REFRESHER COURSE OUTLINE $5 Agonist-antagonist opioids: theory and clinical practice Carl Rosow MD This presentation will deal with the heterogeneous group The diversion and abuse of fentanyl by anaesthetic of opioid analgesics possessing opioid antagonist proper- personnel was not widely appreciated until recently. ties. The clinically available drugs of this class are pentazocine, butorphanol, nalbuphine, buprenorphine, Mechanism of action and meptazinol (in the UK). At this writing, dezocine has When an opioid binds to its receptor it may produce a completed human trials and awaits FDA approval in the variable degree of effect: A full agonist like fentanyl or US. morphine can produce intense analgesia and respiratory The prototype agonist-antagonist, N-allylnormorphine depression, while a competitive antagonist like naloxone (nalorphine), was tested in animals and shown to be a binds with high affinity but produces little or no effect. morphine antagonist as early as 1930. Nalorphine was Nalorphine and all of the other agonist-antagonists thought to be devoid of analgesic effects until the early behave as partial agonists; these drugs tend to have 1950's when Lasagna and Beecher discovered that it had shallow dose-response curves and produce lower maxi- analgesic potency comparable to morphine. ~ They noted mal effects. Although this means that there is a "ceiling" that it produced typical morphine-like effects such as to the analgesic effects, toxic effects are limited as well. miosis and respiratory depression, but it also produced Keats and Telford showed, for example, that increasing unexpected effects like dysphoria and hallucinations. doses of nalorphine produced very limited increases in At nearly the same time Wikler and others showed that respiratory depression. 3 nalorphine could precipitate a violent withdrawal syn- Martin and his coworkers have postulated that the drome in opioid-dependent individuals. 2 When it was opioid alkaloids interact with (at least) three different given to former heroin addicts they experienced no receptors called mu, kappa, and sigma (Table I). 4 Each euphoria or drug craving. opioid may act as an agonist, a partial agonist or an The dysphoric effects and hallucinations made nalor- antagonist at each receptor (Table II). Nalorphine, pen- phine unacceptable as an analgesic (although it was used tazocine, butorphanol, and nalbuphine are thought to for years as an antagonist). It is much more significant that produce their analgesic and sedative effects by interacting nalorphine was the first potent analgesic which had little with kappa receptors. Each of them has affinity, but no or no addictive liability. The pharmaceutical industry was efficacy, at mu receptors and therefore acts as a morphine motivated to synthesize and test thousands of nalorphine antagonist. Dysphoria and hallucinations are thought to congeners, and a few of these have proved to be useful be mediated by sigma receptors. analgesics with a very low potential for abuse. Buprenorphine, dezocine, and meptazinol also have Thus far, the agonist-antagonist analgesics have not agonist and antagonist effects, but they are thought to be attained widespread popularity in anaesthetic practice. I partial agonists at mu receptors. Buprenorphine has been attribute this to three factors: shown to have extremely high affinity and relatively low I Much of the research done on these agents is not efficacy at mu receptors. When given alone, it produces directly applicable to the anaesthetic setting. effects which appear similar to morphine. When given 2 There is still widespread misunderstanding of agonist- after morphine, it displaces the full agonist and causes a antagonist pharmacology. These drugs were initially reduction in opioid effect. marketed as less abusable substitutes for morphine and As you might imagine, reversal of morphine with a mu fentanyl. Many anaesthetists were surprised to discover or kappa partial agonist is not as straightforward as that they differed from the pure agonists in some reversal with naloxone. In the presence of a fixed amount important ways. For some perioperative uses of mor- of morphine a small dose of nalorphine may antagonize phine or fentanyl the agonist-antagonist analgesics were probably not satisfactory substitutes. 3 The advantage of low-abuse potential i8 (unfortunately) Massachusetts General Hospital, Anaesthesia Dept., Fruit not generally perceived to be relevant to our specialty. Street, Boston, MA 02114, (617) 726-8812. CAN I ANAESTH 1989 / 36:3 t ppS$-SS S6 CANADIAN JOURNAL OF ANAESTHESIA TABLE l Opioidreceptor subtypesadapted from Martin(Ref. 4) agonist properties are more evident. Given alone, even extremely large doses of these drugs will usually not Receptor produce a state of "anaesthesia" as might be seen with Response mu kappa sigma fentany] or its derivatives.7 Compared with fentanyl, the agonist-antagonists produce more limited decreases in analgesia yes yes no respiratorydepression yes yes no requirements for potent volatile anaesthetics, s bchaviour euphoria sedation dysphoria pupil constriction yes yes no Sedation and mood effects morphine aubsitution yes no no A morphine-like agonist produces pain relief which is usually accompanied by dissociation, drowsiness, and mood elevation. As the dose is raised there is progressive- Table II Receptorinteractions* for variousopioids ly more mental clouding, lethargy, and stupor. Patients Receptor given the kappa-type agonist-antagonist pentazocine may experience floating and dissociation, but usually not Dr~ mu kappa s~ma mood elevation.9 They often appear extremely sedated Fentanyl Ag - yet remain capable of suprisingly lucid conversation. Morphine Ag Ag Sometimes the sedation will appear greater than the self-described relief of pain. With higher doses pat[ants Nalorphine Antag P Ag Ag are much more likely to experience "weird" feelings, Pentazocian Antag P Ag Ag Butorphanol Antag P Ag P Ag depersonalization, or hallucinations. The dysphoric ef- Nalbuphioe Antag P Ag P Ag fects are much more prominent with pentazocine than with butorphanol or nalbuphine. The subjective effects of Buprenorphine P Ag - the mu partial agonists (buprenorphine and dezocine) are Dezecine P Ag - morphine-like throughout the dose range. Meptaninol P Agl" - These mood effects have important therapeutic impli- *Ag = Agonist;P Ag ~ PartialAgonist; Antag = Antagonist. cations. Most physicians are very familiar with the 1"Othermechanisms probably play a role in the analgesiceffect. pleasant mental detachment produced by morphine and use it as a sign of drug effect. Since euphoria does not the opiate effects, while a large dose may actually usually occur with the agonist-antagonists there is a increase them. The net effect therefore depends upon the tendency to ascribe lack of mood elevation to lack of ratio of morphine to nalorphine. 5 analgesia. Kaiko et al. showed that these two effects are These drugs vary widely in antagonist and agonist separable in a multi-dose comparison of meptazinol and potency. Neither agonist vs. antagonist potency nor morphine in postoperafve pain. io Using a standard postop- hypothetical receptor interaction has proved to be a good erative pain model they showed that both drugs produced predictor of clinical utility or patient acceptance. dose-related pain relief, but only morphine produced dose-related improvement in mood. It is important to Clinical pharmacology remember that abuse of morphine is largely attributable to its euphoriant effects. While we want these drugs to make Analgesia our patients feel better, it is not clear whether mood The clinically available agonist-antagonists possess suf- elevation is always necessary or desirable in an analgesic. ficient analgesic activity to be effective in a variety of The prominent sedative effects of butorphanol or acute and chronic pain states. They have been shown to be nalbuphine may be advantageous in some clinical situa- sufficient for treatment of postoperative pain, trauma, tions. Butorphanol has shown promise as a sedative either bums, labour pain, renal colic, etc. They have been given alone or in combination with a benzodiazepine, i] In my intramuscularly, orally, sublingually, intranasally, intra- own practice, small doses (1-4 mg) of butorphanol, with venously by bolus or continuous infusion, and in patient- or without midazolam, are useful adjuncts to regional controlled analgesia systems. Several have been used anaesthetic techniques. The lower end of this dose range successfully by the epidural route. The initial reports on is suitable for elderly patients and those scheduled for epidural butorphanol after Caesarean section seem prom- discharge the same day. ising: Abboud reported that it produces excellent pain relief and little or no pruritus. 6 Respiratory depression Agonist-antagonists can be used successfully as part of Much has been made of the limited respiratory depression a balanced anaesthetic technique, but here their partial exhibited by these drugs. Respiratory depression after 2 or Rosow: AGONIST-ANTAGONIST OPIOIDS: THEORY AND CLINICAL PRACTICE $7 4 mg of butorphanol is equivalent to that produced by 10 much weaker as an antagonist, since it produces only mild mg of morphine, t2 Respiratory depression reaches a abstinence in addicts maintained on 30 mg methadone per maximum after about 30 mg of nalbuphine. ,3 Even larger day. 21 Even appropriate long-term use of opiates can doses are well tolerated by most patients, but severe gradually produce