• Fay Mathai MD
  • Frank Portugal DO
  • Zankhana Mehta MD
  • Mellar Davis MD

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Fay Mathai MD, Frank Portugal DO, and Zankhana Mehta MD, Mellar Davis MD

Background:Nalbuphine (Nubain®) is a unique opioid analgesic that was first manufactured in the 1970’s. It is not a controlled substance in the United States as it was removed from the schedule II drug list in 1976 in response to assuring safety data (1). Considering ongoing opioid shortages in the acute settings, it is prudent to reexamine nalbuphine as an analgesic for seriously ill patients.

Pharmacology:Much like other opioids, nalbuphine causes analgesia principally via mu receptor agonism. However, it is classified in the group of “antagonist/agonist” opioids along with pentazocine, butorphanol, nalorphine and buprenorphine (2,3). Its “neutral” mu receptor antagonism means that at low doses, it can mitigate various opioid side effects including pruritus, respiratory depression, and urinary retention but not analgesia (4). Nalbuphine also affects other receptors which are felt to be involved in the analgesic pathway: it is a partial kappa agonist, 6 transmembrane (TM) mu agonist, 7TM mu antagonist, and partial beta-arrestin agonist (5). Experts theorize that activity on these receptors may contribute to many of its unique pharmacologic properties described below. 

Metabolism:Nalbuphine is an active compound and undergoes conjugation in the liver into an inactive metabolite. Because its metabolites are inactive, it is felt to be safer than morphine or hydromorphone for patients with renal or hepatic impairment.  The time to maximum serum concentration (Tmax) is 30 minutes and its half-life ranges from 2 to 5 hours (6). Clearance is decreased in the elderly due to diminished hepatic blood flow. Renal failure increases nalbuphine concentrations in the blood by 65% so dose reduction is necessary. Parenteral nalbuphine readily crosses the blood brain barrier and analgesia can be experienced within five minutes of parenteral administration (7,8). It is not metabolized via the CYP450 system, hence, there are less drug-drug interactions than with methadone or fentanyl (7,8).

Advantages: The therapeutic index (defined as the ratio of the dose at which toxicity is commonly observed compared with therapeutic doses) of nalbuphine is greater than morphine. This is mainly because nalbuphine has a reduced incidence of pruritus, nausea, vomiting, biliary spasms, constipation, postoperative ileus, and respiratory depression, yet similar analgesic effectiveness as morphine at therapeutic doses (9). In fact, at low parenteral doses (2.5 mg–5 mg), nalbuphine may reverse pruritus, urinary retention, and respiratory depression induced by other opioids such as morphine, hydromorphone, or fentanyl (9-12). Nalbuphine does not adversely affect blood pressure nor alter QTc intervals. It also has a ceiling on respiratory depression. Therefore, it may be a good agent for acute trauma patients, patients with sepsis, or those with multiorgan failure (1,12-15). It is safe in dialysis dependent patients since only 1% of the drug is dialyzed, thus mitigating concerns for post-dialysis pain (16).

Disadvantages: In the United States, nalbuphine is only available in the parenteral form.  While there are prospective studies in chronic pain, postoperative pain, and postpartum pain in which the parenteral formulation was taken by mouth, the most robust data supporting nalbuphine’s use is largely limited to parenteral formulations for acute, inpatient pain for opioid naïve individuals (17,18). Like other opioids, nalbuphine has an abuse potential; although, nalbuphine’s abuse potential may be lower in comparison to its counterparts. Somewhat akin to buprenorphine, its antagonistic effects on the mu receptor could induce an immediate withdrawal syndrome in opioid-tolerant individuals. Hence, rotating a patient from another opioid to nalbuphine or initiating nalbuphine for patients already on opioids often creates clinical challenges. This affects its suitability for many patients with a serious illness like metastatic cancer. Insurance coverage issues, lack of clinician familiarity, and formulary restrictions limit nalbuphine’s availability at most health care institutions and hospice agencies. It is also relatively costly – about $40 per 10 mL which is roughly 10 times the cost of morphine. There have been no direct comparisons to oxycodone, hydromorphone or fentanyl.  Similar cautions apply when co-prescribing with a benzodiazepine, as with any other opioid. Currently, it is not available for outpatient use, therefore, if utilized as an inpatient medication, an opioid rotation would be necessary at or prior to discharge.

Dosing: Nalbuphine is only available in a sterile solution suitable for subcutaneous (SC), intramuscular, and intravenous (IV) use via two concentrations: 10 mg/mL and 20 mg/mL.  Its conversion ratio with IV morphine is 1:1 (9). Experts recommend that when rotating nalbuphine to another opioid, clinicians utilize the equivalent IV morphine dose as a starting point. Usual initial nalbuphine dosing is 5-10 mg SC/IV every 4-6 hours as needed, which can be titrated to 10-20 mg IV/SC every 4 hours as needed or a 1-3 mg/hr. basal rate with 1 mg every 15 minutes by patient-controlled analgesia, as needed. Limited pediatric data are available, although doses of 0.1 to 0.2 mg/kg IV or SC every 3-4 hours as needed have been described for moderate-to-severe pediatric pain (19).

Summary: Nalbuphine is a unique opioid that may have an emerging inpatient analgesic role, especially for hemodynamically unstable patients with organ failure. While the use of nalbuphine is not limited to specialists in pain management, palliative care, or critical care, inpatient clinicians may seek consultation before administration due to a relative lack of familiarity and availability.  Precautions must be exercised due to its cost, availability, and association with opioid withdrawal in opioid tolerant individuals.


1.         Schmidt, W.K., et al., Nalbuphine.Drug Alcohol Depend, 1985. 14(3-4): p. 339-62.

2.         Errick, J.K. and R.C. Heel, Nalbuphine. A preliminary review of its pharmacological properties and therapeutic efficacy.Drugs, 1983. 26(3): p. 191-211.

3.         Pallasch, T.J. and C.J. Gill, Butorphanol and nalbuphine: a pharmacologic comparison.Oral Surg Oral Med Oral Pathol, 1985. 59(1): p. 15-20.

4.         Bullingham, R.E., H.J. McQuay, and R.A. Moore, Clinical pharmacokinetics of narcotic agonist-antagonist drugs.Clin Pharmacokinet, 1983. 8(4): p. 332-43.

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7.         Lo, M.W., W.L. Schary, and C.C. Whitney, Jr., The disposition and bioavailability of intravenous and oral nalbuphine in healthy volunteers.J Clin Pharmacol, 1987. 27(11): p. 866-73.

8.         Lo, M.W., et al., The pharmacokinetics of intravenous, intramuscular, and subcutaneous nalbuphine in healthy subjects.Eur J Clin Pharmacol, 1987. 33(3): p. 297-301.

9.         Zeng, Z., et al., A comparision of nalbuphine with morphine for analgesic effects and safety : meta-analysis of randomized controlled trials.Sci Rep, 2015. 5: p. 10927.

10.       Hammond, J.E., Reversal of opioid-associated late-onset respiratory depression by nalbuphine hydrochloride.Lancet, 1984. 2(8413): p. 1208.

11.       Latasch, L., S. Probst, and R. Dudziak, Reversal by nalbuphine of respiratory depression caused by fentanyl.Anesth Analg, 1984. 63(9): p. 814-6.

12.       Lake, C.L., et al., Cardiorespiratory effects of nalbuphine and morphine premedication in adult cardiac surgical patients.Acta Anaesthesiol Scand, 1984. 28(3): p. 305-9.

13.       Pugh, G.C., D.T. Brown, and G.B. Drummond, Effect of nalbuphine hydrochloride on the ventilatory and occlusion pressure responses to carbon dioxide in volunteers.Br J Anaesth, 1989. 62(6): p. 601-9.

14.       Rosow, C.E., The clinical usefulness of agonist-antagonist analgesics in acute pain.Drug Alcohol Depend, 1987. 20(4): p. 329-37.

15.       Lake, C.L., et al., Cardiovascular effects of nalbuphine in patients with coronary or valvular heart disease.Anesthesiology, 1982. 57(6): p. 498-503.

16.       Hawi, A., et al., Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus.BMC Nephrol, 2015. 16: p. 47.

17.       Okun, R., Analgesic effects of oral nalbuphine and codeine in patients with postoperative pain.Clin Pharmacol Ther, 1982. 32(4): p. 517-24.

18.       Beaver, W.T., G.A. Feise, and D. Robb, Analgesic effect of intramuscular and oral nalbuphine in postoperative pain.Clin Pharmacol Ther, 1981. 29(2): p. 174-80.

19.       Schnabel, A., et al., Nalbuphine for postoperative pain treatment in children.Cochrane Database Syst Rev, 2014(7): p. CD009583.

Conflicts of Interest: Nothing to disclose

Author’s Affiliations: Geisinger Medical Center, Danville, PA

Version History: originally edited by Sean Marks MD; first electronically published in July 2019.

Fast Facts and Conceptsare edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin(PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’scontent. The full set of Fast Facts are available at Palliative Care Network of Wisconsinwith contact information, and how to reference Fast Facts.

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