Nalbuphine

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 0.3mg/kg nalbuphine compared to placebo might be an effective postoperative analgesic" for pain treatment in children. Further research is therefore needed to compare nalbuphine with other postoperative opioids.

In addition to relieving pain, nalbuphine has been shown to reduce morphine-induced pruritus (itching). 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.

Evidence suggests that κ-opioid receptor (KOR) activation can counteract MOR-mediated effects in the brain. 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.

Morphine-induced pruritus may also result from histamine release by mast cells in the skin. Both MORs and KORs are expressed in skin nerves and keratinocytes, indicating potential peripheral mechanisms for opioid-induced pruritus. 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.

Available forms

Nalbuphine is available in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. Both strengths contain 0.94% sodium citrate hydrous, 1.26% citric acid anhydrous, 0.1% sodium metabisulfite, and 0.2% of a 9:1 mixture of methylparaben and propylparaben as preservatives; pH is adjusted, if necessary, with hydrochloric acid. The 10 mg/mL strength contains 0.1% sodium chloride. The drug is also available in a sulfite and paraben-free formulation in two concentrations, 10 mg and 20 mg of nalbuphine hydrochloride per mL. One mL of each strength contains 0.94% sodium citrate hydrous, 1.26% citric acid anhydrous; pH is adjusted, if necessary, with hydrochloric acid. The 10 mg/mL strength contains 0.2% sodium chloride.

An investigational extended-release oral formulation is under development by Trevi Therapeutics.

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.

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. 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.

Pharmacology

Pharmacodynamics

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, and has relatively low affinity for the DOR. 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. Nalbuphine has weak or no affinity for the sigma receptor(s) (e.g., Ki 100,000 nM).

Nalbuphine is said to be more morphine-like at lower doses. However at higher doses, it produces more sedation, drunkenness, dysphoria, and dissociation. As such, its effects are dose-dependent. Such effects include sedation (21–36%), dizziness or vertigo (5%), lightheadedness (1%), anxiety (

Nalbuphine is a potent analgesic. Its analgesic potency is essentially equivalent to that of morphine on a milligram basis, which is based on relative potency studies using intramuscular administration (Beaver et al. 1978). Oral administered nalbuphine is reported to be three times more potent than codeine (Okun et al. 1982). Clinical trials studied single dose experimental oral immediate release nalbuphine tablets for analgesic efficacy over a four- to six-hour time period following administration. Nalbuphine in the 15 to 60 mg range had similar analgesic effects to immediate release codeine in the 30 to 60 mg range (Kantor et al. 1984; Sunshine et al. 1983). Schmidt et al. (1985) reviewed the preclinical pharmacology of nalbuphine and reported comparative data relative to other types of opioid compounds. The authors point out that the nalbuphine moiety is approximately ten times more pharmacologically potent than the mixed opioid agonist/antagonist butorphanol on an "antagonist index" scale which quantitates the drug's ability to act both as an analgesic (via opioid KOR agonism) as well as a MOR antagonist. The opioid antagonist activity of nalbuphine is one-fourth as potent as nalorphine and 10 times that of pentazocine.

Chemistry

Nalbuphine is a derivative of morphine and is also known as N-cyclobutylmethyl-14-hydroxydihydronormorphine.

History

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

In the search for opioid analgesics with less abuse potential than pure MOR agonist opioids, a number of semisynthetic opioids were developed. These substances are referred to as mixed agonist–antagonists analgesics. Nalbuphine belongs to this group of substances. The mixed agonists-antagonists drug class exerts their analgesic actions by agonistic activity at the KOR. While all drugs in this class possess MOR antagonistic activity leading to less abuse potential, nalbuphine is the only approved drug in the mixed agonist–antagonist class listed in terms of its pharmacological actions and selectivities on opioid receptors as a MOR partial agonist or antagonist as well as a KOR agonist (Gustein et al. 2001).

Nubain was approved for marketing in the United States in 1978 and remains as the only opioid analgesic of this type (marketed in the U.S.) not controlled under the Controlled Substances Act (CSA). When the Controlled Substances Act (CSA) was enacted in 1971, nalbuphine was placed in schedule II. Endo Laboratories, Inc. subsequently petitioned the DEA to exclude nalbuphine from all schedules of the CSA in 1973. After receiving a medical and scientific review and a scheduling recommendation from the Department of Health, Education and Welfare, forerunner to the Department of Health and Human Services, nalbuphine was removed from schedule II of the CSA in 1976. Presently, nalbuphine is not a controlled substance under the CSA.

Nalbuphine HCL is currently available only as an injectable in the US and the European Union. Nubain, the Astra USA brand name for injectable nalbuphine HCL, was discontinued from being marketed in 2008 in the United States for commercial reasons (Federal Register 2008); however, other commercial suppliers now provide generic injection formulation nalbuphine for the market.

Society and culture

Brand names

Nalbuphine is marketed primarily under the brand names Nubain, Nalpain, and Nalbuphin. It is also marketed under the brand name Nalufin in Egypt and Nalbun in Bangladesh by Incepta 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.

Legal status

Unlike many other opioids, nalbuphine has a limited potential for euphoria, and in accordance, is rarely abused. This is because whereas MOR agonists produce euphoria, MOR antagonists do not, and KOR agonists like nalbuphine moreover actually produce dysphoria. 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. 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. 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. In Canada, most opioids are classified as Schedule I, but nalbuphine and butorphanol are both listed as Schedule IV substances.

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. The sedation provided by nalbuphine is insufficient for catheterisation and fur clipping and the analgesic effect is insufficient for some pain. 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. One study found that acepromazine and nalbuphine failed to provide adequate analgesia both during and post-surgery in bitches undergoing ovariohysterectomy. Although one study found epidural nalbuphine to provide adequate analgesia there is limited evidence to support epidural administration of nalbuphine. Ophthalmic administration is not recommended in any species as multiple studies demonstrated no analgesia following topical ophthalmic administration.

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 tiletamine-zolazepam respectively.

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

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

Notes

References

1. Anvisa. (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial". [[Diário Oficial da União]].
2. "Nalbuphine Hydrochloride". Drug Enforcement Administration.
3. "Kentucky Penal Code: Title 902 Chapter 55 Regulation 015 - Controlled Substances". © 2024 Kentucky Legislative Research Commission.
4. (14 May 2014). "Pediatric Anesthesia". PMPH-USA.
5. (1988). "Excerpta medica. Section 24: Anesthesiology".
6. (9 June 2011). "Pain Management E-Book". Elsevier Health Sciences.
7. (Mar–Apr 1995). "Determination of nalbuphine in drug abusers' urine". Journal of Analytical Toxicology.
8. (March 2015). "Nalbuphine, a non-controlled opioid analgesic, and its potential use in research mice". Lab Animal.
9. (February 1985). "Nalbuphine". Drug and Alcohol Dependence.
10. (6 September 2012). "Essential Pain Pharmacology: The Prescriber's Guide". Cambridge University Press.
11. US Patent 3393197 - Nusubstituted-14-hydroxydihydronormorphines
12. (2006). "Analogue-based Drug Discovery". John Wiley & Sons.
13. "Nalbuphine".
14. (July 2014). "Nalbuphine for postoperative pain treatment in children". The Cochrane Database of Systematic Reviews.
15. (July 2019). "Fast Facts and Concepts #381: Nalbuphine". Fast Facts & Concepts.
16. (June 2001). "Pharmacological control of opioid-induced pruritus: a quantitative systematic review of randomized trials". European Journal of Anaesthesiology.
17. (June 2022). "Modulation of the kappa and mu opioid axis for the treatment of chronic pruritus: A review of basic science and clinical implications". JAAD International.
18. (June 2015). "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.
19. (January 1993). "Opiates, mast cells and histamine release". Life Sciences.
20. (February 2021). "Morphine acts on spinal dynorphin neurons to cause itch through disinhibition". Science Translational Medicine.
21. (May 1989). "Wheal and flare responses to opioids in humans". Anesthesiology.
22. "Haduvio™". Trevi Therapeutics.
23. "Nalbuphine Hydrochloride Injection Overdosage". ©2025 Pfizer Inc..
24. (July 2024). "Nalbuphine Potentiates Reversal of Fentanyl Overdose by Naloxone". Pharmaceuticals.
25. (May 2007). "Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors". Journal of Medicinal Chemistry.
26. (1993). "The opioid receptor binding of dezocine, morphine, fentanyl, butorphanol and nalbuphine". Life Sciences.
27. (December 1990). "Sigma receptors: biology and function". Pharmacological Reviews.
28. (1998). "Psychiatric Side Effects of Prescription and Over-the-counter Medications: Recognition and Management". American Psychiatric Pub.
29. (23 June 2009). "Sedation - E-Book: A Guide to Patient Management". Elsevier Health Sciences.
30. (11 August 2017). "Non-medical and illicit use of psychoactive drugs". Springer.
31. (26 April 2018). "The Drug Paradox: An Introduction to the Sociology of Psychoactive Substances in Canada". Canadian Scholars.
32. (11 September 2024). "Veterinary Anesthesia and Analgesia, The 6th Edition of Lumb and Jones". Wiley Blackwell.
33. (2018). "Sedative, analgesic, and behavioral effects of nalbuphine-xylazine and nalbuphine-midazolam combinations in dogs". Journal of Veterinary Behavior.
34. (2020). "Evaluation of nalbuphine, butorphanol and morphine in dogs during ovariohysterectomy and on early postoperative pain". Veterinary Anaesthesia and Analgesia.
35. (2014). "Effects of epidural nalbuphine on intraoperative isoflurane and postoperative analgesic requirements in dogs". Acta Cirurgica Brasileira.
36. (2011). "Evaluation of topical nalbuphine or oral tramadol as analgesics for corneal pain in dogs: a pilot study". Veterinary Ophthalmology.
37. (2013). "Effect of Topical Administration of 0.8% Nalbuphine on the Cornea in Dogs after Phacoemulsification". Journal of Veterinary Medical Science.
38. (2010). "Effect of treatment with a topical ophthalmic preparation of 1% nalbuphine solution on corneal sensitivity in clinically normal horses". American Journal of Veterinary Research.
39. (2021). "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.
40. (2020). "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.
41. (2015-09-30). "Analgesic and adjunct actions of nalbuphine hydrochloride in xylazine or xylazine and acepromazine premedicated horses". Indian Journal of Animal Research.
42. (Jul 1987). "Comparative analgesia of xylazine, xylazine/morphine, xylazine/butorphanol, and xylazine/nalbuphine in the horse, using dental dolorimetry". Am J Vet Res.
43. (2014). "Pharmacokinetics and effect of intravenous nalbuphine in weaned H olstein calves after surgical castration". Journal of Veterinary Pharmacology and Therapeutics.
44. (2022-02-18). "Immediate Postoperative Analgesia of Nalbuphine-Ketamine Combination Compared with Ketamine Alone in Xylazine-Sedated Goats Undergoing Left Flank Laparotomy". Animals.