Drugs

, Volume 26, Issue 3, pp 191–211 | Cite as

Nalbuphine

A Preliminary Review of its Pharmacological Properties and Therapeutic Efficacy
  • J. K. Errick
  • R. C. Heel
Drug Evaluations

Summary

Synopsis: Nalbuphine1 is an agonist/antagonist analgesic. After parenteral administration of ‘usual’ doses it is approximately equipotent in analgesic activity to morphine on a weight basis. In studies in patients with moderate to severe pain, usually following surgery, the characteristics of analgesia with nalbuphine were comparable to those seen with equianalgesic doses of morphine or pentazocine. It also appears to produce satisfactory anaesthesia when used as a component of a ‘balanced’ anaesthesia technique, although a relatively low ‘ceiling’ effect for reduction of anaesthetic requirements with nalbuphine may limit its usefulness in this regard. As with other agonist/antagonist analgesics, a ‘ceiling’ effect to nalbuphine-induced respiratory depression is also seen, beyond which further depression does not readily occur. However, with usual analgesic doses, respiratory depression seen with nalbuphine is comparable to that with morphine. Important haemodynamic changes have not occurred after usual doses of nalbuphine, even in patients with cardiac disease. Like other agonist/antagonist analgesic drugs, the abuse potential of nalbuphine seems relatively low, but only wider clinical use for longer periods can establish this with certainty. Thus, nalbuphine appears to offer a useful alternative to morphine in patients with moderate to severe pain.

Pharmacodynamic Studies: The narcotic agonist activity of nalbuphine has been demonstrated in standard animal tests, with a profile of activity in such studies characteristic of agonist/antagonist analgesic compounds. In analgesic potency assays in humans, intramuscularly administered nalbuphine was estimated to be approximately equipotent to morphine and about 3 times as potent as pentazocine on a weight basis. As occurred with morphine, nalbuphine reduced the dose of anaesthetic needed to achieve anaesthesia in animals; but nalbuphine reached a ‘ceiling’ for this effect, beyond which further doses had no additional action, at a much lower maximum reduction of anaesthetic requirement than could be achieved with morphine.

The narcotic antagonist properties of nalbuphine have been demonstrated in various animal tests and found to lie somewhere between the more potent nalorphine and the less potent pentazocine. Studies in humans dependent on morphine estimate nalbuphine to be one-quarter as potent an antagonist as nalorphine. Cases of precipitated withdrawal in patients previously treated with narcotics substantiate the clinical significance of this property.

Respiratory depression with nalbuphine at therapeutic doses (e.g. 10mg/70kg) is similar to that produced by equianalgesic doses of morphine. However, in contrast to the dose-dependent respiratory depression seen with morphine, nalbuphine-induced respiratory depression reaches a ‘ceiling’ in healthy subjects at a dose of 30 to 60mg/70kg, or lower (0.1 mg/kg) in another study, beyond which further respiratory depression does not readily occur.

Importantly, no significant haemodynamic changes after nalbuphine administration were observed in patients undergoing cardiac catheterisation, cardiac surgery, or after myocardial infarction.

Animal and human studies suggest that the abuse potential of nalbuphine is relatively low. Repeated administration of high doses to 6 previous narcotic users consistently produced disturbing side effects, sometimes limiting drug administration. Physical dependence to nalbuphine has been demonstrated after long term administration, and an abstinence syndrome may be precipitated by abrupt withdrawal in some patients, or by naloxone administration. As with other new analgesics, the true abuse potential of nalbuphine will be known with certainty only after much greater clinical experience.

Pharmacokinetic Studies: Only very limited data are available on the disposition of nalbuphine in man. Nalbuphine, administered intramuscularly to healthy adults, is rapidly absorbed with peak concentrations (mean 48 ng/ml) occurring 0.5 hours after a 10mg dose. The elimination half-life is approximately 5 hours in healthy subjects. Both metabolites and unchanged drug have been identified in the urine of healthy subjects, the greatest proportion of dose being excreted as the inactive glucuronide conjugate. Animal data indicates extensive biliary secretion.

Therapeutic Trials: Nalbuphine, usually given intravenously or intramuscularly, has been compared with morphine, pentazocine or pethidine (meperidine) in patients with moderate to severe pain. Generally, similar analgesic effects were evident for nalbuphine and morphine, or pentazocine, with nalbuphine showing a slightly longer duration of analgesic effect than morphine. In postoperative patients, nalbuphine was about 3 times as potent an analgesic on a weight basis as pentazocine, with a similar time until peak effect. The duration of action, however, appeared to be longer with nalbuphine. In the only published comparison with pethidine, nalbuphine was significantly less effective when administered intravenously for the discomfort associated with colonoscopy.

Subjective analgesia ratings were more frequently improved with subcutaneous nalbuphine when compared with subcutaneous morphine in cancer patients treated for at least 3 weeks. Only a small group of patients were studied however, under conditions where ideal control was not always possible, and these preliminary findings thus require confirmation.

Limited data suggest that orally administered nalbuphine is about 25% as potent as intramuscularly administered nalbuphine, and about 3 times as potent as orally administered codeine. When equianalgesic doses were compared in patients with moderate to severe pain nalbuphine was as effective as codeine with a rapid onset and about a 4-hour duration of analgesic effect.

Nalbuphine has been used as a premedication to anaesthesia and as a component of ‘balanced’ anaesthesia with generally favourable results. It has also been used to reverse respiratory depression after oxymorphone or hydromorphone ‘balanced’ anaesthesia, without apparent reversal of analgesia.

Side Effects: The most common side effect associated with nalbuphine administration is sedation (about 36% incidence). Nausea and vomiting may occur in about 6% of patients; less than 1% of patients experience psychomimetic reactions. The degree of respiratory depression after usual doses of nalbuphine is comparable to that with equianalgesic doses of morphine, although some evidence suggests that the incidence of postoperative respiratory depression after ‘balanced’ anaesthesia may be lower with nalbuphine than with morphine. Only very limited data on long term use of nalbuphine for chronic pain are available, and its side effect profile in this clinical setting needs further clarification.

Dosage and Administration: The recommended dose of nalbuphine is 10mg/70kg, repeated every 3 to 6 hours as needed, given by subcutaneous, intramuscular or intravenous routes. The maximum recommended single dose is 20mg, while the maximum recommended daily dose is 160mg. Withdrawal symptoms may be precipitated by nalbuphine in patients who have previously taken narcotics for long periods.

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References

  1. Beaver, W.T. and Feise, G.A.: A comparison of the analgesic effect of intramuscular nalbuphine and morphine in patients with postoperative pain. Journal of Pharmacology and Experimental Therapeutics 204: 487–496 (1978).PubMedGoogle Scholar
  2. Beaver, W.T.; Feise, G.A. and Robb, D.: Analgesic effect of intramuscular and oral nalbuphine in postoperative pain. Clinical Pharmacology and Therapeutics 29: 174–180 (1981).PubMedCrossRefGoogle Scholar
  3. Bikhazi, G.B.: Comparison of morphine and nalbuphine in postoperative pediatric patients. Anesthesiology Review 5: 34–36 (1978).Google Scholar
  4. Blumberg, H.; Dayton, H.B. and Wolf, P.S.: Analgesic properties of the narcotic antagonist EN-2234A. Pharmacologist 10: 197 (1968).Google Scholar
  5. Cowan, A.: Use of the mouse jumping test for estimating antagonistic potencies of morphine antagonists. Journal of Pharmacology and Pharmacodynamics 28: 177–182 (1976).CrossRefGoogle Scholar
  6. DiFazio, C.A.; Moscicki, J.C. and Magmder, M.R.: Anesthetic potency of nalbuphine and interaction with morphine in rats. Anesthesia and Analgesia 60: 629–633 (1981).PubMedCrossRefGoogle Scholar
  7. Elliott, H.W.; Navarro, G. and Nomof, M.: A double blind controlled study of the pharmacological effects of nalbuphine (EN-2234A). Journal of Medicine 1: 74–89 (1970).PubMedGoogle Scholar
  8. Fahmy, N.R.: Nalbuphine as a premedicant drug: A clinical evaluation. Abstracts of Scientific Papers, Annual Meeting of the American Society of Anesthesiologists, pp. 53–54 (977).Google Scholar
  9. Fahmy, N.R.: Nalbuphine in ‘balanced’ anesthesia: Its analgesic efficacy and hemodynamic effects. Anesthesiology 53: S66 (1980).CrossRefGoogle Scholar
  10. Forrest, W.H.: Report of the Veterans Administration Cooperative Analgesic Study. Problems of Drug Dependency Committee Proceedings, pp. 239–281 (1971).Google Scholar
  11. Fragen, R.J. and Caldwell, N.: Acute intravenous premedication with nalbuphine. Anesthesia and Analgesia 56: 808–812 (1977).PubMedCrossRefGoogle Scholar
  12. Gal, T.J. and DiFazio, CA.: Analgesia and ventilatory depression with nalbuphine. Anesthesiology 55: A375 (1981).Google Scholar
  13. Gal, T.J.; DiFazio, C.A. and Moscicki, M.S.: Analgesic and respiratory depressant activity of nalbuphine: A comparison with morphine. Anesthesiology 57: 367–374 (1982).PubMedCrossRefGoogle Scholar
  14. Heel, R.C.; Brogden, R.N.; Speight, T.M. and Avery, G.S.: Butorphanol: A review of its pharmacological properties and therapeutic efficacy. Drugs 16: 473–505 (1978).PubMedCrossRefGoogle Scholar
  15. Heel, R.C.; Brogden, R.N.; Speight, T.M. and Avery, G.S.: Buprenorphine: A review of its pharmacological properties and therapeutic efficacy. Drugs 17: 81–110 (1979).PubMedCrossRefGoogle Scholar
  16. Hofmann, R.F. and Weiler, H.H.: Lorazepam and nalbuphine as local anaesthetic ophthalmic surgery premedications. Annals of Ophthalmology 15: 64–66 (1983).PubMedGoogle Scholar
  17. Houde, R.W.; Wallenstein, S.L.; Rogers, A. and Kaiko, R.F.: Annual report of the analgesic studies section of the Memorial Sloan-Kettering Cancer Center. Problems of Drug Dependency Committee Proceedings, pp.149–168 (1976).Google Scholar
  18. Isbell, H.: The search for the nonaddicting analgesic: Has it been worth it? Clinical Pharmacology and Therapeutics 22: 377–384 (1977).PubMedGoogle Scholar
  19. Jasinski, D.R.: Human pharmacology of narcotic antagonists. British Journal of Clinical Pharmacology 7: 287S–290S (1979).PubMedCrossRefGoogle Scholar
  20. Jasinski, D.R. and Mansky, P.A.: Evaluation of nalbuphine for abuse potential. Clinical Pharmacology and Therapeutics 13: 78–90 (1972).PubMedGoogle Scholar
  21. Julien, R.M.: Effects of nalbuphine on normal and oxymorphone-depressed ventilatory responses to carbon dioxide challenge. Anesthesiology 57: A320 (1982).CrossRefGoogle Scholar
  22. Kosterlitz, H.W.; Waterfield, A.A. and Berthoud, V.: Assessment of the agonist and antagonist properties of narcotic analgesic drugs by their actions on the morphine receptor in the guinea pig ileum; in Braude et al. (Eds) Narcotic Antagonists, pp. 319–334 (Raven Press, New York 1974).Google Scholar
  23. Lake, C.L.; Duckworth, E.N.; DiFazio, C.A.; Durbin, C.G. and Magruder, M.R.: Cardiovascular effects of nalbuphine in patients with coronary or valvular heart disease. Anesthesiology 57: 498–503 (1982a).PubMedCrossRefGoogle Scholar
  24. Lake, C.L.; DiFazio, C.A.; Duckworth, E.N.; Moscicki, J.C; Engle, J.S. and Durbin, C.G.: High performance liquid Chromatographic analysis of plasma levels of nalbuphine in cardiac surgical patients. Journal of Chromatography 233: 410–416 (1982b).PubMedCrossRefGoogle Scholar
  25. Lee, G.; DeMaria, A.N.; Amsterdam, E.A. et al.: Comparative effects of morphine, meperidine and pentazocine on cardiocirculatory dynamics in patients with acute myocardial infarction. American Journal of Medicine 60: 949–955 (1976).PubMedCrossRefGoogle Scholar
  26. Lee, G.; Low, R.I.; Amsterdam, E.A. et al.: Hemodynamic effects of morphine and nalbuphine in acute myocardial infarction. Clinical Pharmacology and Therapeutics 29: 576–581 (1981).PubMedCrossRefGoogle Scholar
  27. Magruder, M.R.; Christofforetti, R. and DiFazio, C.A.: Balanced anesthesia with nalbuphine hydrochloride. Anesthesiology Review 7: 25–29 (1980).Google Scholar
  28. Magmder, M.R.; Delaney, R.D. and DiFazio, C.A.: Reversal of narcotic-induced respiratory depression with nalbuphine hydrochloride. Anesthesiology Review 9: 34–37 (1982).Google Scholar
  29. Murphy, M.R. and Hug, C.C.: The enflurane sparing effect of morphine, butorphanol, and nalbuphine. Anesthesiology 57: 489–492 (1982).PubMedCrossRefGoogle Scholar
  30. Okun, R.: Analgesic effects of oral nalbuphine and codeine in patients with postoperative pain. Clinical Pharmacology and Therapeutics 32: 517–524 (1982).PubMedCrossRefGoogle Scholar
  31. Rita, L.; Seleny, F. and Goodarzi, M.: Comparison of the calming and sedative effects of nalbuphine and pentazocine for paediatric premedication. Canadian Anaesthetists’ Society Journal 27: 546–549 (1980).PubMedCrossRefGoogle Scholar
  32. Romagnoli, A. and Keats, A.S.: Comparative hemodynamic effects of nalbuphine and morphine in patients with coronary artery disease. Cardiovascular Disease, Bulletin of the Texas Heart Institute 5: 19–24 (1978).Google Scholar
  33. Romagnoli, A. and Keats, A.S.: Ceiling effect for respiratory depression by nalbuphine. Clinical Pharmacology and Therapeutics 27: 478–485 (1980).PubMedCrossRefGoogle Scholar
  34. Schaefer, G.J. and Holtzman, S.G.: Discriminative effects of morphine and cyclazocine in the squirrel monkey. Problems of Drug Dependence, pp. 374–392 (1976).Google Scholar
  35. Schaefer, G.J. and Holtzman, S.G.: Discriminative effects of cyclazocine in the squirrel monkey. Journal of Pharmacology and Experimental Therapeutics 205: 291–301 (1978).PubMedGoogle Scholar
  36. Schmauss, C.; Doherty, C. and Yaksh, T.L.: The analgetic effects of an intrathecally administered partial opiate agonist, nalbuphine hydrochloride. European Journal of Pharmacology 86: 1–7 (1983).CrossRefGoogle Scholar
  37. Schmidt, W.K. and Vernier, V.G.: Aspects of the pharmacology of nalbuphine. Seventh World Congress of Anesthesiologists, Hamburg, Germany, 16 September (1980).Google Scholar
  38. Scott, M.E. and Orr, R.: Effects of diamorphine, methadone, morphine and pentazocine in patients with suspected acute myocardial infarction. Lancet 1: 1065–1067 (1969).PubMedCrossRefGoogle Scholar
  39. Shannon, H.E. and Holtzman, S.G.: Morphine training dose: A determinant of stimulus generalization to narcotic antagonists in the rat. Psychopharmacology 61: 239–244 (1979).PubMedCrossRefGoogle Scholar
  40. Stambaugh, J.E.: Evaluation of nalbuphine. Efficacy and safety in the management of chronic pain associated with advanced malignancy. Current Therapeutic Research 31: 393–401 (1982).Google Scholar
  41. Steinfels, G.F.; Young, G.A. and Khazan, N.: Self-administration of nalbuphine, butorphanol and pentazocine by morphine post-addict rats. Pharmacology, Biochemistry and Behaviour 16: 167–171 (1982).CrossRefGoogle Scholar
  42. Sunshine, A.; Zighelboim, I.; de Sarrazin, C.; de Castro, A.; Olson, N.Z. and Laska, E.: A study of the analgesic efficacy of nalbuphine hydrochloride in patients with postpartum pain. Current Therapeutic Research 33: 108–114 (1983).Google Scholar
  43. Tammisto, T. and Tigerstedt, I.: Comparison of the analgesic effects of intravenous nalbuphine and pentazocine in patients with postoperative pain. Acta Anesthesiologica Scandinavica 21: 390–394 (1977).CrossRefGoogle Scholar
  44. Thomas, R.; Malmcrona, R.; Fillmore, S. and Shillingford, J.: Haemodynamic effects of morphine in patients with acute myocardial infarction. British Heart Journal 27: 863–875 (1965).PubMedCrossRefGoogle Scholar
  45. Villarreal, J.E. and Karbowski, M.G.: The actions of narcotic antagonists in morphine-dependent rhesus monkeys; in Braude et al. (Eds) Narcotic Antagonists, pp. 273–289 (1974).Google Scholar
  46. Waye, J.D. and Braunfeld, S.F.: A randomized double-blind study of nalbuphine as an analgesic for colonoscopy. Gastrointestinal Endoscopy 28: 86–87 (1982).PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Australasia Pty Ltd 1983

Authors and Affiliations

  • J. K. Errick
    • 1
  • R. C. Heel
    • 1
  1. 1.New York and ADIS Drug Information ServicesWoodhull Medical and Mental Health CenterBirkenhead, Auckland 10New Zealand

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