Nalbuphine

Nalbuphine hydrochloride should be used with caution in patients with heart insufficiency, paralytic ileus, biliary colic, epilepsy and hypothyroidism.

Alcohol potentiates the sedative effect of morphine-based analgesics. Alcoholic beverages and medicinal products containing alcohol must be avoided.

Patients with moderate and mild renal impairment may show an abnormal reaction upon standard dosages. Therefore, the product should be used with caution in these patients.

Nalbuphine 10 mg causes respiratory depression comparable to that caused by 10 mg morphine. Unlike morphine, there is a ceiling effect to the respiratory depressant effect of nalbuphine.

There is a ceiling for respiratory depression at a dose of approximately 30 mg, and an analgetic ceiling at approximately 50 mg administered during a short period. Patients with pain conditions who have a high opioid requirement should be offered an opioid with no analgetic ceiling.

Respiratory depression raised by nalbuphine may be treated with naloxone hydrochloride, if necessary. Nalbuphine must be administered with great caution and in very small dosages to patients who suffer from impaired respiration (e.g. caused by other medical treatment, uremia, bronchial asthma, serious infections, cyanose or respiratory obstruction).

It is possible that potent analgesics may increase intracranial pressure and so cause respiratory depression. In case of head injury, inner head injury or already existing increased intracranial pressure this effect might be intensified. In addition, potent analgesics can cause effects that may mask the course of the disease in patients with head injury. Therefore, nalbuphine must only be used if really necessary and with the utmost caution.

Studies in humans have not been conducted. Nalbuphine crosses the placental barrier and is contraindicated in pregnant women.

Prolonged maternal use of opioids during pregnancy can result in withdrawal signs in the neonate. Neonatal Opioid Withdrawal Syndrome (NOWS), unlike opioid withdrawal syndrome in adults, may be life-threatening.

Pregnant women using opioids should not discontinue their medication abruptly as this can cause pregnancy complication such as miscarriage or still-birth. Tapering should be slow and under medical supervision to avoid serious adverse events to the fetus.

Since opioids can cross the placental barrier and are excreted in breast milk, nalbuphine is contraindicated in nursing women and is not recommended to be used during labour and delivery unless, in the judgement of the physician, the potential benefits outweigh the risks. Life-threatening respiratory depression can occur in the infant if opioids are administered to the mother. Naloxone, a drug that counters the effects of opiates, should be readily available if nalbuphine is used in this population.

Nalbuphine reduces the ability to respond and has therefore a major influence on the ability to drive and use machines. These activities have to be avoided until the effects of nalbuphine hydrochloride have subsided.

Adverse effects of nalbuphine injection are similar to those of other opioid analgesics, and represent an extension of pharmacological effects of the drug class. The major hazards of opioids include respiratory and central nervous system depression and to a lesser degree, circulatory depression, respiratory arrest, shock and cardiac arrest.

Sedation: Sedation is a common side effect of opioid analgesics, especially in opioid naïve individuals. Sedation may also occur partly because patients often recuperate from prolonged fatigue after the relief of persistent pain. Most patients develop tolerance to the sedative effects of opioids within three to five days and, if the sedation is not severe, will not require any treatment except reassurance. If excessive sedation persists beyond a few days, the dose of the opioid should be reduced and alternate causes investigated. Some of these are: concurrent CNS depressant medication, hepatic or renal dysfunction, brain metastases, hypercalcemia and respiratory failure. If it is necessary to reduce the dose, it can be carefully increased again after three or four days if it is obvious that the pain is not being well controlled. Dizziness and unsteadiness may be caused by postural hypotension, particularly in elderly or debilitated patients, and may be alleviated if the patient lies down.

Nausea and Vomiting: Nausea is a common side effect on initiation of therapy with opioid analgesics and is thought to occur by activation of the chemoreceptor trigger zone, stimulation of the vestibular apparatus and through delayed gastric emptying. The prevalence of nausea declines following continued treatment with opioid analgesics. When instituting therapy with an opioid for chronic pain, the routine prescription of an antiemetic should be considered. In the cancer patient, investigation of nausea should include such causes as constipation, bowel obstruction, uremia, hypercalcemia, hepatomegaly, tumor invasion of celiac plexus and concurrent use of drugs with emetogenic properties. Persistent nausea which does not respond to dosage reduction may be caused by opioid-induced gastric stasis and may be accompanied by other symptoms including anorexia, early satiety, vomiting and abdominal fullness. These symptoms respond to chronic treatment with gastrointestinal prokinetic agents.

Constipation: Practically all patients become constipated while taking opioids on a persistent basis. In some patients, particularly the elderly or bedridden, fecal impaction may result. It is essential to caution the patients in this regard and to institute an appropriate regimen of bowel management at the start of prolonged opioid therapy. Stimulant laxatives, stool softeners, and other appropriate measures should be used as required. As fecal impaction may present as overflow diarrhea, the presence of constipation should be excluded in patients on opioid therapy prior to initiating treatment for diarrhea.

The following adverse effects occur less frequently with opioid analgesics and include those reported in nalbuphine clinical trials, whether related or not to nalbuphine.

In clinical trials with nalbuphine the most frequently reported side effects were: sedation (36% of 1066), sweating or clammy (9%), nausea or vomiting (6%), dizziness or vertigo (5%), dry mouth (4%) and headache (3%).

Less Common Clinical Trial Adverse Drug Reactions

Central Nervous System: nervousness, crying, depression, restlessness, euphoria, hostility, confusion, faintness, floating, unusual dreams, numbness, feeling of heaviness, and psychotomimetic effects such as hallucinations, feeling of unreality and dysphoria. The incidence of psychotomimetic effects, such as unreality, depersonalization, delusions, dysphoria and hallucinations has been shown to be less than that which occurs with pentazocine.

Cardiovascular: Hypertension, hypotension, bradycardia, tachycardia.

Gastrointestinal: Cramps, dyspepsia, bitter taste. Respiration: Depression, dyspnea, asthma.

Dermatological: Itching, burning, urticaria.

Miscellaneous: Speech difficulty, urinary urgency, blurred vision, flushing and warmth.

Allergic Reactions: Anaphylactic/anaphylactoid and other serious hypersensitivity reactions have been reported following the use of nalbuphine and may require immediate, supportive medical treatment. These reactions may include shock, respiratory distress, respiratory arrest, bradycardia, cardiac arrest, hypotension, or laryngeal edema. Other allergic-type reactions reported with patients using nalbuphine include stridor, bronchospasm, wheezing, edema, rash, pruritis, nausea, vomiting, diaphoresis, weakness, and shakiness.

Post-marketing: Other reports include pulmonary edema, agitation and injection site reactions such as pain, swelling, redness, burning and hot sensations.

Androgen deficiency: Chronic use of opioids may influence the hypothalamic-pituitarygonadal axis, leading to androgen deficiency that may manifest as low libido, impotence, erectile dysfunction, amenorrhea, or infertility. The causal role of opioids in the clinical syndrome of hypogonadism is unknown because the various medical, physical, lifestyle, and psychological stressors that may influence gonadal hormone levels have not been adequately controlled for in studies conducted to date. Patients presenting with symptoms of androgen deficiency should undergo laboratory evaluation.