Chemistry:Nalbuphine

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Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain.[1][2][3] It is given by injection into a vein, muscle, or fat.[1][3]

Side effects of nalbuphine include sedation, sweatiness, clamminess, nausea, vomiting, dizziness, vertigo, dry mouth, and headache.[2] Unlike other opioids, it has little to no capacity to cause euphoria or respiratory depression.[1][2] There is also little to no incidence of dysphoria, dissociation, hallucinations, and related side effects at typical therapeutic doses.[1][2] Nalbuphine is a mixed agonist/antagonist opioid modulator.[1][2] Specifically, it acts as a moderate-efficacy partial agonist or antagonist of the μ-opioid receptor (MOR) and as a high-efficacy partial agonist of the κ-opioid receptor (KOR), whereas it has relatively low affinity for the δ-opioid receptor (DOR) and sigma receptors.[4][2]

Nalbuphine was patented in 1968[5] and was introduced for medical use in the United States in 1979.[6][7] It is marketed in many countries throughout the world.[8]

Medical uses

Nalbuphine is indicated for the relief of moderate to severe pain. It can also be used as a supplement to balanced anesthesia, for preoperative and postoperative analgesia, and for obstetrical analgesia during labor and delivery. However, a 2014 Cochrane Systematic Review concluded that from the included studies, there was limited evidence to demonstrate that "0.1 to 0.3 mg/kg nalbuphine compared to placebo might be an effective postoperative analgesic" for pain treatment in children.[9] Further research is therefore needed to compare nalbuphine with other postoperative opioids.[9]

In addition to relieving pain, nalbuphine has been shown to reduce morphine-induced pruritus (itching).[10] Pruritus is a common side effect of morphine and other pure μ-opioid receptor (MOR) agonists. A systematic review of clinical trials concluded that nalbuphine is effective in counteracting morphine-induced pruritus, likely through central nervous system mechanisms.[11]

Evidence suggests that κ-opioid receptor (KOR) activation can counteract MOR-mediated effects in the brain.[12] This interaction may have broader implications for central nervous system disorders, including potential applications in treating Parkinson's disease, where KOR agonism and MOR antagonism have been shown to reduce levodopa-induced dyskinesia and normalize striatal function.[13]

Morphine-induced pruritus may also result from histamine release by mast cells in the skin.[14] Both MORs and KORs are expressed in skin nerves and keratinocytes, indicating potential peripheral mechanisms for opioid-induced pruritus.[15] Histamine-mediated responses such as increased capillary permeability and vasodilation have been observed following intradermal administration of some opioids. However, nalbuphine does not elicit either a wheal or flare response, suggesting it does not promote histamine release from mast cells.[16]

Available forms

An investigational extended-release oral formulation is under development by Trevi Therapeutics.[17]Template:Independent source inline

Side effects

A 2014 Cochrane Systematic Review by Schnabel et al., concluded that due to limited data, analysis of adverse events for children treated with nalbuphine compared to other opioids or placebo for postoperative pain, could not be definitively reported.[9]

Overdose

In case of overdose or adverse reaction, the immediate intravenous administration of naloxone (Narcan) is a specific antidote. Oxygen, intravenous fluids, vasopressors and other supportive measures should be used as indicated.[18] When administered concurrently with naloxone, nalbuphine is also useful for treating overdoses of potent opioids such as fentanyl, and its highly potent derivatives such as remifentanil and sufentanil, when naloxone alone is insufficient.[19]

Pharmacology

Pharmacodynamics

Nalbuphine at opioid receptors
Site Ki EC50 IA Ref
MOR 0.89 nM 14 nM 47% [4]
DOR 240 nM ND ND [4]
KOR 2.2 nM 27 nM 81% [4]

Nalbuphine is a semisynthetic mixed agonist/antagonist opioid modulator of the phenanthrene or morphinan series. It is structurally related to the widely used opioid antagonists naloxone and naltrexone, and to the potent opioid analgesic oxymorphone. Nalbuphine binds with high affinity to the MOR and KOR,[4] and has relatively low affinity for the DOR.[4] It behaves as a moderate-efficacy partial agonist (or mixed agonist/antagonist) of the MOR and as a high-efficacy partial agonist of the KOR.[4] Nalbuphine has weak or no affinity for the sigma receptor(s) (e.g., Ki > 100,000 nM).[2][20][21]

Nalbuphine is said to be more morphine-like at lower doses. However at higher doses, it produces more sedation, drunkenness, dysphoria, and dissociation.[22] As such, its effects are dose-dependent.[23] Such effects include sedation (21–36%), dizziness or vertigo (5%), lightheadedness (1%), anxiety (<1%), dysphoria (<1%), euphoria (<1%), confusion (<1%), hallucinations (<1%), depersonalization (1%), unusual dreams (<1%), and feelings of "unreality" (<1%).[23]


Chemistry

History

Nalbuphine was first synthesized in 1965 and was introduced for medical use in the United States in 1979.[7]



Society and culture

Brand names

Nalbuphine is marketed primarily under the brand names Nubain, Nalpain, and Nalbuphin.[8] It is also marketed under the brand name Nalufin in Egypt and Raltrox in Bangladesh by Opsonin Pharma Limited, under the brand name Rubuphine in India by Rusan Healthcare Pvt Ltd, under the brand name Kinz and Nalbin in Pakistan by Sami and Global Pharmaceuticals, under the brand name Analin by Medicaids in Pakistan, and under the brand name Exnal by Indus Pharma in Pakistan, among many others.[8]

Unlike many other opioids, nalbuphine has a limited potential for euphoria, and in accordance, is rarely abused.[1][23] This is because whereas MOR agonists produce euphoria, MOR antagonists do not, and KOR agonists like nalbuphine moreover actually produce dysphoria.[1][22] Nalbuphine was initially designated as a Schedule II controlled substance in the United States along with other opioids upon the introduction of the 1970 Controlled Substances Act.[1] However, its manufacturer, Endo Laboratories, Inc., petitioned the Food and Drug Administration to remove it from Schedule II in 1973, and after a medical and scientific review, nalbuphine was removed completely from the Controlled Substances Act in 1976 and is not a controlled substance in the United States today.[1][22] For comparison, MOR full agonists are all Schedule II in the United States, whereas the mixed KOR and MOR agonists/antagonists butorphanol and pentazocine are Schedule IV in the United States.[22] In Canada, most opioids are classified as Schedule I, but nalbuphine and butorphanol are both listed as Schedule IV substances.[24]

Veterinary use

There is limited data on nalbuphine's use in the dog, and even less for that of other animals. Nalbuphine induces sedation and analgesia in the dog but is less effective compared to μ-opioid receptor agonists. Nalbuphine has minimal effect on the cardiovascular system.[25] The sedation provided by nalbuphine is insufficient for catheterisation and fur clipping and the analgesic effect is insufficient for some pain.[26][25] Both sedative and analgesic effects of nalbuphine are subject to a ceiling effect. Combination of nalbuphine with an α2-adrenergic receptor agonist or acepromazine provides greater sedation.[25] One study found that acepromazine and nalbuphine failed to provide adequate analgesia both during and post-surgery in bitches undergoing ovariohysterectomy.[27][25] Although one study found epidural nalbuphine to provide adequate analgesia there is limited evidence to support epidural administration of nalbuphine.[28][25] Ophthalmic administration is not recommended in any species as multiple studies demonstrated no analgesia following topical ophthalmic administration.[29][30][31][25]

In cats nalbuphine has been shown to provide an equal sedative effect to butorphanol when adminsistered with acepromazine and an equal sedative and analgesic effect when combined with dexmedetomidine and tiltamine-zolazepam respectively.[25][32][33]

In horses evidence is mixed.[25] One study found that nalbuphine combined with xylazine was more effective than xylazine by itself as an analgesic and anaesthetic,[34] but another study found no difference between xylazine itself and xylazine with nalbuphine.[35][25]

Evidence in livestock is limited.[25] One study in Holstein calves following castration found nalbuphine to provide inadequate analgesia and sedation.[36][25] In goats one study found that nalbuphine combined with ketamine provided better post-operative analgesia than ketamine by itself at a higher dose.[37][25]

See also

Notes

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 "Nalbuphine, a non-controlled opioid analgesic, and its potential use in research mice". Lab Animal 44 (3): 106–110. March 2015. doi:10.1038/laban.701. PMID 25693108. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 "Nalbuphine". Drug and Alcohol Dependence 14 (3–4): 339–362. February 1985. doi:10.1016/0376-8716(85)90066-3. PMID 2986929. 
  3. ↑ 3.0 3.1 Essential Pain Pharmacology: The Prescriber's Guide. Cambridge University Press. 6 September 2012. pp. 343–. ISBN 978-0-521-75910-6. https://books.google.com/books?id=ymry3quAw6IC&pg=PA343. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 4.5 4.6 "Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors". Journal of Medicinal Chemistry 50 (9): 2254–2258. May 2007. doi:10.1021/jm061327z. PMID 17407276. 
  5. ↑ US Patent 3393197 - Nusubstituted-14-hydroxydihydronormorphines
  6. ↑ (in en) Analogue-based Drug Discovery. John Wiley & Sons. 2006. p. 528. ISBN 978-3-527-60749-5. https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA528. 
  7. ↑ 7.0 7.1 Sedation - E-Book: A Guide to Patient Management. Elsevier Health Sciences. 23 June 2009. pp. 336–. ISBN 978-0-323-07596-1. https://books.google.com/books?id=Abp9ci5-n1wC&pg=PA336. 
  8. ↑ 8.0 8.1 8.2 "Nalbuphine". https://www.drugs.com/international/nalbuphine.html. 
  9. ↑ 9.0 9.1 9.2 "Nalbuphine for postoperative pain treatment in children". The Cochrane Database of Systematic Reviews 2014 (7). July 2014. doi:10.1002/14651858.CD009583.pub2. PMID 25079857. 
  10. ↑ "Fast Facts and Concepts #381: Nalbuphine". Fast Facts & Concepts. July 2019. https://www.mypcnow.org/fast-fact/nalbuphine/?print=print. 
  11. ↑ "Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials". European Journal of Anaesthesiology 18 (6): 346–357. June 2001. doi:10.1046/j.0265-0215.2000.00826.x. PMID 11412287. 
  12. ↑ "Modulation of the kappa and mu opioid axis for the treatment of chronic pruritus: A review of basic science and clinical implications". JAAD International 7: 156–163. June 2022. doi:10.1016/j.jdin.2022.03.007. PMID 35497636. 
  13. ↑ "Dual κ-agonist/μ-antagonist opioid receptor modulation reduces levodopa-induced dyskinesia and corrects dysregulated striatal changes in the nonhuman primate model of Parkinson disease". Annals of Neurology 77 (6): 930–941. June 2015. doi:10.1002/ana.24375. PMID 25820831. 
  14. ↑ "Opiates, mast cells and histamine release". Life Sciences 53 (18): 1391–1399. January 1993. doi:10.1016/0024-3205(93)90581-m. PMID 7694026. 
  15. ↑ "Morphine acts on spinal dynorphin neurons to cause itch through disinhibition". Science Translational Medicine 13 (579). February 2021. doi:10.1126/scitranslmed.abc3774. PMID 33536279. 
  16. ↑ "Wheal and flare responses to opioids in humans". Anesthesiology 70 (5): 756–760. May 1989. doi:10.1097/00000542-198905000-00008. PMID 2470272. 
  17. ↑ "Haduvio™" (in en). Trevi Therapeutics. https://www.trevitherapeutics.com/haduvio/. 
  18. ↑ "Nalbuphine Hydrochloride Injection Overdosage". ©2025 Pfizer Inc.. https://www.pfizermedicalinformation.com/nalbuphine/overdose. 
  19. ↑ "Nalbuphine Potentiates Reversal of Fentanyl Overdose by Naloxone". Pharmaceuticals 17 (7): 866. July 2024. doi:10.3390/ph17070866. PMID 39065717. 
  20. ↑ "The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine". Life Sciences 52 (4): 389–396. 1993. doi:10.1016/0024-3205(93)90152-s. PMID 8093631. 
  21. ↑ "Sigma receptors: biology and function". Pharmacological Reviews 42 (4): 355–402. December 1990. doi:10.1016/S0031-6997(25)00047-X. PMID 1964225. 
  22. ↑ 22.0 22.1 22.2 22.3 Non-medical and illicit use of psychoactive drugs. Springer. 11 August 2017. pp. 48–. ISBN 978-3-319-60016-1. https://books.google.com/books?id=cbswDwAAQBAJ&pg=PA48. 
  23. ↑ 23.0 23.1 23.2 Psychiatric Side Effects of Prescription and Over-the-counter Medications: Recognition and Management. American Psychiatric Pub. 1998. pp. 2–. ISBN 978-0-88048-868-6. https://books.google.com/books?id=K7kevbILCuQC&pg=RA2-PA159. 
  24. ↑ The Drug Paradox: An Introduction to the Sociology of Psychoactive Substances in Canada. Canadian Scholars. 26 April 2018. pp. 84–. ISBN 978-1-77338-052-0. https://books.google.com/books?id=hbpaDwAAQBAJ&pg=PA84. 
  25. ↑ 25.00 25.01 25.02 25.03 25.04 25.05 25.06 25.07 25.08 25.09 25.10 25.11 "Opioids". Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones. Wiley Blackwell. 11 September 2024. pp. 382–383. ISBN 978-1-119-83027-6. 
  26. ↑ "Sedative, analgesic, and behavioral effects of nalbuphine-xylazine and nalbuphine-midazolam combinations in dogs". Journal of Veterinary Behavior 28: 40–45. 2018. doi:10.1016/j.jveb.2018.07.002. https://linkinghub.elsevier.com/retrieve/pii/S1558787817301661. 
  27. ↑ "Evaluation of nalbuphine, butorphanol and morphine in dogs during ovariohysterectomy and on early postoperative pain". Veterinary Anaesthesia and Analgesia 47 (6): 803–809. 2020. doi:10.1016/j.vaa.2020.07.035. PMID 32891492. https://linkinghub.elsevier.com/retrieve/pii/S1467298720301768. 
  28. ↑ "Effects of epidural nalbuphine on intraoperative isoflurane and postoperative analgesic requirements in dogs". Acta Cirurgica Brasileira 29 (1): 38–46. 2014. doi:10.1590/S0102-86502014000100006. ISSN 0102-8650. PMID 24474176. https://www.scielo.br/j/acb/a/rhVfF5kxqxhKtj6SbXn3sMJ/?lang=en&format=pdf. 
  29. ↑ "Evaluation of topical nalbuphine or oral tramadol as analgesics for corneal pain in dogs: a pilot study". Veterinary Ophthalmology 14 (6): 358–364. 2011. doi:10.1111/j.1463-5224.2011.00883.x. ISSN 1463-5216. PMID 22050712. https://onlinelibrary.wiley.com/doi/10.1111/j.1463-5224.2011.00883.x. 
  30. ↑ "Effect of Topical Administration of 0.8% Nalbuphine on the Cornea in Dogs after Phacoemulsification". Journal of Veterinary Medical Science 75 (8): 1041–1047. 2013. doi:10.1292/jvms.12-0125. ISSN 0916-7250. PMID 23708961. https://www.jstage.jst.go.jp/article/jvms/75/8/75_12-0125/_pdf. 
  31. ↑ "Effect of treatment with a topical ophthalmic preparation of 1% nalbuphine solution on corneal sensitivity in clinically normal horses". American Journal of Veterinary Research 71 (2): 223–228. 2010. doi:10.2460/ajvr.71.2.223. ISSN 0002-9645. PMID 20113231. https://avmajournals.avma.org/downloadpdf/journals/ajvr/71/2/ajvr.71.2.223.pdf. 
  32. ↑ "Sedative effects of acepromazine in combination with nalbuphine or butorphanol, intramuscularly or intravenously, in healthy cats: a randomized, blinded clinical trial". Journal of Feline Medicine and Surgery 23 (6): 540–548. 2021. doi:10.1177/1098612X20962754. ISSN 1098-612X. PMID 33044122. 
  33. ↑ "Use of nalbuphine as a substitute for butorphanol in combination with dexmedetomidine and tiletamine/zolazepam: a randomized non-inferiority trial". Journal of Feline Medicine and Surgery 22 (2): 100–107. 2020. doi:10.1177/1098612X19826715. ISSN 1098-612X. PMID 30735096. 
  34. ↑ "Analgesic and adjunct actions of nalbuphine hydrochloride in xylazine or xylazine and acepromazine premedicated horses". Indian Journal of Animal Research (OF). 2015-09-30. doi:10.18805/ijar.5585. ISSN 0976-0555. http://arccjournals.com/index.php?option=com_journals&view=article&id=6227&Itemid=641. 
  35. ↑ "Comparative analgesia of xylazine, xylazine/morphine, xylazine/butorphanol, and xylazine/nalbuphine in the horse, using dental dolorimetry". American Journal of Veterinary Research (Am J Vet Res) 48 (7): 1087–1091. Jul 1987. doi:10.2460/ajvr.1987.48.07.1087. ISSN 0002-9645. PMID 3631691. 
  36. ↑ "Pharmacokinetics and effect of intravenous nalbuphine in weaned H olstein calves after surgical castration". Journal of Veterinary Pharmacology and Therapeutics 37 (2): 169–177. 2014. doi:10.1111/jvp.12077. ISSN 0140-7783. PMID 23931676. https://onlinelibrary.wiley.com/doi/10.1111/jvp.12077. Retrieved 2025-06-05. 
  37. ↑ "Immediate Postoperative Analgesia of Nalbuphine-Ketamine Combination Compared with Ketamine Alone in Xylazine-Sedated Goats Undergoing Left Flank Laparotomy". Animals 12 (4): 509. 2022-02-18. doi:10.3390/ani12040509. ISSN 2076-2615. PMID 35203217. 



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