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Home , Agonist, Meptazinol, Nalbuphine, Nalorphine

REFRESHER COURSE OUTLINE $5 -antagonist : theory and clinical practice Carl Rosow MD

This presentation will deal with the heterogeneous group The diversion and abuse of by anaesthetic of possessing proper- personnel was not widely appreciated until recently. ties. The clinically available of this class are , , , , and (in the UK). At this writing, has When an opioid binds to its it may produce a completed human trials and awaits FDA approval in the variable degree of effect: A full agonist like fentanyl or US. can produce intense analgesia and respiratory The prototype agonist-antagonist, N-allylnormorphine depression, while a competitive antagonist like (), 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 effects until the early behave as partial ; these drugs tend to have 1950's when Lasagna and Beecher discovered that it had shallow dose-response curves and produce lower maxi- analgesic 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 and . 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 addicts they experienced no receptors called mu, kappa, and sigma (Table I). 4 Each or craving. opioid may act as an agonist, a 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 , 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 . 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 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 , 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 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 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 , 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 per maximum after about 30 mg of nalbuphine. ,3 Even larger day. 21 Even appropriate long-term use of can doses are well tolerated by most patients, but severe gradually produce a low level of , respiratory embarrassment can still be produced in sensi- and this subclinical state can be unmasked by administra- tive individuals and in those with concomitant pulmonary tion of an opioid antagonist. It seems prudent to avoid or central nervous system disease. Respiratory depression agonist-antagonists in patients with significant prior use may be reversed with naloxone. of morphine, meperidine, , etc. A ceiling effect on respiration has also been demon- In theory, administration of an opioid antagonist might strated for buprenorphine in animals, and it probably create problems if one later switched to a pure agonist occurs in humans. This is important, since buprenorphine (e.g., nalbuphine premedication followed by fentanyl is not reliably antagonized by naloxone. ~4 The other mu intraoperatively). In practice, this interaction has not been partial agonist, dezocine, has substantially higher intrin- a problem. sic activity than the other agonist-antagonists, ts and it produced apooea in one of our study patients (Rosow, Chronic use~abuse unpublished observations). At present pentazocine is the only agonist-antagonist available in an oral formulation (sublingual buprenor- Smooth muscle effects phine is marketed in the UK). It is possible to give these The kappa type agonist-antagonists have all been shown drugs parenterally for long periods of time, but there is to produce much less spasm of gastrointestinal smooth little clinical data on such use. Tolerance and physical muscle than morphine. Pentazocine, nalbuphine, and dependence can occur, but the withdrawal syndrome is butorphanol do not cause appreciable elevation of intrabi- usually brief and not like that of morphine. liary pressure, and they may be particularly useful in The World Health Organization has reviewed the abuse patients who experience biliary colic after morphine.16 of agonist-antagonists and concluded that there is no basis for instituting controls. There has been very Cardiovascular effects little abuse of the kappa type agonists, and addicts tend to Pentazocine and butorphanol have been reported to cause avoid them. Pentazocine tablets were abused parenterally unique cardiovascular effects in animals and in patients for a short time along with the tripellenam- with cardiovascular disease. The mechanism(s) for these ine (so-called "T's and Blues"). The problem was solved effects are unknown. They have not been reported to by a reformulation in 1983. The subject of agonist- occur with nalbuphine or buprenorphine. antagonist abuse has recently been reviewed. 22 In contrast to morphine, pentazocine may increase heart rate, systemic and pulmonary arterial pressure, and Conclusions cardiac work. 17 It is likely that myocardial oxygen The agonist-antagonists are effective analgesics with consumption increases, so pentazocine may be a poor some significant differences from the pure agonists. The choice in the setting of myocardial ischaemia or in- clinical indications for these two classes overlap but are farction. not identical. All of the agonist-antagonists have excel- Butorphanol has been reported to increase pulmonary lent safety profiles: life-threatening respiratory depres- artery pressure, while heart rate and systemic pressure sion is uncommon, and minor toxic effects like , usually decrease slightly, is High doses have been given constipation, and urinary retention occur less frequently safely to patients undergoing coronary bypass grafting,19 than with morphine. Several of these agents have been although other opioids may be more desirable in this widely available for over ten years, and during that time setting. they have been subject to remarkably little diversion or abuse. Antagonist effects There are at least thre~ promising applications for these Nalbuphine and buprenorphine are relatively strong an- drugs in anaesthesia: tagonists and have been used clinically for this purpose.2~ 1 The kappa type drugs appear to be useful as sedatives I have not seen convincing evidence that reversal with an and adjuncts to local or regional anaesthesia. We need agonist-antagonist is safer or more reliable than with better dosage guidelines for this indication and more naloxone. data on interactions with other sedative drugs like Therapeutic doses of pentazocine, nalbuphine and . buprenorphine unequivocally precipitate withdrawal in 2 Epidural butorphanol has already shown some promise opioid-dependent individuals. Butorphanol seems to be in obstetrics. A single dose provides relief of post- sg CANADIAN JOURNAL OF ANAESTHESIA

Caesarean pain for six to ten hours without pruritus or 13 Gal TJ, Di Fazio CA, Moscicki J. Analgesic and respirato- excessive sedation. ry depressant activity of nalbuphine: a comparison with 3 Finally, these analgesics may have advantages for morphine. Anesthesiology 1982; 57: 367-74. Patient Controlled Analgesia, since they do not require 14 Heel RC, Brogden RN, Speight TM, Avery GS. Buprenor- locked pumps or narcotic inventory control. If the use phine: a review of its pharmacological properties and of agonist-antagonists can significantly reduce phar- therapeutic efficacy. Drugs 1979; 17: 81-110. macy paperwork, their total costs will probably com- 15 Malis JL, Rosenthale ME, Gluckman MI. Animal pharma- pare favourably with morphine and meperidine. cology of WY-16225, a new analgesic agent. J Phar- macol Exp Ther 1975; 194: 488-98. References 16 Radnay PA, Duncalf D, Novakovic M, Lesser ML. Com- 1 Lasagna L, Beeeher HK. The analgesic effectiveness mon duct pressure changes after fentanyl, mor- of nalorphine and nalorphine-morphine combinations in phine, meperidine, butorphanol, and naloxone. Anesth man. J Pharmacol Exp Ther 1954; 112: 356-363. Analg 1984; 63: 4. 2 Wikler A, Fraser HF, Isbell H. N-allylnormorphine: 17 Alderman EL, Barry WH, Graham AF, Harrison effects of single doses and precipitation of acute DC. Hemodynamic effects of morphine and pentazo- "abstinence syndromes" during to morphine, cine differ in cardiac patients. New Eng J Med 1972; 27: methadone or heroin in man (postaddicts). J Pharmaeol 623-7. Exp Ther 1953; 109: 8-20. 18 Popio KA, Jackson DH, Ross AM, Schreiner BF, Yu PAl. 3 Keats AS, TelfordJ. Studies of analgesic drugs. X. Hemodynamie and respiratory effects of morphine and Respiratory effects of narcotic antagonists. J Pharmacol butorphanol. Clin Phaar~ Ther 1978; 23: 281-7. Exp Ther 1966; 151: 126-32. 19 Aldrete JA, de Campo T, Usubiaga LE, Renck R, Suzuki D, 4 Martin WR, Eades CG, Thompson JA, Huppler RE, Win WO. Comparison of butorphanol and morphine as Gilbert PE. The effects of morphine- and nalorphine- analgesics for coronary bypass surgery: a double-blind, like drugs in the non-dependent and morphine-dependent randomized study. Anesth Analg 1983; 62: 78-83. chronic spinal dog. J Pharmacol Exp Ther 1976; 197: 20 Latasch L, Probst S, Dudziak R. Reversal by nalbuphine 517-32. of respiratory depression caused by fentanyl. Anesth 5 Houde RW, Wallenstein SL. Clinical studies of morphine- Analg 1984; 63: 814-6. nalorphine combination. Fed Proc 1956; 15: 440-1. 21 Preston KL, Bigelow GE, Liebson IA. Butorphanol- 6 Abboud TK, Moore M, Zhu J, et al. Epidural bntorphanol precipitated withdrawal in opioid.dependent human or morphine for the relief of pest-cesarean section pain: volunteers. J Pharm Exp "l'her 1988; 246: 441-8. ventilatory responses to carbon dioxide. Anesth Analg 22 Johanson CE, Yanagita T (Eds.). WHO Symposium on 1987; 66: 887-93. Drug Dependence: Benefit-Risk Ratio Assessment of 7 Stanley TH, Reddy P, Gilmore S, Bennett G. The cardio- Agonist-Antagonist Analgesics. Drug Dep. 1987; vascular effects of high-dose butorphanol- 20: 289-409. anaesthesia before and during operation. Can Anesth Soc J 1983; 30: 337-41. 8 Murphy MR, Hug CC. The sparing effect of morphine, butorphanol and nalbuphine. Anesthesiology 1982; 57: 489-92. 9 Houde RW. Analgesic effectiveness of the narcotic agonist-antagonists. Br J Clin Pharmacol 1979; 7: 297S-308S. 10 Kaiko RF, Wallenstein SL, Rogers AG, Canel A, Jacobs B, Houde RW. Intramuscular meptaziuol and morphine in postoperative pain. Clin Pharmacol Ther 1985; 37: 589- 96. 11 Bacon BR, Marshall JB. Randomized, prospective, double-blind of butorphanol and in patients undergoing upper gastrointestinal endoscopy. Acute Care 1988; 12(Suppl 1): 57-62. 12 Nagashima H, Karamanian A, Malovany R, et al. Respir- atory and circulatory effects of intravenous butorphanol and morphine. Clin Pharmacol Ther 1976; 19: 738-45.