Nalbuphine: Mechanisms of Action, Clinical Applications and Adverse Effects

Nalbuphine is a potent opioid analgesic¹ sold under the brand name Nubain.² Nalbuphine was first synthesized in 1965 and approved by the United States Food and Drug Administration (FDA) in 1979.³ Nalbuphine is FDA approved for moderate to severe pain for which non-opioid treatments have been insufficient, though there are several non-FDA approved uses as well.⁴ Because of nalbuphine’s usefulness in providing analgesia, anesthesia providers should have knowledge of its biological mechanisms, clinical uses and side effects.

Nalbuphine is a semisynthetic mixed opioid receptor agonist-antagonist.⁵ Like buprenorphine, it exerts its therapeutic effects through agonism of the κ-opioid receptor and partial antagonism of the µ-opioid receptor.⁶ It is different from other agonist-antagonist analgesics in that it has greater antagonistic activity and fewer behavioral effects at analgesic doses than pentazocine, butorphanol and buprenorphine.¹ Nalbuphine’s molecular formula is C₂₁H₂₇NO₄,⁷ and it integrates the molecular features of the opioid agonist oxymorphone hydrochloride (sold as Numorphan) with that of the opioid antagonist naloxone hydrochloride (sold as Narcan).³ Nalbuphine is lipophilic and has a large volume of distribution, allowing it to have a quick onset of action (about two to three minutes) and relatively long duration of action (three to six hours).⁸ It is extensively metabolized in the liver to inactive glucuronide conjugates, which—along with nalbuphine itself—are excreted mostly in the feces.⁵

The clinical uses of nalbuphine vary from those of other opioids given its role as an agonist-antagonist. Nalbuphine can be used for moderate to severe pain during the perioperative period, labor pain, opioid-induced urinary retention and pruritus (itching) associated with neuraxial opioid use.⁴ Interestingly, nalbuphine can be used as an opioid antagonist in place of naloxone⁸ because it has the ability to reverse respiratory depression caused by overdose from other opioids.⁵ Nalbuphine is usually administered through intravenous, intramuscular or subcutaneous injection.⁴ It has an analgesic potency 0.8 to 0.9 times that of morphine, but in clinical practice, it is considered equianalgesic to morphine when administered in equal doses.³ As an agonist-antagonist, nalbuphine has an advantage over pure agonists such as morphine and fentanyl, in that increasing the dosage of nalbuphine does not significantly increase the degree of respiratory depression.⁹ Unlike many other opioids, nalbuphine is not generally used to induce preoperative sedation.⁸ However, it is valuable for analgesia and for combatting the adverse effects of other opioids.

Nalbuphine, like other opioids, is accompanied by a variety of side effects. Though it does not come with the increased cardiovascular workload found with butorphanol,⁹ nalbuphine administration commonly causes sedation, sweating, nausea, dizziness, vertigo, dry mouth or headache.⁴ Less common side effects include nervousness, depression, mood changes, confusion, hallucinations or numbness.⁴ Severe effects, such as elevated or low blood pressure or heart rate, respiratory depression and severe anaphylaxis (i.e., allergic reaction), are rare.⁴ However, if a patient is using other drugs such as benzodiazepines or alcohol, nalbuphine administration can result in critical sedation, respiratory depression, coma and death.⁴ Long-term nalbuphine use can also result in physical dependence.⁵ Given its side effects and potential drug interactions, anesthesia providers should be cautious when prescribing nalbuphine to patients.

Nalbuphine is an opioid agonist-antagonist that can be used for pain management or the reversal of side effects induced by opioid agonists. Nalbuphine works primarily through agonism of the κ-opioid receptor and partial antagonism of the µ-opioid receptor, and it is metabolized in the liver into inactive metabolites. Nalbuphine is unique among opioid drugs in that it can be used like the opioid antagonist naloxone to reverse respiratory depression. Like other opioids, nalbuphine comes with side effects ranging from nausea and vomiting to physical dependence to respiratory depression, coma or death. As with all opioid drugs, anesthesia providers should be careful when opting to use nalbuphine for pain relief.

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