Nalbuphine is FDA indicated for moderate to severe pain in where the patient requires an opioid agent, and other alternative treatments have been insufficient. Non-FDA approved uses of nalbuphine do exist such as treatment of labor pain, opioid-induced urinary retention, opioid-induced respiratory depression, and pruritus associated with neuraxial opioid use.

Pruritus is usually secondary to opioid activation of the mu-opioid receptor. Because nalbuphine is an antagonist at the mu-opioid receptor, it has utility as a treatment for opioid-induced pruritus. In fact, research has found that nalbuphine to be superior in treating opioid-induced pruritus when compared with placebo, diphenhydramine, naloxone, or propofol in patients receiving neuraxial opioids for acute pain related to surgery or childbirth1.[1]

Although nalbuphine can result in respiratory depression, due to its antagonism of the mu-opioid receptor, it antagonizes the respiratory depressant effects of other opioid medications while concomitantly adding to the analgesic activities of these drugs.[2] When used acutely in the perioperative period, nalbuphine is useful for providing analgesic benefits with less respiratory depression than morphine. In one study, researchers used intravenous nalbuphine to reduce opioid-induced respiratory suppression following intrathecal morphine administration in post-thoracotomy patients.[3] 

Nalbuphine is a kappa-opioid receptor agonist and a partial mu-opioid receptor antagonist. Analgesic properties are mediated through agonist activity at the kappa-opioid receptor. Because of this unique mixed agonist-antagonist opioid receptor activity of nalbuphine, it provides analgesia with less nausea, pruritus, and respiratory depression when compared to morphine.[4]

Pharmacology:

• Absorption: The onset of action of nalbuphine after intravenous injection is 2 to 3 minutes. With subcutaneous or intramuscular administration, the onset of action is within 15 minutes. The duration of action of nalbuphine ranges from 3 to 6 hours. 

• Distribution: Protein binding not significant.

• Metabolism: Nalbuphine is hepatically metabolized.

• Elimination: Elimination half-life of about 5 hours. Excreted in urine and feces.

Nalbuphine is available in 10 mg/ml and 20 mg/ml injectable solutions. Nalbuphine is not available in oral form secondary to poor oral bioavailability. [5]

Adult Dosing:

A typical recommended dose is 10 mg for a 70 kg individual. Administration is subcutaneous, intramuscular, or intravenous; this dose may be repeated every 3 to 6 hours as necessary. The recommended single maximum dose is 20mg in an opioid nontolerant individual with a total maximum daily dose is 160mg. In opioid-dependent patients the dose should be reduced by ¼ and the patient should be observed for signs of opioid withdrawal. In patients who are not opioid tolerant, withdrawal symptoms have not been seen from other opioid medications that have been given in the same acute setting as nalbuphine. The potency of nalbuphine is comparable to morphine on a mg-to-mg basis.[6]

Pediatric Dosing:

Less than one year: safety and efficacy not established.

Greater than one year: 0.1-0.2 mg/kg intravenously, intramuscularly or subcutaneously every 3-4 hours as needed. The maximum single dose is 20 mg. Maximum daily dose 160 mg.

Renal impairment: use caution, may require a reduced dose.

Hepatic impairment: use caution, may require a reduced dose.

The most common adverse effects following nalbuphine administration are sedation, sweating, nausea, vomiting, dizziness, vertigo, dry mouth, or a headache. [7][8]

The following are less common adverse effects have been reported at an incidence of less than 1%:

• Central nervous system: Nervousness, depression, restlessness, crying, euphoria, floating, hostility, unusual dreams, confusion, faintness, hallucinations, dysphoria, a feeling of heaviness, numbness, tingling, or unreality.

• Cardiovascular: hypertension, hypotension, bradycardia, or tachycardia.

• Gastrointestinal: cramps, dyspepsia, or bitter taste.

• Respiratory: depression, dyspnea, or asthma.

• Dermatologic: itching, burning, or urticaria.

• Allergic Reactions: anaphylactic, anaphylactoid, or severe hypersensitivity reactions have been reported with nalbuphine use, and care should be given providing immediate supportive medical treatment should they occur.

Black Box Warning

Concomitant use of nalbuphine with benzodiazepines or other CNS depressants, including alcohol, may result in critical sedation, respiratory depression, coma, and death.

Concomitant prescribing should only be used in patients for whom alternative treatment options have proved inadequate; dose and duration should be limited to the minimum required, and follow patients for signs and symptoms of respiratory depression and sedation.

Cautions

Because of altered pharmacokinetics and clearance in elderly, debilitated, or cachectic patients, caution should be used when administering nalbuphine to these patient populations because life-threatening respiratory depression can result. The respiratory depressant effects of nalbuphine can result in carbon dioxide retention which can further increase intracranial pressure in patients with baseline elevated intracranial pressure, head injury, or intracranial lesions as well as possibly confound the ability to obtain and follow an accurate neurological examination due to sedative properties. Therefore, nalbuphine should be used with extreme in these clinical scenarios.

Like other commonly used opioid medications, nalbuphine can alter normal mental or physical abilities required to perform potentially dangerous tasks, including driving or operating heavy machinery. Patients counseling regarding these risks prior to the administration of this medication is indicated.

Nalbuphine has been used for obstetrical analgesia, and there are reports of severe fetal bradycardia in laboring women. In one study, fetal heart rate flattening occurred in 53% of the cases.[9] The benefits of analgesia versus risks to the fetus should be weighed in this clinical situation. If nalbuphine is administered to the laboring woman, fetal heart rate monitoring should be utilized and appropriate procedures in place to manage any adverse effects to the fetus. Naloxone may reverse these effects.

Due to antagonist action at the µ-opioid receptor, caution should be used in nalbuphine administration to patients on sustained release opioids because withdrawal symptoms are possible.[4] When using nalbuphine in these patients, reduced dosing is advised, and the patient should be observed for signs of withdrawal.

Even though nalbuphine is an antagonist at the µ-opioid receptor, it still provides drug liking properties and has abuse potential.[4]  Of note, naloxone was initially classified as a scheduled II controlled substance, however through subsequent petitioning to the FDA by its manufacturer, it was removed from all schedules and is no longer a controlled substance in the U.S.

Nalbuphine is contraindicated in patients with:

• Significant respiratory depression
• Severe or active bronchial asthma
• Known or suspected gastrointestinal obstruction including ileus
• Hypersensitivity to nalbuphine or any other ingredients in the injection