'· patients (27), and both intravenous and sublingual buprenorphine produced a longer duration of relief before another dose was requested (0.25 to 24 hours and 5.3 to 7.9 hours, respectively) than in-travenous or intramuscular 'Omnopon' (0.25 to 3 hours and 3.2 to 4.2 hours, respectively).

The incidence and nature of side effects was usually similar with both morphine and buprenorphine (see section 4). Although I author (McQuillan, 1976) has commented on the absence of sedation with buprenorphine, in other studies buprenorphine produced at least as much sedation as morphine.

3.2.2 Comparisons with Pentazocine

Postoperative Patients. Parenteral Administration: Although no statistically significant differences in the degree of overall pain relief were detectable between

• Total opium alkaloids containing the equivalent of 50 % anhydrous morphine.


single intravenous doses of buprenorphine 2 to 4Jlg/kg and a relatively low dose of pentazocine (300Jlg/kg) in a small study in patients who had un-dergone hysterectomy (Dodson et aI., 1977), the duration of analgesia was longer with buprenorphine (mean of 6.4 and 7.4 hours with 2 and 4Jlg/kg, res-pectively) than with pentazocine (mean of 3.2 hours).

Similarly, in a . larger study using higher in-tramuscular doses of both drugs (Hovell, 1976, I 977a,b; see table 11),2 and 4Jlg/kg ofbuprenorphine did not differ significantly from 600Jlg/kg of pen-tazocine. However, 8Jlg/kg of buprenorphine pro-duced greater (p < 0.05) sum of pain intensity differ-ence scores (SPID) than did pentazocine at rest, although the 2 drugs did not differ significantly in their effect on pain during movement.

When a very high intramuscular dose of buprenorphine (15 or 20Jlg/kg) was compared with only a moderately high dose of pentazocine (0.86mg/kg; Buckley, 1976), buprenorphine pro-vided greater pain relief, as might be expected. How-ever, the incidence of adverse effects with bu-prenorphine also tended to be higher than with pen-tazocine when these doses were used.

Postoperative Patients, Sublingual Administration: In a double-blind study comparing a single dose of sublingual buprenorphine (0.4 or 0.8mg) with oral pentazocine 50mg in 150 patients with moderate to severe postoperative pain, the higher dose of buprenorphine resulted in significantly (p < 0.01 or 0.05) greater pain relief at I to 4 hours after ad-ministration, but at 30 minutes the effect of both drugs was similar (Masson, 1976; table II). O.4mg of buprenorphine did not differ from pentazocine at any observation time. Both drugs produced similar side effects although the higher dose of buprenorphine produced a significantly (p < 0.05) higher incidence of dizziness than occurred with pentazocine (see section 4).

Chronic Pain: In unpublished studies (Beyerle, data on me, Reckitt & Colman; Robbie, 1976) in patients with chronic cancer pain, 2 or 4Jlg/kg of bu-

103

prenorphine intramuscularly was as effective as 0.6mg/kg of pentazocine in ~2 patients while 0.3mg of buprenorphine produced greater pain relief than 30mg of pentazocine in 50 patients (duration of treat-ment not stated). In I study euphoria occurred in 5 of 25 patients receiving buprenorphine, 4 of whom had received high doses of other analgesics prior to the trial, but only occurred with pentazocine (2 of 22 patients) in the other trial.

In another unpublished crossover trial in 27 patients with cancer pain, a single sublingual dose of 0.4 or 0.8mg ofbuprenorphine produced greater pain relief than 75mg of oral pentazocine or 60mg of dihydrocodeine (Robbie, I 977a).

3.2.3 Comparisons with Pethidine

Postoperative Patients: A single intramuscular dose of 4 or 8Jlg/kg of buprenorphine produced greater pain relief than I mg/kg of pethidine in a study involving I 72 postoperative patients (usually abdominal surgery) [Hovell, 1976; I 977a,b; table II]. A 2Jlg/kg dose of buprenorphine however did not significantly differ from I mg/kg of pethidine in analgesic effect. Similarly, 5}Jg/kg of buprenorphine was superior to Img/kg of pethidine intravenously from 2 hours post-administration onward in 60 patients who had undergone gynaecological surgery (Kamel and Geddes, 1977), reflecting the longer dura-tion of action with buprenorphine (mean of 10.6 hours versus 2.6 hours with pethidine). The onset of pain relief was similar with both drugs, the max-imum effect occurring between 15 and 60 minutes after administration. In both studies side effects were similar with either drug, although 8Jlg/kg of buprenorphine tended to cause more sedation than did pethidine.

Findings somewhat at variance with these have been reported by Gibbs and Johnson (1978) in patients after elective gynaecological surgery, pethidine appearing to be somewhat more effective and as long acting as buprenorphine (see table II). However, none of the drugs used were adequate in


the gynaecological patients by generally accepted cri-teria according to the trial results. The authors con-sider that inappropriate factors in their study design and characteristics of their patient population were major factors in influencing the trial results.

Labour Pain: In a placebo-controlled study in 67 females in labour a single sublingual dose of buprenorphine O.8mg was about as effective as IOOmg of pethidine intramuscularly (Fairbrother, I 977). Both drugs were more effective in 'late' than in 'early' labour. There was no evidence of neonatal depression in either active treatment group. However, drowsiness in the mothers occurred more frequently (incidence not stated) with buprenorphine than with pethidine.

3.2.4 Comparison with Dextropropoxyphene plus Paracetamol In a double-blind, placebo controlled, crossover

study comparing single doses of sublingual buprenorphine O.4mg and oral 'Distalgesic' (dex-tropropoxyphene 65mg plus paracetamol 650mg) in 25 patients with orthopaedic pain, the latter appeared to be more effective than buprenorphine for 3 to 4 hours after administration (Sargison, 1977). 13 patients preferred 'Distalgesic' while 5 preferred buprenorphine, possibly partially as a result of a greater incidence of drowsiness (I8 of 25 with buprenorphine, II of 25 with 'Distalgesic') and nausea (3 of 25 and 0 of 25, respectively) with buprenorphine.

4. Side Effects

The overall profile of side effects which have been reported with buprenorphine appear similar to those which occur with other strong analgesics such as morphine, pethidine or pentazocine. In rising-dose tolerance studies in healthy volunteers (unpublished data, Reckitt & Colman), the incidence of side effects was dose related, with the exception of sedation for

104

which a clear dose-response relationship was not apparent.

Respiratory depression (as indicated by laboratory measurements of respiratory function) and some (usually small) haemodynamic changes have been ob-served in pharmacodynamic studies (see sections 1.3 and 1.4), but have not usually been a problem in clini-cal trials (see section 5.1 below). However, studies to date have usually involved fit patients undergoing surgery. The clinical significance of the respiratory and haemodynamic effects of buprenorphine in 'poor risk' patients, such as those with respiratory disease or congestive heart failure, has not been clearly established.

5. The Place of Buprenorphine in Therapy

Buprenorphine appears to be an effective strong analgesic when given by the intramuscular, intra-venous or sublingual routes. Although studies of oral usage are underway (unpublished data, Reckitt & Colman), its relative effectiveness when given by this route is not yet established.

In comparative studies usually involving single doses administered to postoperative patients, buprenorphine has been at least as effective as usual doses of other strong analgesics such as morphine, pentazocine or pethidine, and was usually longer act-ing (adequate pain relief for about 6 to 8 hours in many studies compared with about 3 to 4 hours for comparison drugs). The relative effectiveness, tolerability, and most appropriate areas of use of buprenorphine, compared with butorphanol, another new analgesic agent with both narcotic agonist and antagonist properties (see Heel et ai., 1978), have not yet been clearly established.

The number of chronic pain patients treated with repeated doses of buprenorphine 'is relatively small and its effectiveness, tolerability and safety when used in this manner needs further study. However, its long duration of action would likely be an important ad-vantage in such patients.


Some authors have used buprenorphine as an ad-junct to anaesthesia or as an analgesic/ anaesthetic reversing agent following fentanyl anaesthesia, but the numbers of patients treated in this way is relatively small; thus, an authoritative statement of its effectiveness in these areas must await further well designed studies.

The incidence and nature of side effects which have occurred with buprenorphine (see section 4) seem to be similar to those which occur with other strong analgesics. As with morphine, apparently dose related (in man) respiratory depression does occur with buprenorphine, although further studies are needed to clarify the effects of 'higher' doses on res-piratory function. There appears to be no specific antagonist for buprenorphine induced respiratory depression (or other effects of buprenorphine), nar-cotic antagonists such as naloxone often being only partially effective even at very high doses; but the res-piratory stimulant drug doxapram has been effective in this regard in a few healthy volimteers and a small number of patients.

Although from animal studies and a direct addic-tion study in a few volunteers it appears that the de-pendence liability of buprenorphine is low, slowly developing abstinence did occur after a very high dose given for I to 2 months. Only wider spread use over a period of time will determine its relative dependence liability compared with other strong analgesics with any certainty.

Buprenorphine's long duration of action combined with its ability to antagonise the effects of concomi-tantly administered morphine (see section 1.2), sug-gest that it may be a useful agent in narcotic addiction maintenance programmes, but its effectiveness and its potential for abuse in such a therapeutic setting have not been investigated.

5.1 Studies Using One or a Few Doses

With the exception of a few small groups of patients with chronic pain and a small number of others who received 2 or 3 doses, most studies of

105

buprenorphine have involved single dose (0.2 to O.4mg) parenteral administration, usually to postoperative patients who had received a general anaesthetic. In such studies nausea and/ or vomiting were frequently reported (overall incidence in published studies about IS %), but in these patients the relative contribution of buprenorphine compared with the general anaesthetic to producing gastro-intestinal upset cannot be determined.

Sedation, which could possibly be considered a desirable effect for postoperative analgesia (and in some pre-operative patients), has also occurred fre-quently in most studies (usually about 40 to 45 % of patients, up to 75 % in some studies such as Hovell, I 977a; Kay, 1978). However, McQuillan (J 976) reported that all of 30 post-caesarian section patients who received O.4mg ofbuprenorphine intravenously, followed by O.4mg sublingually if needed, remained alert and were rapidly mobilised, while monitored release data for several thousand patients reports the incidence of sedation to be about 6 % (unpublished data, Reckitt & Colman). Such widely varying reported incidences likely reflect differing evaluation criteria for the occurrence of sedation. In those studies in which sedation did occur patients were usually easily arousable.

Respiratory depression has not been reported to be a problem in most studies. In a report on the monitored release of buprenorphine injection (data on file, Reckitt & Colman), respiratory rates of less than lO per minute (an arbitrarily chosen figure) were ob-served in 96 of 8187 patients (1.2 %), but in many of these patients this did not appear to be of clinical con-cern. Specific treatment (usually with doxapram; see section 1.5) was instituted in 35 patients.

Dizziness and sweating have occurred in some studies with a widely varying incidence (about 4 to 40 % and 2 to 12 %, respectively), the reported inci-dence probably at least partially depending on whether patients were actively questioned for their occurrence. Other adverse effects such as headache, confusion, depression and difficulty urinating have occasionally been reported. Although euphoria and hallucinations have occasionally been said to have


occurred after buprenorphine administration, the validity of such reports often appeared questionable. In any case, the reported incidence of such reactions has been very low (about 0.1 to 0.3 %; unpublished data, Reckitt & Colman).

Whether typical narcotic-like adverse effects are more exaggerated in ambulatory than in bed-ridden patients with buprenorphine, as occurs with other morphine-like analgesics, has not been examined in published studies; but in an unpublished study (data on file, Reckitt & Colman) nausea and vomiting in volunteers who received single doses occurred most frequently when the subjects sat up or moved about after drug administration.

5.2 Chronic Administration

In a trial of chronic (a few days to more than 5 months) administration (Adriaensen and Van De Walle, 1976), sublingual buprenorphine (0.15mg 6-hourly to O.Smg 4-hourly) had to be discontinued in S of 22 patients due to side effects (nausea and vomiting in 5, mental confusion in 3). When a very high dose (Smg) was administered subcutaneously to 5 volun-teers for 40 to 50 days in an addiction study (Jasinski etal., 1976, 1977, 1978; section 1.6),somereversible changes in laboratory values occurred including decreased haemoglobin and total serum protein and an increase in sedimentation rate. A decrease in serum alkaline phosphatase levels persisted (duration not stated) after discontinuing the drug. Further studies of chronic administration using usual therapeutic doses are needed to clearly establish the side effect profile when the drug is used in this way.

6. Dosage and Administration

Buprenorphine is presently generally available only for parenteral use. The usual recommended

106

dosage is 0.3 to 0.6mg by intramuscular or slow in-travenous injection, repeated every 6 to S hours as required.

In those studies using the sublingual route of ad-ministration, a dose of 0.4 or O.Smg has usually been used.

Buprenorphine should be administered with caution to patients already receiving large doses of narcotic analgesics, since the possibility of precipi-tated abstinence as a result of its antagonistic proper-ties must be considered in this situation. Although tests to determine the dependence liability of buprenorphinehave been encouraging, as with other strong analgesics it is nevertheless important to avoid increases in dose and frequency of administration, and to prevent the use of the drug in anticipation of pain rather than for pain relief.

Ambulant patients who receive buprenorphine should be cautioned regarding possible central ner-vous system depression and drowsiness. Although no specific interaction studies have been reported, cross potentiation between buprenorphine and other central nervous system depressants could be expected.

7. Overdosage

No reports of overdosage with buprenorphine have been published. In an unpublished report of a suicide attempt (data on file, Reckitt & Colman), a young (age not stated) man, who reportedly placed 35 to 40 sublingual tablets of O.4mg strength in his mouth until they dissolved, recovered without inci-dent over 24 hours. The only symptoms present were vomiting, drowsiness and depression (present before the overdosage). Respiration was normal. Blood levels of the drug were not determined and the extent of absorption is thus unknown.

There is no specific antagonist for buprenorphine's effects, even large doses of the narcotic antagonist naloxone being only partially effective. In healthy volunteers who received standard doses of buprenorphine, the respiratory stimulant drug dox-


apram reversed the respiratory effects as determined by laboratory measurements of respiratory function, but whether or not it would be effective in patients who had received an overdose (if respiratory depres-sion was a problem) is not known.

References

Andriaensen, H. and Van De Walle, J.: Clinical use of buprenorphine in chronic administration. Acta Anaes-thesiologica Belgica 27: 187 (J 976).

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Samayoa De Leon, R.: Clinical use of fentathienyl in sequentia,l analgesic anaesthesia. 6th World Congress of Anaesthesiology, Session III Mexico City: Symposium on new morphinic, morphinoid and anti-morphinic drugs and potentiators of morphinics. Societe d'Anesthesie de Charleroi, Belgium, p.211 (1976).

Simon, E.1.; Hiller, 1.M.; Groth, 1. and Edelman. l.: Further pro-perties of stereospecific opiate binding sites in rat brain: On the nature of the sodium effect. 10urnal of Pharmacology and Ex-perimental Therapeutics 192: 531 (I 975).

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Woods, 1.H.: Narcotic-reinforced responding. A rapid screening procedure. Reported to the Committee on Problems of Drug Dependence, Boston, p.420 (I 977).

Wust, H.1.: Clinical report on buprenorphine in patients following aorto-femoral bypass operation. Unpublished report, on file Reckitt & Colman (I 976).

Authors' address: R.C. Heel, R.N. Brogden, T.M. Speight and G.S. Avery, Australasian Drug Information Services, P.O. Box 34-030, Birkenhead, Auckland 10 (New Zealand).

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