REVIEW ARTICLE
Drugs 41 (3): 326-344. 1991 ()() 12-666 7/ 91 / 0003-0326/$09.50/ 0 © Adis International Limited. All rights reserved. ORUl639
Opioid Agonist-Antagonist Drugs in Acute and Chronic Pain States P.J. Hoskin and G. W. Hanks Royal Marsden Hospital, London, and Institute of Cancer Research, University of London, London, England
Contents 326 327 328 328 328 329 329 330
332 333 334 334 338 340
Summary
Summary 1. Introduction 1.1 Opioid Receptors 1.2 Agonist-Antagonist Opioid Analgesics 1.3 Acute and Chronic Pain 2. Nalorphine-Like Agonist-Antagonists 2.1 Pentazocine 2.2 Butorphanol 2.3 Nalbuphine 2.4 Dezocine 3. Morphine-Like Agonist-Antagonists 3.1 Buprenorphine 4. Meptazinol 5. Conclusions
The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category. Pentazocine, butorphanol and nalbuphine are weak wantagonists and K-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation. At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action. All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such
Agonist-Antagonist Opioid Analgesics
327
as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions. Buprenorphine is a potent partial agonist at the It-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2ltg tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours. There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects. Naloxone is relatively ineffective in reversing serious respiratory depression caused by buprenorphine. Buprenorphine has a lower abuse potential than morphine, but misuse of this drug has been a growing problem in some areas. Buprenorphine is now a controlled drug. Meptazinol is a synthetic hexahydroazepine derivative with opioid agonist and antagonist properties, but is unlike either the nalorphine-type agonist-antagonists, or buprenorphine. Meptazinol has central cholinergic properties which may account at least in part for its analgesic effects. Receptor binding studies show it to be a specific Itl-agonist. Meptazinol is one-tenth as potent as morphine by intramuscular injection and has a duration of action of about 4 hours. Adverse effects - nausea, vomiting, sweating, dizziness and psychotomimetic symptoms - have been more frequent in some studies than with morphine, though respiratory depression and constipation appear to be less. When viewed overall the evidence indicates few significant advantages of this group of drugs over the strong opioid agonists in the treatment of acute pain. Buprenorphine has established a place in the treatment of postoperative pain, partly because until recently it was not subject to controlled drug regulations. The recent change in its legal status removes an important advantage in the postoperative situation. Nalbuphine is an effective analgesic in myocardial infarction pain and has an advantage over morphine in that it is still not subject to the same legal restrictions on its storage and use. This has facilitated its use for emergency administration, particularly outside the hospital setting. The agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Buprenorphine is potentially the most useful member of the group because it is potent, longacting and effective when given sublingually.
1. Introduction The group of drugs known as agonist-antagonist opioid analgesics includes a number of agents with moderate to strong analgesic activity which differ from their pure agonist counterparts such as morphine by their action on opioid receptors. The terminology in this area is confusing, partly because it has changed in recent years. The term agonistantagonist was used as a general term to describe drugs acting as partial agonists at opioid receptors; a partial agonist binds to the receptor but has low intrinsic activity, so that its dose-response curve exhibits a ceiling effect at less than the maximal effect produced by a full agonist. However, the term
agonist-antagonist now refers to 2 distinct groups of drugs: true partial agonists acting on a single receptor subtype and drugs which may behave as agonists, partial agonists or antagonists at different opioid receptors. A third group, represented by meptazinol, does not fit into either of these categories. Nalorphine (N-allyl normorphine), the prototype agonist-antagonist opioid analgesic, was synthesised initially as an antagonist of morphine (Hart 1941), but was subsequently shown to have powerful analgesic activity (Lasagna & Beecher 1954). This perplexing combination of effects stimulated the formulation of 2 concepts: first, that there are several classes of opioid receptors, and second, that
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it is possible for some drugs to act an an agonist at one type of receptor and as an antagonist at another ('receptor dualism'). Nalorphine has subsequently been shown to act as a partial agonist at the K-receptor and as an antagonist at the wreceptor. l.l Opioid Receptors
Despite the expansion of knowledge in the field of opioid receptors over recent years, the precise role of different receptor subtypes in the modulation of pain remains unclear. There is some evidence from animal experiments to support the concept of both spatial differentiation, with wreceptors important in supraspinal analgesia and Kreceptors important in spinal analgesia (Martin et al. 1976), and functional differentiation, with wreceptors sensitive to heat stimuli and K-receptors sensitive to pressure stimuli (Upton et al. 1982). In clinical use, however, such differentiation between receptor types does not appear to have any consequence as far as analgesia is concerned. A drug with agonist properties at the K-receptor, such as pentazocine, appears to produce similar analgesia to a ~-agonist such as codeine. The effect on different receptors does, however, appear to result in a different spectrum of adverse effects. Table I shows the principal drugs in this group, together with their actions at the main opioid receptors. 1.2 Ago'nist-Antagonist Opioid Analgesics Agonist-antagonist opioids can be conveniently classified into those that produce pharmacological effects resembling those of nalorphine (nalorphine-
like) and those that produce pharmacological effects which resemble morphine's (morphine-like) [Jasinski 1979]. The ~ I-selective agonist-antagonist meptazinol is considered separately. The mixed agonist-antagonist drugs were developed in the hope of maintaining powerful analgesia while reducing serious adverse effects (particularly respiratory depression) and the potential for drug abuse and dependence. Although there are some differences in these respects between this group of drugs and the pure agonists, they have not generally constituted major advances in clinical practice and the agonist-antagonists have failed to displace established pure agonist drugs. 1.3 Acute and Chronic Pain Acute and chronic pain are very different clinical entities (table II) requiring different approaches to their management. In general, acute pain will have a specific and obvious predisposing factor, such as postoperative pain, acute trauma or obstetric pain. Acute pain has a positive role in drawing attention to a particular danger or threat; it is of predictable and limited duration, and tends to get better when the source of the pain is treated or heals. In contrast, chronic pain is maladaptive: it serves no 'useful purpose', is of unpredictable duration and tends to worsen. Chronic pain is often differentiated into chronic 'malignant' pain and chronic 'benign' pain. This is misleading because so-called chronic benign pain is often much more difficult to treat than chronic cancer pain. A better classification is one which
Table I. The actions of agonist-antagonist opioid analgesics at opioid receptors
Drug
Pentazocine Butorphanol Nalbuphine Buprenorphine Meptazinol a
Receptor subtype Il
K
Antagonist Antagonist Antagonist Partial agonist Agonist
Partial agonist Partial agonist Partial agonist
",Receptors are not true opioid receptors but may be responsible for dysphoric or psychotomimetic effects.
,ji
Agonist Agonist
Agonist-Antagonist Opioid Analgesics
329
2.1 Pentazocine
Table II. Acute and chronic pain Acute pain
Chronic pain
Event Duration predictable and limited Tends to get better Has meaning and purpose
Situation Duration unpredictable Tends to get worse Has no meaning, or negative meaning
differentiates chronic cancer pain from chronic noncancer pain. Chronic cancer pain has been characterised as longstanding acute pain, because it is associated with a continuous nociceptive input (Loeser 1980). In contrast, chronic noncancer pain often has no readily identifiable pathology and thus no identifiable nociceptive stimulus. Cancer pain in general responds to anti nociceptive measures, induding conventional analgesic drugs, whereas chronic pain which is associated with a nonmalignant disease process generally responds poorly to these measures. This differential response is relevant to any discussion of the place of agonist-antagonist opioid analgesics in the management of chronic pain. This group of drugs has been particularly advocated for use in patients with chronic noncancer pain who require potent analgesics because of a reluctance to use morphine-like opioid agonists for long periods of time in patients with a normal life expectancy. However, the agonist-antagonist analgesics are antinociceptive agents: their usefulness in the management of chronic noncancer pain is limited, like that of other conventional analgesic agents. Thus, if they have a place in the management of chronic pain at all, these drugs are more likely to be applicable to the management of chronic cancer pain, and here they have to be measured against the strong agonists of which morphine is the prototype.
Pentazocine was the first drug in this group to be widely available for analgesic use, and is formulated for oral, rectal and parenteral administration. 2.1.1 Relative Analgesic Potency A dose of 30 to 60mg pentazocine administered in single doses by intramuscular or subcutaneous injection produces similar analgesia to 10mg morphine (Beaver et al. 1966; Paddock et al. 1969) and 100mg pethidine (meperidine) [Scott et al. 1973], but with a slightly shorter overall duration of action. Table III shows equivalent doses of pentazocine and other agonist-antagonists compared with single doses of 10mg morphine intramuscularly or subcutaneously.
Pentazocine
Nalbuphine
2. Nalorphine-Like Agonist-Antagonists Pentazocine, butorphanol and nalbuphine are weak JL-antagonists and K-partial-agonists. Their chemical structures are shown in figure 1.
Butorphanol
Fig. 1. Structures of pentazocine, nalbuphine and butorphanol.
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Table III. Equivalent analgesic doses. based on single parenteral doses relative to morphine 10mg intramuscularly or subcutaneously
Drug
Dose (mg)
Pentazocine Butorphanol Nalbuphine Dezocine Buprenorphine Meptazinol
30-60 1-3 12 10 0.2-0.3 100
When given orally, pentazocine has relatively weak and unpredictable analgesic activity. In randomised studies in postoperative patients, 35mg pentazocine given orally gave equivalent analgesia to 600mg aspirin, and 50mg pentazocine gave equivalent analgesia to 60mg codeine, but was more effective than 60mg dihydrocodeine (Kantor et al. 1966). However, in other studies 50mg pentazocine was less effective than 650mg aspirin (Daniel et al. 1971; Moertel et al. 1972) or combination preparations containing codeine 8mg with 500mg aspirin, or dextropropoxyphene (propoxyphene HCI) 32.5mg with 325mg paracetamol (acetaminophen) [Huskisson 1974; Robbie & Samarasinghe 1973]. 2.1.2 Acute Pain Pentazocine has been used as a moderate analgesic in postoperative patients. Fewer adverse effects - in particular nausea, vomiting, sedation and hypotension - have been claimed, but in equianalgesic doses no advantage for pentazocine compared with pethidine or morphine has been demonstrated (Paddock et al. 1969). The drug has also been used in acute renal and biliary colic, and less smooth muscle contraction has been reported compared to morphine (Economou & Ward-McQuaid 1971). However, when compared with buprenorphine for biliary colic, significant elevations in intrabiliary pressure have been demonstrated (Storitz et al. 1985), and the use of pentazocine in this situation is no longer recommended. Pentazocine is effective in obstetric pain, pro-
ducing analgesia in the majority of patients. It may increase uterine activity and shorten the first stage oflabour (Duncan et al. 1969; Filler & Filler 1966). There is some evidence that pentazocine causes less nausea and vomiting than pethidine in equianalgesic doses, though no difference in respiratory depression in the neonate has been demonstrated. In acute myocardial infarction pentazocine is an effective analgesic, but it has potentially hazardous haemodynamic effects resulting in increased left ventricular end diastolic pressure, increased left ventricular work and increased pulmonary artery pressure (Alderman et al. 1972; Jewitt et al. 1974). Alternative opioid drugs are therefore recommended for the pain of acute myocardial infarction (Editorial 1976). 2.1.3 Chronic Pain Pentazocine has been evaluated in both chronic cancer pain and noncancer pain. In patients with rheumatoid arthritis pentazocine 50mg was less effective than aspirin 600mg, 2 tablets of aspirin 500mg + codeine 8mg ('Codis') and 2 tablets of paracetamol 325mg + dextropropoxyphene 32.5mg ('Distalgesic') [Huskisson 1974]. Similarly, in a randomised study in cancer patients, pentazocine was not as effective as either the above paracetamol/dextropropoxyphene combination or aspirin with codeine tablets (Robbie & Samarasinghe 1973). Furthermore, pentazocine was associated with a higher incidence of adverse effects, in particular psychotomimetic effects (hallucinations, euphoria, depersonalisation) which have been described in up to 20% of patients (Taylor et al. 1978). These are usually dose-related and are particularly prevalent in long term use (Houde 1979). In chronic pain, therefore, pentazocine appears less effective than established moderate analgesic drugs and has a higher incidence of adverse effects.
2.2 Butorphanol Butorphanol is structurally related to pentazocine (fig. I). It is no longer available in the UK, and elsewhere can be used only for parenteral administration.
Agonist-Antagonist Opioid Analgesics
2.2.1 Relative Analgesic Potency Butorphanol is 3.5 to 7 times more potent than morphine, 30 to 40 times more potent than pethidine, and 20 times more potent than pentazocine in single-dose studies in postoperative pain (Gilbert et at. 1976). After intramuscular injection peak effects are seen at 30 minutes, with a duration of analgesia of up to 4 hours. 2.2.2 Acute Pain Butorphanol appears to be an effective postoperative analgesic for orthopaedic and abdominal surgery. In randomised double-blind comparisons with morphine in equianalgesic doses given intramuscularly or intravenously, both drugs produce analgesia with a similar pattern for peak effect and duration of analgesia. No significant difference in overall analgesic efficacy or adverse effects has been observed (Del Pizzo 1976; Dobkin et at. 1974; Lippman et at. 1976; Tavakoli et at. 1976). Similarly, in comparisons with pethidine, equianalgesic doses of butorphanol give a similar profile of analgesia in postoperative patients, with perhaps a slightly longer duration of analgesia after butorphanol (Galloway et at. 1977). The most common adverse effect after butorphanol in this setting is drowsiness, which may be dose-related, the incidence increasing in one study from 50% after Img intramuscular butorphanol to 62% as the dose was increased to 4mg (Dobkin et at. 1975). In other studies, however, the incidence of drowsiness has varied considerably, with no clear dose-response effect being seen. Nausea and vomiting is seen after butorphanol but the incidence is no greater than with other strong opioid analgesics such as morphine (Heel et al. 1978). Unlike its analgesic and other effects, the severity of respiratory depression does not appear to be dose related, with a ceiling effect at 1 to 2mg in healthy volunteers. However, while this may appear to be a potential advantage in postoperative use, the duration of respiratory depression is dose related, increasing in one study in healthy volunteers from 0.5 hours after 0.5mg intramuscularly to 6 hours after 4mg (Heel et al. 1978). Butorphanol has been given by the epidural
331
route for postoperative pain. In randomised studies butorphanol 4mg gave a similar degree of analgesia to morphine 5mg, with a more rapid onset but a shorter duration of only 6 to 8 hours (Abboud et at. 1987; Lippman & Mok 1988). Significant respiratory depression of greater duration than that seen with morphine was also reported, and in the light of this it is unlikely that butorphanol will have a major role as a spinal opioid analgesic. Two large randomised double-blind studies have evaluated butorphanol in severe renal colic (Elliott et at. 1979; Henry et at. 1987), both comparing 2mg and 4mg butorphanol with 80mg pethidine. In each study 2mg butorphanol was equivalent to 80mg pethidine, and .4mg butorphanol was superior to both. There was a tendency to earlier requirements for a further dose of analgesia in the pethidine groups, consistent with a longer duration of analgesia with butorphanol. No significant differences in adverse effects were seen. Butorphanol has been evaluated as an analgesic in labour pain in several large randomised studies in which it has been compared with morphine in single intramuscular or intravenous doses (Heel et at. 1978; Maduska & HajghassemaJi 1978). No overall difference in either analgesic efficacy, maternal adverse effects or foetal adverse effects have been reported. In post-partum episiotomy pain, oral doses of 8mg or 16mg butorphanol have been demonstrated to be as effective as 60mg codeine. Other reports of oral butorphanol indicate that it is effective in mild to moderate postoperative pain and musculoskeletal pain (Heel et al. 1978). However, no particular advantages over established oral drugs such as paracetamol or codeine have been demonstrated and no oral formulation ofbutorphanol is currently available for clinical use. 2.2.3 Chronic Pain Butorphanol has been studied in chronic cancer pain (Heel et at. 1978; Stambaugh & McAdams 1987), where it may produce effective analgesia, but on regular administration a high incidence of sedation and psychotomimetic effects has been reported. Butorphanol has no advantages over morphine in this setting and the need for intramuscular
332
administration in the absence of an oral formulation makes it an inappropriate drug for long term use. 2.3 Nalbuphine Nalbuphine is structurally closely related to naloxone (a specific opioid antagonist) and to oxymorphone (a strong agonist) [fig. I]. Nalbuphine is only available for parenteral administration. 2.3.1 Relative Analgesic Potency Single-dose studies after intramuscular administration have shown that using the same dose nalbuphine produces a total analgesic effect which is 80 to 90% that of morphine and a peak analgesic effect 70 to 80% that of morphine, but with a slightly longer duration of action (Beaver & Feise 1978; Errick & Heel 1983). The onset of analgesia after intramuscular nalbuphine is at about 15 minutes, with peak effects 30 minutes after intravenous and I hour after intramuscular administration. Duration of analgesia after parenteral nalbuphine is 3 to 5 hours, giving a similar pattern of analgesia to morphine (Fragen & Caldwell 1977). Comparison of nalbuphine with pentazocine given either intramuscularly or intravenously shows it to be about 3 times as potent as pentazocine with a slightly longer duration of action (Houde et al. 1976; Tammisto & Tigerstedt 1977). In single doses a ceiling effect for analgesia is seen at 20 to 30mg. When given orally, nalbuphine has analgesic potency 20 to 25% that of intramuscular nalbuphine, with a peak effect only 10% that of intramuscular nalbuphine. This is consistent with substantial presystemic elimination of the drug when given by the oral route. The peak analgesic effect after oral administration of nalbuphine is seen after 1 to 2 hours, with an overall duration of analgesia of 4 hours (Kantor & Hopper 1984; Okun 1982). Clinical studies of oral nalbuphine in single doses of 15 and 45mg have shown that nalbuphine 15mg gives a similar analgesic effect to 60 to 90mg codeine (Kantor & Hopper 1984; Okun 1982). One study found no difference between 15 and 45mg nalbuphine given orally in terms of analgesic po-
Drugs 41 (3) 1991
tency (Okun 1982). No oral formulation of nalbuphine is available for clinical use. 2.3.2 Acute Pain Nalbuphine is effective in postoperative pain when given by both intermittent injection and patient-controlled administration devices, but recent studies have suggested that, compared with morphine or buprenorphine, analgesia is less reliable and may even fail to be achieved (Brady et al. 1986; Pugh et al. 1987). In a study of a patientcontrolled intravenous infusion of nalbuphine after abdominal surgery, 9 of 29 patients were given alternative analgesia because of inadequate pain relief despite increasing doses of nalbuphine (Pugh et al. 1987). This has been interpreted as in keeping with a small effective maximum dose for analgesic effect (Kay & Krishnan 1986), or, alternatively, antagonism of analgesia as the dose of drug is escalated. The most frequent adverse effect after parenteral nalbuphine is drowsiness, the incidence of which has been variously reported as between 11 and 74% (Forrest 1971), and other opioid-related adverse effects such as nausea, vomiting, respiratory depression and psychotomimetic effects occur in a similar pattern to that seen with morphine. One study has documented significantly fewer psychotomimetic effects compared with pentazocine, with an incidence of 7% after intramuscular nalbuphine 10 or 20mg and 52% after intramuscular pentazocine 60mg (Houde et al. 1976). An overall incidence of less than I % is cited by the manufacturers (Errick & Heel 1983). Amnesia has been reported in over 50% of patients receiving nalbuphine postoperatively, even where severe pain was experienced (Kay & Krishnan 1986; Pugh et al. 1987). A lower incidence of nausea and vomiting compared with pethidine in postoperative patients has also been reported (Hew et al. 1987). Nalbuphine has also been used as a perioperative analgesic in cardiac surgery in conjunction with diazepam and nitrous oxide (Zsigmond et al. 1987). A continuous infusion with a mean loading dose of 6.66 mg/kg in the first hour, and 1.65 to 4.73 mg/kg/h subsequently, produced a pain-free
333
Agonist-Antagonist Opioid Analgesics
state without significant changes in haemodynamic parameters, postoperative respiratory function, or plasma cortisol or histamine. The absence of hypotension, bradycardia, postoperative respiratory depression and other problems associated with fentanyl in this setting may be an important advantage of nalbuphine but there are no prospective randomised studies in which the 2 agents have been compared. An earlier study (Lake et al. 1982) found that nalbuphine used as the sole analgesic agent gave inadequate analgesia during cardiac surgery. In obstetric pain nalbuphine has been evaluated after both parenteral and oral administration. A randomised study of patient-controlled intravenous nalbuphine and pethidine found significantly lower pain scores in the nalbuphine group, but this could be explained by the use of 3mg boluses of nalbuphine compared with ISmg boluses of pethidine, and accumulation of nalbuphine due to its longer half-life during labour (Frank et al. 1987). No difference in adverse effects and no foetal respiratory depression were seen in this study. Currently, nalbuphine is licensed for use in obstetric pain in the USA but not in the UK. In acute myocardial infarction nalbuphine has been shown to be an effective analgesic. Two prospective randomised studies have demonstrated satisfactory pain relief after 20mg nalbuphine intravenously, and no difference in analgesic efficacy or adverse effects when compared with Smg diamorphine intravenously (Greenbaum et al. 1987; Jamidar et al. 1987) [fig. 2). The haemodynamic effects ()f nalbuphine in acute myocardial infarction have been studied in a series of IS patients and no deleterious effects on cardiac function were demonstrated (Lee & Low 1981). One important advantage of nalbuphine over diamorphine in this setting is that nalbuphine is not subject to the legal restrictions that apply to other strong opioid analgesics, thereby facilitating both its storage and access for emergency administration, particularly outside the hospital setting. There are only limited clinical trial data on oral nalbuphine. In a randomised double-blind comparison with 30mg oral dihydrocodeine in patients who had had a dental extraction, 30mg oral nal-
•
o
c: 'OJ
10 a. 80 0 Q) "0 60 ~ CJ 40
;.;
.~ 0
0
Nalbuphine Diamorphine
20 0
0
30
60
120
Time (min)
Fig. 2. Percentage of post-myocardial infarction patients with Grade 0 pain following nalbuphine ~ 20mg or diamorphine ~ 5mg intravenously at various time intervals following administration (reproduced with permission from Jamidar et al. 1987).
buphine was equivalent and 60mg oral nalbuphine superior in both intensity and duration of analgesia (Kay et al. 1988). Adverse effects were similar. Oral nalbuphine has been compared to codeine and placebo in post-partum pain (Kantor & Hopper 1984). In a prospective randomised single-dose study ISmg nalbuphine gave equivalent analgesia and similar adverse effects to 60mg codeine. However, since no oral formulation of nalbuphine is currently available, this is not a use which can be explored in current clinical practice. 2.3.3 Chronic Pain Nalbuphine has no major role in the management of chronic pain, principally because it is only available in a parenteral form. Long term subcutaneous administration over periods of up to 32 weeks have been associated with sedation and confusion in a significant proportion of patients but resulted in less psychotomimetic effects and constipation than morphine (Stambaugh 1982). Abnormalities in liver function tests have been reported after repeated intramuscular injections (Elliott et al. 1970). Nalbuphine has no obvious advantages over other established drugs for parenteral use in chronic pain, and when given to patients already taking opioid drugs withdrawal phenomena may be precipitated (Stambaugh 1982).
2.4 Dezocine Dezocine is a synthetic bridged aminotetralin compound (O'Brien & Benfield 1990) whose structure is shown in figure 3. Nalorphine-like antag-
Drugs 41 (3) 1991
334
~C~ C CH2~OH CH 3 Dezocine
Fig. 3. Structure of dezocine.
onist activity has been demonstrated in animal models, with opioid agonist effects which are reversible with naloxone. 2.4.1 Relative Analgesic Potency After intramuscular administration 10mg dezocine produces analgesia equivalent to IOmg morphine or 50 to 100mg pethidine in postoperative pain, with a more rapid onset of action but a slightly shorter duration of analgesia compared with morphine (Camu & Gepts 1979; Downing et al. 1981; Fragen & Caldwell 1978). 2.4.2 Acute Pain Dezocine appears as effective as morphine or pethidine in postoperative pain in the doses described above (Downing et al. 1981; Fragen & Caldwell 1978; Vinik et al. 1982). In a placebocontrolled double-blind comparison IOmg dezocine intravenously was found to be superior to 5mg dezocine or I mg butorphanol, both of which were superior to placebo (Galloway & Varmer 1986). No significant respiratory depression has been seen following the use of dezocine in postoperative patients and no greater incidence of other opioid adverse effects, in particular drowsiness, nausea or vomiting, has been reported in the above studies. 2.4.3 Chronic Pain Dezocine has been evaluated in cancer pain. A prospective double-blind study found a single intramuscular injection of IOmg dezocine to be superior to placebo in only II of 20 selected cancer patients previously receiving pentazocine for pain control. Seven patients had significant nausea following dezocine (Staquet 1980). A more recent study compared single and repeated intramuscular injections of dezocine 10mg, butorphanol 2mg and placebo in 60 cancer patients. Dezocine gave better
analgesia and was better tolerated than butorphanol, both of which were superior to placebo. The principal adverse effect of dezocine was drowsiness; there were no psychotomimetic reactions, nausea or vomiting (Stambaugh & McAdams 1987). However, the absence of an oral formulation of this drug means that it is unsuitable for chronic pain treatment.
3. Morphine-Like Agonist-Antagonists 3.1 Buprenorphine Buprenorphine is a semi-synthetic derivative of thebaine and chemically closely related to the strong agonist etorphine (fig. 4.) Buprenorphine is a true partial agonist at the wreceptor and exhibits a ceiling effect in dose-response curves in various animal models. In some a bell-shaped curve is seen, indicating that at doses above a certain level the pharmacological effect actually decreases with increasing dose (Rance 1979; fig. 5). Buprenorphine is unique within this group of drugs in being available for sublingual administration, and appears almost as effective by this route as by intramuscular administration. Buprenorphine OAmg sublingually gives similar analgesia to 0.2 to 0.3mg intramuscularly, with an onset of analgesia within 30 to 60 minutes of administration and a duration of analgesia of 6 to 9 hours (Bullingham et al. 1981; Wallenstein et al. 1986) [fig. 6]. In contrast, if taken orally, buprenorphine is a poor analgesic due to extensive presystemic elimination (Bullingham et al. 1983). The long duration HO
CH30
HO-C-CH3 I
/~"
CH3 CH3 CH3 Buprenorphine
Fig. 4. Structure of buprenorphine.
Agonist-Antagonist Opioid Analgesics
~
J
20 18
.!!!. 15 >u
c
12
-" .!.l
6
~
;;:
'ffi I-
335
3 0
I
0.001
I
I
I
I
0.010 0.100 1.00 10.0 Dose (mg/kg subcutaneously)
I
100
Fig. 5. Log dose-response curves for a series of narcotic drugs in the radiant heat rat tail flick assay: etorphine (e), buprenorphine (.&), morphine (.), propiram (0) and pentazocine (0). Each point represents a mean of 10 determinations on individual animals. Buprenorphine produced a 'bell'-shaped dose-response curve (reproduced with permission from Rance 1979).
of analgesia with buprenorphine may be related to its high affinity for the /L-opioid-receptor and an unusually slow dissociation constant for the drugreceptor complex. 3.1.1 Relative Analgesic Potency Direct single-dose comparison with other analgesics such as codeine and morphine is complicated by the long duration of analgesia after buprenorphine, but results from a number of studies in postoperative pain suggest that single doses of 0.3mg buprenorphine parenterally or O.4mg buprenorphine sublingually give equivalent analgesia to 10 to 15mg intramuscular morphine (Heel et al. 1979; Tigerstedt & Tammisto 1980). A ceiling effect for subjective responses to buprenorphine in humans has been alluded to (Heel et al. 1979) but there are no reliable data to allow a maximal dose to be defined. A practical ceiling exists for sublingual use in that the only available formulation is a 2/Lg tablet and few patients will accept more than 3 or 4 of these in a single dose. 3.1.2 Acute Pain Buprenorphine is an effective and useful drug for postoperative pain, when it may be given by intermittent parenteral administration, via patientcontrolled administration systems, by sublingual
administration or by the spinal route. Its efficacy has been demonstrated after major abdominal, orthopaedic and thoracic surgery (MacLean & MacConnachie 1987). The long duration of action of buprenorphine is an advantage in the postoperative situation when compared with drugs such as morphine. Most studies comparing the 2 drugs show similar onset and depth of analgesia but a more prolonged effect after buprenorphine (fig. 6) so that fewer doses are required and the overall quality of postoperative pain relief is better (Heel et al. 1979). One potential problem which may be encountered with buprenorphine given sublingually for postoperative pain is an initial delay of up to 1 hour in the onset of analgesia because of slow absorption by this route, particularly when the mouth is dry following an anaesthetic. In one double-blind, placebo-controlled crossover study in orthopaedic pain comparing O.4mg buprenorphine sublingually and 2 tablets each containing dextropropoxyphene 32.5mg and paracetamol 325mg ('Coproxamol'), the dextropropoxyphene/paracetamol combination was preferred by 13 of 25 patients (Heel et al. 1979). Better analgesia was obtained over the first 4 hours with the above drug combination and a much lower incidence of adverse effects, in particular drowsiness and nausea, were seen. Overall, in postoperative use, adverse effects appear to be similar to those with other opioid drugs. Nausea and vomiting may be more frequent but psychotomimetic effects after single parenteral doses are unusual (Drug and Therapeutics Bulletin 1979). If they do occur, however, they may be severe (Paraskevaides 1988). In one study using sublingual buprenorphine following abdominal hysterectomy, equivalent analgesia to 20mg intramuscular papaveretum was seen but nausea or vomiting occurred in 50% of patients receiving buprenorphine (Fry 1979). A prospective comparison of sublingual buprenorphine, intramuscular morphine and self-administered intravenous pethidine found no difference in analgesia but significantly higher scores for drowsiness and nausea after buprenorphine in patients who had had cholecystectomy, but not in those who had had hysterectomy
336
Drugs 41 (3) 1991
or herniorrhaphy (Ellis et al. 1982). In a comparative study of buprenorphine and morphine in children, an incidence of nausea and vomiting of 16% was seen after morphine but 28% after buprenorphine, with again no observed difference in analgesic activity (Maunuksela et al. 1988). However, other studies have shown no difference in the incidence of adverse effects when buprenorphine is compared with intermittent injections of morphine (Downing et al. 1977). A synergistic respiratory depressant effect has been reported when buprenorphine is given with fentanyl and phenoperidone to patients undergoing abdominal surgery (Cook et al. 1982), and prolonged respiratory depression with repeated doses of buprenorphine has also been observed (Thorn et al. 1988). In general, however, in the absence of other opioid drugs, less respiratory depression is seen compared with morphine (MacLean & MacConnachie 1987). Patient-controlled administration is increasingly used for the administration of postoperative analgesia. A recent study of 51 patients undergoing abdominal surgery who received intravenous buprenorphine using bolus injections of 0.1 or 0.2mg given via a patient-operated syringe driver reported excellent analgesia in 47 patients (94%), but
clinically significant respiratory depression was observed in 2 patients (Gibbs et al. 1982). A prospective randomised double-blind placebocontrolled comparison of 'patient demand' intramuscular buprenorphine (0. 15mg) with sublingual buprenorphine (O.2mg) found both routes equally effective in achieving analgesia, with a nonsignificant trend towards higher dose requirements over the first 24 hours when the drug was given sublingually (Shah et al. 1986). In prospective comparisons of 'on demand' buprenorphine with other opioid drugs given in the same way, 90~g increments of buprenorphine were equivalent to 30mg increments of pethidine given intravenously (Chakravarty et al. 1979) and in a comparison of intramuscular buprenorphine (O.15mg increments) with meptazinol (50mg), morphine (5mg) and pethidine (50mg), buprenorphine gave the lowest pain scores and longest lasting analgesia, with no significant differences in adverse effects (Harmer et al. 1983) [fig. 7]. The spinal route is also increasingly used for the administration of opioids in postoperative pain, although this is a controversial area and some authorities are not convinced that significant advantages over parenteral administration have been demonstrated (Editorial 1986).
2
~.-- - - - A. __--:"".....:~__ 1.5
i='
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"
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Time (hours) Fig. 6. Time-etTect curves for O.8mg sublingual buprenorphine (A) and 4mg intramuscular morphine (_) in 42 patients with postoperative pain (reproduced with permission from Wallenstein et al. 1986).
337
Agonist-Antagonist Opioid Analgesics
Drugs 41 (3): 326-344. 1991 ()() 12-666 7/ 91 / 0003-0326/$09.50/ 0 © Adis International Limited. All rights reserved. ORUl639
Opioid Agonist-Antagonist Drugs in Acute and Chronic Pain States P.J. Hoskin and G. W. Hanks Royal Marsden Hospital, London, and Institute of Cancer Research, University of London, London, England
Contents 326 327 328 328 328 329 329 330
332 333 334 334 338 340
Summary
Summary 1. Introduction 1.1 Opioid Receptors 1.2 Agonist-Antagonist Opioid Analgesics 1.3 Acute and Chronic Pain 2. Nalorphine-Like Agonist-Antagonists 2.1 Pentazocine 2.2 Butorphanol 2.3 Nalbuphine 2.4 Dezocine 3. Morphine-Like Agonist-Antagonists 3.1 Buprenorphine 4. Meptazinol 5. Conclusions
The agonist-antagonist opioid analgesics are a heterogeneous group of drugs with moderate to strong analgesic activity comparable to that of the pure agonist opioids such as codeine and morphine but with a limited effective dose range. The group includes drugs which act as an agonist or partial agonist at one receptor and an antagonist at another (pentazocine, butorphanol, nalbuphine, dezocine) and drugs acting as a partial agonist at a single receptor (buprenorphine). These drugs can be classified as nalorphine-like or morphine-like. Meptazinol does not fit into either classification and occupies a separate category. Pentazocine, butorphanol and nalbuphine are weak wantagonists and K-partial-agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is slightly less potent than morphine, and butorphanol is 3.5 to 7 times as potent. The duration of analgesia is similar to that of morphine (3 to 4 hours). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol (acetaminophen) than the weak opioid analgesics such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation. At usual therapeutic doses nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (though the duration of such effects with butorphanol may be longer). Unlike morphine there appears to be a ceiling to both the respiratory depression and the analgesic action. All of these 3 drugs have a lower abuse potential than the pure agonist opioid analgesics such
Agonist-Antagonist Opioid Analgesics
327
as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to Controlled Drug restrictions. Buprenorphine is a potent partial agonist at the It-receptor, and by intramuscular injection is 30 times as potent as morphine. A ceiling to the analgesic effect of buprenorphine has been demonstrated in animals and it is also claimed in humans. However, there are no reliable data available to define the maximal dose of buprenorphine in humans. A practical ceiling exists for sublingual use in that the only available formulation is a 2ltg tablet and few patients will accept more than 3 or 4 of these in a single dose. The duration of analgesia is longer than that of morphine, at 6 to 9 hours. There have been suggestions that buprenorphine causes less respiratory depression than morphine, but viewed overall it appears that in equianalgesic doses the 2 drugs have similar respiratory depressant effects. Naloxone is relatively ineffective in reversing serious respiratory depression caused by buprenorphine. Buprenorphine has a lower abuse potential than morphine, but misuse of this drug has been a growing problem in some areas. Buprenorphine is now a controlled drug. Meptazinol is a synthetic hexahydroazepine derivative with opioid agonist and antagonist properties, but is unlike either the nalorphine-type agonist-antagonists, or buprenorphine. Meptazinol has central cholinergic properties which may account at least in part for its analgesic effects. Receptor binding studies show it to be a specific Itl-agonist. Meptazinol is one-tenth as potent as morphine by intramuscular injection and has a duration of action of about 4 hours. Adverse effects - nausea, vomiting, sweating, dizziness and psychotomimetic symptoms - have been more frequent in some studies than with morphine, though respiratory depression and constipation appear to be less. When viewed overall the evidence indicates few significant advantages of this group of drugs over the strong opioid agonists in the treatment of acute pain. Buprenorphine has established a place in the treatment of postoperative pain, partly because until recently it was not subject to controlled drug regulations. The recent change in its legal status removes an important advantage in the postoperative situation. Nalbuphine is an effective analgesic in myocardial infarction pain and has an advantage over morphine in that it is still not subject to the same legal restrictions on its storage and use. This has facilitated its use for emergency administration, particularly outside the hospital setting. The agonist-antagonist analgesics do not have a major role in the treatment of chronic pain. Buprenorphine is potentially the most useful member of the group because it is potent, longacting and effective when given sublingually.
1. Introduction The group of drugs known as agonist-antagonist opioid analgesics includes a number of agents with moderate to strong analgesic activity which differ from their pure agonist counterparts such as morphine by their action on opioid receptors. The terminology in this area is confusing, partly because it has changed in recent years. The term agonistantagonist was used as a general term to describe drugs acting as partial agonists at opioid receptors; a partial agonist binds to the receptor but has low intrinsic activity, so that its dose-response curve exhibits a ceiling effect at less than the maximal effect produced by a full agonist. However, the term
agonist-antagonist now refers to 2 distinct groups of drugs: true partial agonists acting on a single receptor subtype and drugs which may behave as agonists, partial agonists or antagonists at different opioid receptors. A third group, represented by meptazinol, does not fit into either of these categories. Nalorphine (N-allyl normorphine), the prototype agonist-antagonist opioid analgesic, was synthesised initially as an antagonist of morphine (Hart 1941), but was subsequently shown to have powerful analgesic activity (Lasagna & Beecher 1954). This perplexing combination of effects stimulated the formulation of 2 concepts: first, that there are several classes of opioid receptors, and second, that
Drugs 41 (3) 1991
328
it is possible for some drugs to act an an agonist at one type of receptor and as an antagonist at another ('receptor dualism'). Nalorphine has subsequently been shown to act as a partial agonist at the K-receptor and as an antagonist at the wreceptor. l.l Opioid Receptors
Despite the expansion of knowledge in the field of opioid receptors over recent years, the precise role of different receptor subtypes in the modulation of pain remains unclear. There is some evidence from animal experiments to support the concept of both spatial differentiation, with wreceptors important in supraspinal analgesia and Kreceptors important in spinal analgesia (Martin et al. 1976), and functional differentiation, with wreceptors sensitive to heat stimuli and K-receptors sensitive to pressure stimuli (Upton et al. 1982). In clinical use, however, such differentiation between receptor types does not appear to have any consequence as far as analgesia is concerned. A drug with agonist properties at the K-receptor, such as pentazocine, appears to produce similar analgesia to a ~-agonist such as codeine. The effect on different receptors does, however, appear to result in a different spectrum of adverse effects. Table I shows the principal drugs in this group, together with their actions at the main opioid receptors. 1.2 Ago'nist-Antagonist Opioid Analgesics Agonist-antagonist opioids can be conveniently classified into those that produce pharmacological effects resembling those of nalorphine (nalorphine-
like) and those that produce pharmacological effects which resemble morphine's (morphine-like) [Jasinski 1979]. The ~ I-selective agonist-antagonist meptazinol is considered separately. The mixed agonist-antagonist drugs were developed in the hope of maintaining powerful analgesia while reducing serious adverse effects (particularly respiratory depression) and the potential for drug abuse and dependence. Although there are some differences in these respects between this group of drugs and the pure agonists, they have not generally constituted major advances in clinical practice and the agonist-antagonists have failed to displace established pure agonist drugs. 1.3 Acute and Chronic Pain Acute and chronic pain are very different clinical entities (table II) requiring different approaches to their management. In general, acute pain will have a specific and obvious predisposing factor, such as postoperative pain, acute trauma or obstetric pain. Acute pain has a positive role in drawing attention to a particular danger or threat; it is of predictable and limited duration, and tends to get better when the source of the pain is treated or heals. In contrast, chronic pain is maladaptive: it serves no 'useful purpose', is of unpredictable duration and tends to worsen. Chronic pain is often differentiated into chronic 'malignant' pain and chronic 'benign' pain. This is misleading because so-called chronic benign pain is often much more difficult to treat than chronic cancer pain. A better classification is one which
Table I. The actions of agonist-antagonist opioid analgesics at opioid receptors
Drug
Pentazocine Butorphanol Nalbuphine Buprenorphine Meptazinol a
Receptor subtype Il
K
Antagonist Antagonist Antagonist Partial agonist Agonist
Partial agonist Partial agonist Partial agonist
",Receptors are not true opioid receptors but may be responsible for dysphoric or psychotomimetic effects.
,ji
Agonist Agonist
Agonist-Antagonist Opioid Analgesics
329
2.1 Pentazocine
Table II. Acute and chronic pain Acute pain
Chronic pain
Event Duration predictable and limited Tends to get better Has meaning and purpose
Situation Duration unpredictable Tends to get worse Has no meaning, or negative meaning
differentiates chronic cancer pain from chronic noncancer pain. Chronic cancer pain has been characterised as longstanding acute pain, because it is associated with a continuous nociceptive input (Loeser 1980). In contrast, chronic noncancer pain often has no readily identifiable pathology and thus no identifiable nociceptive stimulus. Cancer pain in general responds to anti nociceptive measures, induding conventional analgesic drugs, whereas chronic pain which is associated with a nonmalignant disease process generally responds poorly to these measures. This differential response is relevant to any discussion of the place of agonist-antagonist opioid analgesics in the management of chronic pain. This group of drugs has been particularly advocated for use in patients with chronic noncancer pain who require potent analgesics because of a reluctance to use morphine-like opioid agonists for long periods of time in patients with a normal life expectancy. However, the agonist-antagonist analgesics are antinociceptive agents: their usefulness in the management of chronic noncancer pain is limited, like that of other conventional analgesic agents. Thus, if they have a place in the management of chronic pain at all, these drugs are more likely to be applicable to the management of chronic cancer pain, and here they have to be measured against the strong agonists of which morphine is the prototype.
Pentazocine was the first drug in this group to be widely available for analgesic use, and is formulated for oral, rectal and parenteral administration. 2.1.1 Relative Analgesic Potency A dose of 30 to 60mg pentazocine administered in single doses by intramuscular or subcutaneous injection produces similar analgesia to 10mg morphine (Beaver et al. 1966; Paddock et al. 1969) and 100mg pethidine (meperidine) [Scott et al. 1973], but with a slightly shorter overall duration of action. Table III shows equivalent doses of pentazocine and other agonist-antagonists compared with single doses of 10mg morphine intramuscularly or subcutaneously.
Pentazocine
Nalbuphine
2. Nalorphine-Like Agonist-Antagonists Pentazocine, butorphanol and nalbuphine are weak JL-antagonists and K-partial-agonists. Their chemical structures are shown in figure 1.
Butorphanol
Fig. 1. Structures of pentazocine, nalbuphine and butorphanol.
Drugs 41 (3) 1991
330
Table III. Equivalent analgesic doses. based on single parenteral doses relative to morphine 10mg intramuscularly or subcutaneously
Drug
Dose (mg)
Pentazocine Butorphanol Nalbuphine Dezocine Buprenorphine Meptazinol
30-60 1-3 12 10 0.2-0.3 100
When given orally, pentazocine has relatively weak and unpredictable analgesic activity. In randomised studies in postoperative patients, 35mg pentazocine given orally gave equivalent analgesia to 600mg aspirin, and 50mg pentazocine gave equivalent analgesia to 60mg codeine, but was more effective than 60mg dihydrocodeine (Kantor et al. 1966). However, in other studies 50mg pentazocine was less effective than 650mg aspirin (Daniel et al. 1971; Moertel et al. 1972) or combination preparations containing codeine 8mg with 500mg aspirin, or dextropropoxyphene (propoxyphene HCI) 32.5mg with 325mg paracetamol (acetaminophen) [Huskisson 1974; Robbie & Samarasinghe 1973]. 2.1.2 Acute Pain Pentazocine has been used as a moderate analgesic in postoperative patients. Fewer adverse effects - in particular nausea, vomiting, sedation and hypotension - have been claimed, but in equianalgesic doses no advantage for pentazocine compared with pethidine or morphine has been demonstrated (Paddock et al. 1969). The drug has also been used in acute renal and biliary colic, and less smooth muscle contraction has been reported compared to morphine (Economou & Ward-McQuaid 1971). However, when compared with buprenorphine for biliary colic, significant elevations in intrabiliary pressure have been demonstrated (Storitz et al. 1985), and the use of pentazocine in this situation is no longer recommended. Pentazocine is effective in obstetric pain, pro-
ducing analgesia in the majority of patients. It may increase uterine activity and shorten the first stage oflabour (Duncan et al. 1969; Filler & Filler 1966). There is some evidence that pentazocine causes less nausea and vomiting than pethidine in equianalgesic doses, though no difference in respiratory depression in the neonate has been demonstrated. In acute myocardial infarction pentazocine is an effective analgesic, but it has potentially hazardous haemodynamic effects resulting in increased left ventricular end diastolic pressure, increased left ventricular work and increased pulmonary artery pressure (Alderman et al. 1972; Jewitt et al. 1974). Alternative opioid drugs are therefore recommended for the pain of acute myocardial infarction (Editorial 1976). 2.1.3 Chronic Pain Pentazocine has been evaluated in both chronic cancer pain and noncancer pain. In patients with rheumatoid arthritis pentazocine 50mg was less effective than aspirin 600mg, 2 tablets of aspirin 500mg + codeine 8mg ('Codis') and 2 tablets of paracetamol 325mg + dextropropoxyphene 32.5mg ('Distalgesic') [Huskisson 1974]. Similarly, in a randomised study in cancer patients, pentazocine was not as effective as either the above paracetamol/dextropropoxyphene combination or aspirin with codeine tablets (Robbie & Samarasinghe 1973). Furthermore, pentazocine was associated with a higher incidence of adverse effects, in particular psychotomimetic effects (hallucinations, euphoria, depersonalisation) which have been described in up to 20% of patients (Taylor et al. 1978). These are usually dose-related and are particularly prevalent in long term use (Houde 1979). In chronic pain, therefore, pentazocine appears less effective than established moderate analgesic drugs and has a higher incidence of adverse effects.
2.2 Butorphanol Butorphanol is structurally related to pentazocine (fig. I). It is no longer available in the UK, and elsewhere can be used only for parenteral administration.
Agonist-Antagonist Opioid Analgesics
2.2.1 Relative Analgesic Potency Butorphanol is 3.5 to 7 times more potent than morphine, 30 to 40 times more potent than pethidine, and 20 times more potent than pentazocine in single-dose studies in postoperative pain (Gilbert et at. 1976). After intramuscular injection peak effects are seen at 30 minutes, with a duration of analgesia of up to 4 hours. 2.2.2 Acute Pain Butorphanol appears to be an effective postoperative analgesic for orthopaedic and abdominal surgery. In randomised double-blind comparisons with morphine in equianalgesic doses given intramuscularly or intravenously, both drugs produce analgesia with a similar pattern for peak effect and duration of analgesia. No significant difference in overall analgesic efficacy or adverse effects has been observed (Del Pizzo 1976; Dobkin et at. 1974; Lippman et at. 1976; Tavakoli et at. 1976). Similarly, in comparisons with pethidine, equianalgesic doses of butorphanol give a similar profile of analgesia in postoperative patients, with perhaps a slightly longer duration of analgesia after butorphanol (Galloway et at. 1977). The most common adverse effect after butorphanol in this setting is drowsiness, which may be dose-related, the incidence increasing in one study from 50% after Img intramuscular butorphanol to 62% as the dose was increased to 4mg (Dobkin et at. 1975). In other studies, however, the incidence of drowsiness has varied considerably, with no clear dose-response effect being seen. Nausea and vomiting is seen after butorphanol but the incidence is no greater than with other strong opioid analgesics such as morphine (Heel et al. 1978). Unlike its analgesic and other effects, the severity of respiratory depression does not appear to be dose related, with a ceiling effect at 1 to 2mg in healthy volunteers. However, while this may appear to be a potential advantage in postoperative use, the duration of respiratory depression is dose related, increasing in one study in healthy volunteers from 0.5 hours after 0.5mg intramuscularly to 6 hours after 4mg (Heel et al. 1978). Butorphanol has been given by the epidural
331
route for postoperative pain. In randomised studies butorphanol 4mg gave a similar degree of analgesia to morphine 5mg, with a more rapid onset but a shorter duration of only 6 to 8 hours (Abboud et at. 1987; Lippman & Mok 1988). Significant respiratory depression of greater duration than that seen with morphine was also reported, and in the light of this it is unlikely that butorphanol will have a major role as a spinal opioid analgesic. Two large randomised double-blind studies have evaluated butorphanol in severe renal colic (Elliott et at. 1979; Henry et at. 1987), both comparing 2mg and 4mg butorphanol with 80mg pethidine. In each study 2mg butorphanol was equivalent to 80mg pethidine, and .4mg butorphanol was superior to both. There was a tendency to earlier requirements for a further dose of analgesia in the pethidine groups, consistent with a longer duration of analgesia with butorphanol. No significant differences in adverse effects were seen. Butorphanol has been evaluated as an analgesic in labour pain in several large randomised studies in which it has been compared with morphine in single intramuscular or intravenous doses (Heel et at. 1978; Maduska & HajghassemaJi 1978). No overall difference in either analgesic efficacy, maternal adverse effects or foetal adverse effects have been reported. In post-partum episiotomy pain, oral doses of 8mg or 16mg butorphanol have been demonstrated to be as effective as 60mg codeine. Other reports of oral butorphanol indicate that it is effective in mild to moderate postoperative pain and musculoskeletal pain (Heel et al. 1978). However, no particular advantages over established oral drugs such as paracetamol or codeine have been demonstrated and no oral formulation ofbutorphanol is currently available for clinical use. 2.2.3 Chronic Pain Butorphanol has been studied in chronic cancer pain (Heel et at. 1978; Stambaugh & McAdams 1987), where it may produce effective analgesia, but on regular administration a high incidence of sedation and psychotomimetic effects has been reported. Butorphanol has no advantages over morphine in this setting and the need for intramuscular
332
administration in the absence of an oral formulation makes it an inappropriate drug for long term use. 2.3 Nalbuphine Nalbuphine is structurally closely related to naloxone (a specific opioid antagonist) and to oxymorphone (a strong agonist) [fig. I]. Nalbuphine is only available for parenteral administration. 2.3.1 Relative Analgesic Potency Single-dose studies after intramuscular administration have shown that using the same dose nalbuphine produces a total analgesic effect which is 80 to 90% that of morphine and a peak analgesic effect 70 to 80% that of morphine, but with a slightly longer duration of action (Beaver & Feise 1978; Errick & Heel 1983). The onset of analgesia after intramuscular nalbuphine is at about 15 minutes, with peak effects 30 minutes after intravenous and I hour after intramuscular administration. Duration of analgesia after parenteral nalbuphine is 3 to 5 hours, giving a similar pattern of analgesia to morphine (Fragen & Caldwell 1977). Comparison of nalbuphine with pentazocine given either intramuscularly or intravenously shows it to be about 3 times as potent as pentazocine with a slightly longer duration of action (Houde et al. 1976; Tammisto & Tigerstedt 1977). In single doses a ceiling effect for analgesia is seen at 20 to 30mg. When given orally, nalbuphine has analgesic potency 20 to 25% that of intramuscular nalbuphine, with a peak effect only 10% that of intramuscular nalbuphine. This is consistent with substantial presystemic elimination of the drug when given by the oral route. The peak analgesic effect after oral administration of nalbuphine is seen after 1 to 2 hours, with an overall duration of analgesia of 4 hours (Kantor & Hopper 1984; Okun 1982). Clinical studies of oral nalbuphine in single doses of 15 and 45mg have shown that nalbuphine 15mg gives a similar analgesic effect to 60 to 90mg codeine (Kantor & Hopper 1984; Okun 1982). One study found no difference between 15 and 45mg nalbuphine given orally in terms of analgesic po-
Drugs 41 (3) 1991
tency (Okun 1982). No oral formulation of nalbuphine is available for clinical use. 2.3.2 Acute Pain Nalbuphine is effective in postoperative pain when given by both intermittent injection and patient-controlled administration devices, but recent studies have suggested that, compared with morphine or buprenorphine, analgesia is less reliable and may even fail to be achieved (Brady et al. 1986; Pugh et al. 1987). In a study of a patientcontrolled intravenous infusion of nalbuphine after abdominal surgery, 9 of 29 patients were given alternative analgesia because of inadequate pain relief despite increasing doses of nalbuphine (Pugh et al. 1987). This has been interpreted as in keeping with a small effective maximum dose for analgesic effect (Kay & Krishnan 1986), or, alternatively, antagonism of analgesia as the dose of drug is escalated. The most frequent adverse effect after parenteral nalbuphine is drowsiness, the incidence of which has been variously reported as between 11 and 74% (Forrest 1971), and other opioid-related adverse effects such as nausea, vomiting, respiratory depression and psychotomimetic effects occur in a similar pattern to that seen with morphine. One study has documented significantly fewer psychotomimetic effects compared with pentazocine, with an incidence of 7% after intramuscular nalbuphine 10 or 20mg and 52% after intramuscular pentazocine 60mg (Houde et al. 1976). An overall incidence of less than I % is cited by the manufacturers (Errick & Heel 1983). Amnesia has been reported in over 50% of patients receiving nalbuphine postoperatively, even where severe pain was experienced (Kay & Krishnan 1986; Pugh et al. 1987). A lower incidence of nausea and vomiting compared with pethidine in postoperative patients has also been reported (Hew et al. 1987). Nalbuphine has also been used as a perioperative analgesic in cardiac surgery in conjunction with diazepam and nitrous oxide (Zsigmond et al. 1987). A continuous infusion with a mean loading dose of 6.66 mg/kg in the first hour, and 1.65 to 4.73 mg/kg/h subsequently, produced a pain-free
333
Agonist-Antagonist Opioid Analgesics
state without significant changes in haemodynamic parameters, postoperative respiratory function, or plasma cortisol or histamine. The absence of hypotension, bradycardia, postoperative respiratory depression and other problems associated with fentanyl in this setting may be an important advantage of nalbuphine but there are no prospective randomised studies in which the 2 agents have been compared. An earlier study (Lake et al. 1982) found that nalbuphine used as the sole analgesic agent gave inadequate analgesia during cardiac surgery. In obstetric pain nalbuphine has been evaluated after both parenteral and oral administration. A randomised study of patient-controlled intravenous nalbuphine and pethidine found significantly lower pain scores in the nalbuphine group, but this could be explained by the use of 3mg boluses of nalbuphine compared with ISmg boluses of pethidine, and accumulation of nalbuphine due to its longer half-life during labour (Frank et al. 1987). No difference in adverse effects and no foetal respiratory depression were seen in this study. Currently, nalbuphine is licensed for use in obstetric pain in the USA but not in the UK. In acute myocardial infarction nalbuphine has been shown to be an effective analgesic. Two prospective randomised studies have demonstrated satisfactory pain relief after 20mg nalbuphine intravenously, and no difference in analgesic efficacy or adverse effects when compared with Smg diamorphine intravenously (Greenbaum et al. 1987; Jamidar et al. 1987) [fig. 2). The haemodynamic effects ()f nalbuphine in acute myocardial infarction have been studied in a series of IS patients and no deleterious effects on cardiac function were demonstrated (Lee & Low 1981). One important advantage of nalbuphine over diamorphine in this setting is that nalbuphine is not subject to the legal restrictions that apply to other strong opioid analgesics, thereby facilitating both its storage and access for emergency administration, particularly outside the hospital setting. There are only limited clinical trial data on oral nalbuphine. In a randomised double-blind comparison with 30mg oral dihydrocodeine in patients who had had a dental extraction, 30mg oral nal-
•
o
c: 'OJ
10 a. 80 0 Q) "0 60 ~ CJ 40
;.;
.~ 0
0
Nalbuphine Diamorphine
20 0
0
30
60
120
Time (min)
Fig. 2. Percentage of post-myocardial infarction patients with Grade 0 pain following nalbuphine ~ 20mg or diamorphine ~ 5mg intravenously at various time intervals following administration (reproduced with permission from Jamidar et al. 1987).
buphine was equivalent and 60mg oral nalbuphine superior in both intensity and duration of analgesia (Kay et al. 1988). Adverse effects were similar. Oral nalbuphine has been compared to codeine and placebo in post-partum pain (Kantor & Hopper 1984). In a prospective randomised single-dose study ISmg nalbuphine gave equivalent analgesia and similar adverse effects to 60mg codeine. However, since no oral formulation of nalbuphine is currently available, this is not a use which can be explored in current clinical practice. 2.3.3 Chronic Pain Nalbuphine has no major role in the management of chronic pain, principally because it is only available in a parenteral form. Long term subcutaneous administration over periods of up to 32 weeks have been associated with sedation and confusion in a significant proportion of patients but resulted in less psychotomimetic effects and constipation than morphine (Stambaugh 1982). Abnormalities in liver function tests have been reported after repeated intramuscular injections (Elliott et al. 1970). Nalbuphine has no obvious advantages over other established drugs for parenteral use in chronic pain, and when given to patients already taking opioid drugs withdrawal phenomena may be precipitated (Stambaugh 1982).
2.4 Dezocine Dezocine is a synthetic bridged aminotetralin compound (O'Brien & Benfield 1990) whose structure is shown in figure 3. Nalorphine-like antag-
Drugs 41 (3) 1991
334
~C~ C CH2~OH CH 3 Dezocine
Fig. 3. Structure of dezocine.
onist activity has been demonstrated in animal models, with opioid agonist effects which are reversible with naloxone. 2.4.1 Relative Analgesic Potency After intramuscular administration 10mg dezocine produces analgesia equivalent to IOmg morphine or 50 to 100mg pethidine in postoperative pain, with a more rapid onset of action but a slightly shorter duration of analgesia compared with morphine (Camu & Gepts 1979; Downing et al. 1981; Fragen & Caldwell 1978). 2.4.2 Acute Pain Dezocine appears as effective as morphine or pethidine in postoperative pain in the doses described above (Downing et al. 1981; Fragen & Caldwell 1978; Vinik et al. 1982). In a placebocontrolled double-blind comparison IOmg dezocine intravenously was found to be superior to 5mg dezocine or I mg butorphanol, both of which were superior to placebo (Galloway & Varmer 1986). No significant respiratory depression has been seen following the use of dezocine in postoperative patients and no greater incidence of other opioid adverse effects, in particular drowsiness, nausea or vomiting, has been reported in the above studies. 2.4.3 Chronic Pain Dezocine has been evaluated in cancer pain. A prospective double-blind study found a single intramuscular injection of IOmg dezocine to be superior to placebo in only II of 20 selected cancer patients previously receiving pentazocine for pain control. Seven patients had significant nausea following dezocine (Staquet 1980). A more recent study compared single and repeated intramuscular injections of dezocine 10mg, butorphanol 2mg and placebo in 60 cancer patients. Dezocine gave better
analgesia and was better tolerated than butorphanol, both of which were superior to placebo. The principal adverse effect of dezocine was drowsiness; there were no psychotomimetic reactions, nausea or vomiting (Stambaugh & McAdams 1987). However, the absence of an oral formulation of this drug means that it is unsuitable for chronic pain treatment.
3. Morphine-Like Agonist-Antagonists 3.1 Buprenorphine Buprenorphine is a semi-synthetic derivative of thebaine and chemically closely related to the strong agonist etorphine (fig. 4.) Buprenorphine is a true partial agonist at the wreceptor and exhibits a ceiling effect in dose-response curves in various animal models. In some a bell-shaped curve is seen, indicating that at doses above a certain level the pharmacological effect actually decreases with increasing dose (Rance 1979; fig. 5). Buprenorphine is unique within this group of drugs in being available for sublingual administration, and appears almost as effective by this route as by intramuscular administration. Buprenorphine OAmg sublingually gives similar analgesia to 0.2 to 0.3mg intramuscularly, with an onset of analgesia within 30 to 60 minutes of administration and a duration of analgesia of 6 to 9 hours (Bullingham et al. 1981; Wallenstein et al. 1986) [fig. 6]. In contrast, if taken orally, buprenorphine is a poor analgesic due to extensive presystemic elimination (Bullingham et al. 1983). The long duration HO
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Fig. 5. Log dose-response curves for a series of narcotic drugs in the radiant heat rat tail flick assay: etorphine (e), buprenorphine (.&), morphine (.), propiram (0) and pentazocine (0). Each point represents a mean of 10 determinations on individual animals. Buprenorphine produced a 'bell'-shaped dose-response curve (reproduced with permission from Rance 1979).
of analgesia with buprenorphine may be related to its high affinity for the /L-opioid-receptor and an unusually slow dissociation constant for the drugreceptor complex. 3.1.1 Relative Analgesic Potency Direct single-dose comparison with other analgesics such as codeine and morphine is complicated by the long duration of analgesia after buprenorphine, but results from a number of studies in postoperative pain suggest that single doses of 0.3mg buprenorphine parenterally or O.4mg buprenorphine sublingually give equivalent analgesia to 10 to 15mg intramuscular morphine (Heel et al. 1979; Tigerstedt & Tammisto 1980). A ceiling effect for subjective responses to buprenorphine in humans has been alluded to (Heel et al. 1979) but there are no reliable data to allow a maximal dose to be defined. A practical ceiling exists for sublingual use in that the only available formulation is a 2/Lg tablet and few patients will accept more than 3 or 4 of these in a single dose. 3.1.2 Acute Pain Buprenorphine is an effective and useful drug for postoperative pain, when it may be given by intermittent parenteral administration, via patientcontrolled administration systems, by sublingual
administration or by the spinal route. Its efficacy has been demonstrated after major abdominal, orthopaedic and thoracic surgery (MacLean & MacConnachie 1987). The long duration of action of buprenorphine is an advantage in the postoperative situation when compared with drugs such as morphine. Most studies comparing the 2 drugs show similar onset and depth of analgesia but a more prolonged effect after buprenorphine (fig. 6) so that fewer doses are required and the overall quality of postoperative pain relief is better (Heel et al. 1979). One potential problem which may be encountered with buprenorphine given sublingually for postoperative pain is an initial delay of up to 1 hour in the onset of analgesia because of slow absorption by this route, particularly when the mouth is dry following an anaesthetic. In one double-blind, placebo-controlled crossover study in orthopaedic pain comparing O.4mg buprenorphine sublingually and 2 tablets each containing dextropropoxyphene 32.5mg and paracetamol 325mg ('Coproxamol'), the dextropropoxyphene/paracetamol combination was preferred by 13 of 25 patients (Heel et al. 1979). Better analgesia was obtained over the first 4 hours with the above drug combination and a much lower incidence of adverse effects, in particular drowsiness and nausea, were seen. Overall, in postoperative use, adverse effects appear to be similar to those with other opioid drugs. Nausea and vomiting may be more frequent but psychotomimetic effects after single parenteral doses are unusual (Drug and Therapeutics Bulletin 1979). If they do occur, however, they may be severe (Paraskevaides 1988). In one study using sublingual buprenorphine following abdominal hysterectomy, equivalent analgesia to 20mg intramuscular papaveretum was seen but nausea or vomiting occurred in 50% of patients receiving buprenorphine (Fry 1979). A prospective comparison of sublingual buprenorphine, intramuscular morphine and self-administered intravenous pethidine found no difference in analgesia but significantly higher scores for drowsiness and nausea after buprenorphine in patients who had had cholecystectomy, but not in those who had had hysterectomy
336
Drugs 41 (3) 1991
or herniorrhaphy (Ellis et al. 1982). In a comparative study of buprenorphine and morphine in children, an incidence of nausea and vomiting of 16% was seen after morphine but 28% after buprenorphine, with again no observed difference in analgesic activity (Maunuksela et al. 1988). However, other studies have shown no difference in the incidence of adverse effects when buprenorphine is compared with intermittent injections of morphine (Downing et al. 1977). A synergistic respiratory depressant effect has been reported when buprenorphine is given with fentanyl and phenoperidone to patients undergoing abdominal surgery (Cook et al. 1982), and prolonged respiratory depression with repeated doses of buprenorphine has also been observed (Thorn et al. 1988). In general, however, in the absence of other opioid drugs, less respiratory depression is seen compared with morphine (MacLean & MacConnachie 1987). Patient-controlled administration is increasingly used for the administration of postoperative analgesia. A recent study of 51 patients undergoing abdominal surgery who received intravenous buprenorphine using bolus injections of 0.1 or 0.2mg given via a patient-operated syringe driver reported excellent analgesia in 47 patients (94%), but
clinically significant respiratory depression was observed in 2 patients (Gibbs et al. 1982). A prospective randomised double-blind placebocontrolled comparison of 'patient demand' intramuscular buprenorphine (0. 15mg) with sublingual buprenorphine (O.2mg) found both routes equally effective in achieving analgesia, with a nonsignificant trend towards higher dose requirements over the first 24 hours when the drug was given sublingually (Shah et al. 1986). In prospective comparisons of 'on demand' buprenorphine with other opioid drugs given in the same way, 90~g increments of buprenorphine were equivalent to 30mg increments of pethidine given intravenously (Chakravarty et al. 1979) and in a comparison of intramuscular buprenorphine (O.15mg increments) with meptazinol (50mg), morphine (5mg) and pethidine (50mg), buprenorphine gave the lowest pain scores and longest lasting analgesia, with no significant differences in adverse effects (Harmer et al. 1983) [fig. 7]. The spinal route is also increasingly used for the administration of opioids in postoperative pain, although this is a controversial area and some authorities are not convinced that significant advantages over parenteral administration have been demonstrated (Editorial 1986).
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337
Agonist-Antagonist Opioid Analgesics
