VA Class:CN101

AHFS Class:

• Opioid Partial Agonists 28:08.12

Generic Name(s):

• Nalbuphine Hydrochloride

Nalbuphine hydrochloride is a synthetic opiate partial agonist analgesic.

Nalbuphine hydrochloride is used for the relief of pain that is severe enough to require an opiate analgesic; because of the risks of addiction, abuse, and misuse associated with opiates even at recommended dosages, nalbuphine should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics) have not been, or are not expected to be, adequate or tolerated.704 The drug also is used to provide preoperative and postoperative sedation and analgesia and as a supplement to balanced surgical anesthesia. However, nalbuphine should be used with caution in patients undergoing surgery of the biliary tract. The drug also is used for obstetrical analgesia during labor and delivery; however, nalbuphine should be used with caution in women during labor and delivery, since adverse effects associated with nalbuphine may occur in the neonate.106 (See Cautions: Pregnancy.) There are few published studies comparing the effectiveness of nalbuphine with other analgesics; determination of the relative value and potential for abuse of nalbuphine must await further studies and more extensive use of the drug.

Because it does not suppress the abstinence syndrome and may induce withdrawal in opiate-dependent patients, nalbuphine cannot be substituted for opiate agonists after physical dependence has been established without prior detoxification. Because the drug's antagonist activity appears to be selective for the µ opiate receptor and relatively weak compared with nalorphine, nalbuphine is probably not an effective antidote in the treatment of many effects induced by opiate agonists. However, nalbuphine has effectively reversed or prevented postoperative respiratory depression induced by opiate agonists† (without reversing analgesia) in many107,108,109,110,111,112,113,114,115,116,117 but not all118,119 patients.

For further information on the role of opiate analgesics in pain management, see Uses: Pain, in the Opiate Agonists General Statement 28:08.08.

Administration

Nalbuphine hydrochloride is administered by subcutaneous, IM, or IV injection. As with other parenteral products, nalbuphine hydrochloride injection should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Dosage

Opiate analgesics should be given at the lowest effective dosage and for the shortest duration of therapy consistent with the treatment goals of the patient.411,413,431,432,435 Dosage of nalbuphine hydrochloride should be adjusted according to the severity of pain, physical status of the patient, and other drugs that the patient is receiving. If concomitant therapy with other CNS depressants is required, the lowest effective dosages and shortest possible duration of concomitant therapy should be used.700,703 (See Cautions: Precautions and Contraindications and Drug Interactions: Benzodiazepines and Other CNS Depressants.) Care should be taken to avoid increases in dose or frequency of administration which in susceptible individuals might result in physical dependence.

For analgesia, the usual parenteral dose of nalbuphine hydrochloride is 10 mg in an adult weighing 70 kg (about 0.14 mg/kg) who is not dependent on opiate agonists. This dose may be repeated every 3-6 hours as necessary. In patients who are not tolerant to opiate agonists, the maximum single dose is 20 mg and the maximum total daily dose is 160 mg.

In patients who have been chronically receiving morphine, meperidine, codeine, or other opiate agonists with a similar duration of action, 25% of the usual dose of nalbuphine hydrochloride is given initially. The patient is observed for withdrawal symptoms (i.e., abdominal cramps, nausea, vomiting, lacrimation, rhinorrhea, anxiety, restlessness, increased temperature, piloerection). If these symptoms are troublesome, morphine may be given IV slowly in small increments until withdrawal symptoms are relieved. However, since withdrawal symptoms induced by the opiate antagonist effect of nalbuphine are self-limited, waiting until the abstinence syndrome abates is probably preferred. If withdrawal symptoms do not occur, nalbuphine doses may be increased progressively until the desired level of analgesia is obtained.

For acute pain not related to trauma or surgery, the prescribed quantity should be limited to the amount needed for the expected duration of pain severe enough to require opiate analgesia (generally 3 days or less and rarely more than 7 days).411,433,434,435

When nalbuphine hydrochloride is used as a supplement to balanced anesthesia, doses larger than those recommended for analgesia are required. For induction, doses of the drug range from 0.3-3 mg/kg given IV over a period of 10-15 minutes. For maintenance, doses of 0.25-0.5 mg/kg may be given IV as necessary.

For further information on the management of opiate analgesic therapy, see Dosage and Administration: Dosage, in the Opiate Agonists General Statement 28:08.08.

Adverse effects of nalbuphine are qualitatively similar to those of morphine. Sedation is the most frequent adverse reaction and occurs in about 36% of patients receiving nalbuphine. Sweatiness, clamminess, nausea, vomiting, dizziness, vertigo, dry mouth, miosis, and headache occur in 1-10% of patients.

Nervous System Effects

Sedation, dizziness, vertigo, miosis, and headache are among the most common adverse effects of nalbuphine. Other adverse CNS effects, such as nervousness, depression, restlessness, crying, euphoria, drunkenness, floating, hostility, unusual dreams, confusion, faintness, feeling of heaviness, numbness, and tingling, occur in less than 1% of patients receiving the drug. In equianalgesic dosage, adverse psychotomimetic effects such as unreality, depersonalization, delusions, dysphoria, and hallucinations reportedly occur less frequently with nalbuphine than with pentazocine.

GI Effects

Nausea, vomiting, and dry mouth are among the most common adverse effects of nalbuphine. Other adverse GI effects, including cramps, dyspepsia, and bitter taste, occur in less than 1% of patients receiving the drug.

Cardiovascular Effects

Adverse cardiovascular effects occur in less than 1% of patients receiving nalbuphine and may include hypertension, hypotension, bradycardia, pulmonary edema, and tachycardia. During studies evaluating nalbuphine as a supplement to balanced anesthesia, bradycardia occurred more frequently in patients who did not receive atropine preoperatively than in those who did.

Dermatologic and Hypersensitivity Reactions

Adverse dermatologic effects, such as itching, burning, and urticaria, occur in less than 1% of patients receiving nalbuphine. Anaphylactic or anaphylactoid and other serious hypersensitivity reactions, including shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, and laryngeal edema, have been reported in patients receiving nalbuphine.106 These reactions may require immediate supportive treatment.106 Other allergic-type reactions may include stridor, bronchospasm, wheezing, edema, rash, pruritus, nausea, vomiting, diaphoresis, weakness, and shakiness.106

Respiratory Effects

Respiratory depression, dyspnea, and asthma have occurred in less than 1% of patients receiving nalbuphine. In doses above the usual therapeutic range, nalbuphine causes less respiratory depression than does morphine. Nalbuphine-induced respiratory depression can be reversed by naloxone. Acute pulmonary edema also has occurred in patients receiving nalbuphine,106,121,122,123 although a causal relationship remains to be established.120

Genitourinary and Endocrine Effects

Urinary urgency occurs in less than 1% of patients receiving nalbuphine.

Adrenal insufficiency has been reported in patients receiving opiate agonists or opiate partial agonists.400 Manifestations of adrenal insufficiency are nonspecific and may include nausea, vomiting, anorexia, fatigue, weakness, dizziness, and hypotension.400 The onset generally has occurred after at least 1 month of opiate agonist or partial agonist use, although the time to onset has ranged from within 1 day to more than 1 year.400 In many of the reported cases, patients required hospitalization.400 If adrenal insufficiency is suspected, appropriate laboratory testing should be performed promptly and physiologic (replacement) dosages of corticosteroids provided; therapy with the opiate agonist or partial agonist should be tapered and discontinued to allow recovery of adrenal function.400 If the opiate agonist or partial agonist can be discontinued, follow-up assessment of adrenal function should be performed to determine if corticosteroid replacement therapy can be discontinued.400 In some patients, switching to a different opiate improved symptoms.400

Hypogonadism and androgen deficiency have been reported in patients receiving long-term opiate agonist or opiate partial agonist therapy,400,401,402,403,404 although a causal relationship has not been established.400 Patients receiving long-term opiate agonist or partial agonist therapy who present with manifestations of hypogonadism (e.g., decreased libido, impotence, erectile dysfunction, amenorrhea, infertility) should undergo laboratory evaluation.400

Other Adverse Effects

Other adverse effects, such as speech difficulty, blurred vision, flushing, and warmth, occur in less than 1% of patients receiving nalbuphine.

Precautions and Contraindications

Concomitant use of opiate agonists or opiate partial agonists and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiates, alcohol) may result in profound sedation, respiratory depression, coma, and death.416,417,418,700,701,702,703 Concomitant use of such drugs should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703 Patients receiving nalbuphine and/or their caregivers should be apprised of the risks associated with concomitant therapeutic or illicit use of benzodiazepines, alcohol, or other CNS depressants.700,703 Concomitant use with alcohol should be avoided.700 (See Drug Interactions: Benzodiazepines and Other CNS Depressants.)

Because of possible adverse CNS effects, such as drowsiness and dizziness, ambulatory patients receiving nalbuphine should be cautioned against performing hazardous tasks requiring mental alertness or physical coordination, such as driving a motor vehicle or operating machinery, and warned about possible additive effects with other drugs that cause CNS depression. (See Drug Interactions: Benzodiazepines and Other CNS Depressants.) When nalbuphine is used in emergency procedures, the patient should be kept under observation until recovery from the drug's effects that would affect driving or other potentially hazardous tasks has occurred. Although nalbuphine appears to have a low physical dependence liability (see Chronic Toxicity), the drug should be used cautiously in patients who are emotionally unstable or have a history of opiate abuse, and these patients should be closely supervised during long-term nalbuphine therapy.

Nalbuphine should be administered with caution and in low doses in patients with impaired respiration caused by other drugs, uremia, bronchial asthma, severe infection, cyanosis, or respiratory obstruction. When nalbuphine is used as a supplement to general anesthesia, the drug should be administered only by individuals who are experienced in the use of parenteral anesthetics and in the maintenance of an adequate airway and respiratory support. Facilities and personnel necessary for intubation, administration of oxygen, and assisted or controlled respiration should be readily available; an opiate antagonist (e.g., naloxone) should also be readily available.

Because of the potential for fatal respiratory depression following opiate overdosage, clinicians should routinely discuss the availability of the opiate antagonist naloxone with all patients receiving new or reauthorized prescriptions for opiate analgesics.750 Patients should be advised of the benefits of naloxone administration following an overdose and of their options for obtaining the drug.750 Clinicians should consider prescribing naloxone for patients receiving opiate analgesics who are at increased risk of opiate overdosage (e.g., those receiving concomitant therapy with benzodiazepines or other CNS depressants, those with a history of opiate or substance use disorder, those with medical conditions that could increase sensitivity to opiate effects, those who have experienced a prior opiate overdose)411,431,750 or who have household members, including children, or other close contacts who are at risk for accidental ingestion or overdosage.750 Even if patients are not receiving an opiate analgesic, a naloxone prescription should be considered if the patient is at increased risk of opiate overdosage (e.g., those with a current or past diagnosis of opiate use disorder [OUD], those who have experienced a prior opiate overdose).750 (See Naloxone Hydrochloride 28:10.)

Nalbuphine should be used with caution in patients with myocardial infarction who exhibit nausea and vomiting and in patients about to undergo biliary tract surgery because nalbuphine may cause spasm of the sphincter of Oddi.

Because nalbuphine's respiratory depressant effect and potential for elevating CSF pressure (resulting from vasodilation following carbon dioxide retention) may be markedly exaggerated in patients with head injury, intracranial lesions or preexisting increased intracranial pressure, the drug should be used in these patients only when it is essential and with extreme caution. In patients with head injury, the drug may also interfere with evaluation of CNS function.

Nalbuphine should be used with caution in patients who have been chronically receiving opiate agonists because nalbuphine does not suppress the abstinence syndrome in these patients, and high doses may precipitate withdrawal symptoms as a result of opiate antagonist effect. (See Dosage and Administration: Dosage.)

In patients with renal or hepatic dysfunction, nalbuphine should be used with caution and in reduced dosage.

Some commercially available formulations of nalbuphine hydrochloride injection contain sodium metabisulfite, a sulfite that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals.105 The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.105

Nalbuphine is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

Pediatric Precautions

Safety and efficacy of nalbuphine in children younger than 18 years of age have not been established. Neonates whose mothers received nalbuphine during labor and delivery should be monitored for drug-associated adverse effects.106 (See Cautions: Pregnancy.)

Pregnancy

Pregnancy

Safe use of nalbuphine during pregnancy (except during labor and delivery) has not been established. Although animal reproduction studies have not revealed teratogenic or embryotoxic effects, nalbuphine should not be administered to pregnant women unless the possible benefits outweigh the potential risks. When nalbuphine is administered during labor and delivery, fetal bradycardia, respiratory depression, apnea, and cyanosis may occur in the neonate. These adverse effects may resolve in some cases following maternal administration of naloxone during labor.106 However, fetal bradycardia may be severe and prolonged and permanent neurological damage associated with fetal bradycardia has been reported.106 In addition, a sinusoidal fetal heart rate pattern has been associated with maternal use of nalbuphine.106 The drug should be used with caution in women during labor and delivery, especially in those delivering premature infants; neonates should be monitored for respiratory depression, apnea, bradycardia, and cardiac arrhythmias.106

Benzodiazepines and Other CNS Depressants

Concomitant use of opiate agonists or opiate partial agonists, including nalbuphine, and benzodiazepines or other CNS depressants (e.g., anxiolytics, sedatives, hypnotics, tranquilizers, muscle relaxants, general anesthetics, antipsychotics, other opiates, alcohol) may result in profound sedation, respiratory depression, coma, and death.416,417,418,700,701,702,703 Opiate analgesics frequently are implicated as contributing to fatal overdoses involving other CNS depressants, and epidemiologic studies have shown that a substantial proportion of fatal opiate overdoses involve the concurrent use of benzodiazepines, alcohol, or other CNS depressants.416,417,418,435,700,701,702 Whenever possible, concomitant use of opiates and benzodiazepines should be avoided.410,411,415,435 Alcohol also should be avoided in patients receiving opiates.700 Concomitant use of opiate analgesics and benzodiazepines or other CNS depressants should be reserved for patients in whom alternative treatment options are inadequate; the lowest effective dosages and shortest possible duration of concomitant therapy should be used, and the patient should be monitored closely for respiratory depression and sedation.700,703

If a benzodiazepine or other CNS depressant is required for any indication other than epilepsy in a patient receiving nalbuphine, the drug should be initiated at a lower dosage than indicated in the absence of opiate therapy and titrated based on clinical response.700,703 In patients receiving a CNS depressant, nalbuphine, if required, should be initiated at a reduced dosage and titrated based on clinical response.700,703 Clinicians should consider prescribing the opiate antagonist naloxone for patients receiving opiates who are at increased risk of opiate overdosage, including those receiving benzodiazepines or other CNS depressants concomitantly.411,431,750 (See Cautions: Precautions and Contraindications.)

Opiate Agonists

Although nalbuphine has weak opiate antagonist activity, usual doses of the drug do not antagonize the effects of an opiate agonist administered immediately before, concurrently, or just after nalbuphine is given in patients who are not dependent on opiate agonists.

Drugs Associated with Serotonin Syndrome

Serotonin syndrome may occur in patients receiving opiate partial agonists concomitantly with other serotonergic drugs, including serotonin (5-hydroxytryptamine; 5-HT) type 1 receptor agonists (“triptans”), selective serotonin-reuptake inhibitors (SSRIs), selective serotonin- and norepinephrine-reuptake inhibitors (SNRIs), tricyclic antidepressants, antiemetics that are 5-HT₃ receptor antagonists, buspirone, cyclobenzaprine, dextromethorphan, lithium, St. John's wort ( Hypericum perforatum ), tryptophan, other serotonin modulators (e.g., mirtazapine, nefazodone, trazodone, vilazodone), and monoamine oxidase (MAO) inhibitors (both those used to treat psychiatric disorders and others, such as linezolid, methylene blue, and selegiline).400 Serotonin syndrome may occur within the recommended dosage ranges for these drugs.400 Manifestations of serotonin syndrome may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination, rigidity), and/or GI symptoms (e.g., nausea, vomiting, diarrhea).400 Symptom onset generally occurs within several hours to a few days of concomitant use, but may occur later, particularly after dosage increases.400

If concomitant use of other serotonergic drugs is warranted, patients should be monitored for serotonin syndrome, particularly during initiation of therapy and dosage increases.400 If serotonin syndrome is suspected, treatment with nalbuphine, other opiate agonist or partial agonist therapy, and/or any concurrently administered serotonergic agents should be discontinued.400

For further information on serotonin syndrome, including manifestations and treatment, see Drug Interactions: Serotonergic Drugs, in Fluoxetine Hydrochloride 28:16.04.20.

Acute Toxicity

Manifestations

Expected symptoms of nalbuphine overdosage would be respiratory depression, cardiovascular effects, and other CNS effects. In healthy individuals, a single IM dose of 72 mg of nalbuphine hydrochloride caused sleepiness and mild dysphoria.

Treatment

Treatment of nalbuphine overdosage consists of immediate IV administration of naloxone. Appropriate supportive measures such as administration of oxygen, IV fluids, and vasopressors should also be used if necessary.

Chronic Toxicity

Tolerance and psychological and physical dependence may occur in patients receiving nalbuphine, and unnecessary increases in dosage or frequency of administration should be avoided. The potential for abuse of nalbuphine is approximately equal to that of pentazocine and is reportedly less than that of codeine or propoxyphene. Following abrupt discontinuance after prolonged use of nalbuphine, withdrawal symptoms, which are similar to but more intense than those produced by pentazocine, have occurred and may include abdominal cramps, nausea, vomiting, rhinorrhea, lacrimation, restlessness, anxiety, increased temperature, and piloerection.

Pharmacology

Nalbuphine hydrochloride has analgesic and opiate antagonistic effects. The exact mechanisms of actions of the drug are not known. However, the analgesic effect is believed to result from an interaction with an opiate receptor site in the CNS (probably in or associated with the limbic system); the opiate antagonistic effect may result from competitive inhibition at the opiate receptor, but other mechanisms are probably also involved. It is thought that nalbuphine exerts its agonist effects principally at the κ opiate receptor, possibly as a partial agonist at this receptor.100,101,102,103,107 The drug has antagonist or partial antagonist activity at the µ receptor100,102,107 and appears to have minimal agonist activity at the Σ receptor.100,103 On a weight basis, the analgesic activity of IM, IV, or subcutaneous nalbuphine hydrochloride is approximately equal to that of IM, IV, or subcutaneous morphine sulfate, and the analgesic activity of IM or IV nalbuphine hydrochloride is about 3-4 times that of IM or IV pentazocine. The opiate antagonist activity of subcutaneous nalbuphine hydrochloride is about 10 times that of subcutaneous pentazocine. The antagonist activity at the µ opiate receptor is about one-fourth to one-third that of nalorphine.107,108

Like opiate agonists, nalbuphine produces respiratory depression, sedation, and miosis. In adults, a single 10-mg IV dose of nalbuphine hydrochloride (about 0.14 mg/kg) decreases respiration to the same degree as 10 mg of morphine sulfate IV. In contrast to morphine, however, respiratory depression in healthy adults plateaus with cumulative IV doses of 30 mg of nalbuphine hydrochloride (given in doses of 10 mg/hour). Unlike butorphanol, the duration of respiratory depression produced by nalbuphine apparently is not increased with increasing dosage (i.e., a cumulative IV dose of 60 mg/70 kg caused respiratory depression for 3 hours). Naloxone reverses the respiratory depressant, analgesic, and sedative effects of nalbuphine. Studies to determine whether nalbuphine has antitussive activity have not been published.

In patients with coronary artery disease or acute myocardial infarction, IV administration of 10 mg of nalbuphine hydrochloride produces no substantial changes in heart rate, pulmonary artery or wedge pressure, left ventricular end-diastolic pressure, pulmonary vascular resistance, and cardiac index.

Pharmacokinetics

Absorption

Nalbuphine hydrochloride is about 1/5 as effective for pain relief when given orally as when given IM, apparently because the orally administered drug undergoes first-pass metabolism in the GI mucosa and/or the liver. Following IM administration of 10 mg of nalbuphine hydrochloride in healthy individuals, peak plasma concentrations of 48 ng/mL occur in 30 minutes. Following IV administration of a single 20-mg dose in pregnant women in active labor, plasma nalbuphine concentrations averaged 297 ng/mL (range: 197-459 ng/mL) 1-3 minutes after administration of the dose.104

After IV administration of nalbuphine hydrochloride, the onset of action occurs within 2-3 minutes, and peak effects occur in about 30 minutes. After IM or subcutaneous administration, the onset of action is within 15 minutes. After IV, IM, or subcutaneous administration, the duration of action is usually 3-6 hours. In one study, however, pain had returned to the preinjection level in 2.5 hours in 60% of the patients who received 0.14 mg/kg IV immediately after surgery.

Distribution

Nalbuphine is not appreciably bound to plasma proteins. Nalbuphine readily crosses the placenta, with fetal plasma concentrations approximately equivalent to or higher than concurrent maternal plasma concentrations of the drug.104

Elimination

In healthy individuals, the plasma half-life of nalbuphine is 5 hours. Following a single IV dose in pregnant women in active labor, the elimination half-life averaged 2.4 hours (range: 1.3-3.9 hours).104

Nalbuphine is metabolized in the liver. Animal studies indicate that the drug and its metabolites are excreted in urine and feces, and fecal excretion resulting principally from biliary secretion is the major route of elimination. In a study in healthy individuals, approximately 7% of a single 10-mg IM dose of nalbuphine hydrochloride was recovered in urine as unchanged drug and 2 metabolites in 3 days.

Chemistry and Stability

Chemistry

Nalbuphine hydrochloride is a synthetic opiate partial agonist analgesic. The drug is structurally related to naloxone and oxymorphone but pharmacologically similar to pentazocine and butorphanol.

Nalbuphine hydrochloride occurs as a white to slightly off-white powder and is soluble in water and slightly soluble in alcohol. The drug has pK_a values of 8.71 and 9.96. Nalbuphine hydrochloride injection is a sterile, nonpyrogenic solution of the drug in water for injection; the injection also contains citric acid and sodium citrate and may also contain parabens, sodium chloride, and sodium metabisulfite. The pH of nalbuphine hydrochloride injection is adjusted to 3.5 with hydrochloric acid and/or sodium hydroxide as necessary.

Stability

Nalbuphine hydrochloride injection should be protected from light and stored at 15-30°C. Commercially available single-dose containers of nalbuphine hydrochloride contain no preservatives and unused portions should be discarded.

Nalbuphine hydrochloride is reportedly physically compatible with some drugs (e.g., atropine sulfate, diphenhydramine hydrochloride, droperidol, glycopyrrolate, hydroxyzine hydrochloride, prochlorperazine, scopolamine hydrobromide) and with 5% dextrose, lactated Ringer's, and 0.9% sodium chloride injections but incompatible with other drugs (e.g., diazepam, pentobarbital sodium). Compatibility depends on several factors (e.g., the concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

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