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Synopsis: Nalbuphine1 is an agonist/antagonist analgesic. After parenteral administration of ‘usual’ doses it is approximately equipotent in analgesic activity to morphine on a weight basis. In studies in patients with moderate to severe pain, usually following surgery, the characteristics of analgesia with nalbuphine were comparable to those seen with equianalgesic doses of morphine or pentazocine. It also appears to produce satisfactory anaesthesia when used as a component of a ‘balanced’ anaesthesia technique, although a relatively low ‘ceiling’ effect for reduction of anaesthetic requirements with nalbuphine may limit its usefulness in this regard. As with other agonist/antagonist analgesics, a ‘ceiling’ effect to nalbuphine-induced respiratory depression is also seen, beyond which further depression does not readily occur. However, with usual analgesic doses, respiratory depression seen with nalbuphine is comparable to that with morphine. Important haemodynamic changes have not occurred after usual doses of nalbuphine, even in patients with cardiac disease. Like other agonist/antagonist analgesic drugs, the abuse potential of nalbuphine seems relatively low, but only wider clinical use for longer periods can establish this with certainty. Thus, nalbuphine appears to offer a useful alternative to morphine in patients with moderate to severe pain.
Pharmacodynamic Studies: The narcotic agonist activity of nalbuphine has been demonstrated in standard animal tests, with a profile of activity in such studies characteristic of agonist/antagonist analgesic compounds. In analgesic potency assays in humans, intramuscularly administered nalbuphine was estimated to be approximately equipotent to morphine and about 3 times as potent as pentazocine on a weight basis. As occurred with morphine, nalbuphine reduced the dose of anaesthetic needed to achieve anaesthesia in animals; but nalbuphine reached a ‘ceiling’ for this effect, beyond which further doses had no additional action, at a much lower maximum reduction of anaesthetic requirement than could be achieved with morphine.
The narcotic antagonist properties of nalbuphine have been demonstrated in various animal tests and found to lie somewhere between the more potent nalorphine and the less potent pentazocine. Studies in humans dependent on morphine estimate nalbuphine to be one-quarter as potent an antagonist as nalorphine. Cases of precipitated withdrawal in patients previously treated with narcotics substantiate the clinical significance of this property.
Respiratory depression with nalbuphine at therapeutic doses (e.g. 10mg/70kg) is similar to that produced by equianalgesic doses of morphine. However, in contrast to the dose-dependent respiratory depression seen with morphine, nalbuphine-induced respiratory depression reaches a ‘ceiling’ in healthy subjects at a dose of 30 to 60mg/70kg, or lower (0.1 mg/kg) in another study, beyond which further respiratory depression does not readily occur.
Importantly, no significant haemodynamic changes after nalbuphine administration were observed in patients undergoing cardiac catheterisation, cardiac surgery, or after myocardial infarction.
Animal and human studies suggest that the abuse potential of nalbuphine is relatively low. Repeated administration of high doses to 6 previous narcotic users consistently produced disturbing side effects, sometimes limiting drug administration. Physical dependence to nalbuphine has been demonstrated after long term administration, and an abstinence syndrome may be precipitated by abrupt withdrawal in some patients, or by naloxone administration. As with other new analgesics, the true abuse potential of nalbuphine will be known with certainty only after much greater clinical experience.
Pharmacokinetic Studies: Only very limited data are available on the disposition of nalbuphine in man. Nalbuphine, administered intramuscularly to healthy adults, is rapidly absorbed with peak concentrations (mean 48 ng/ml) occurring 0.5 hours after a 10mg dose. The elimination half-life is approximately 5 hours in healthy subjects. Both metabolites and unchanged drug have been identified in the urine of healthy subjects, the greatest proportion of dose being excreted as the inactive glucuronide conjugate. Animal data indicates extensive biliary secretion.
Therapeutic Trials: Nalbuphine, usually given intravenously or intramuscularly, has been compared with morphine, pentazocine or pethidine (meperidine) in patients with moderate to severe pain. Generally, similar analgesic effects were evident for nalbuphine and morphine, or pentazocine, with nalbuphine showing a slightly longer duration of analgesic effect than morphine. In postoperative patients, nalbuphine was about 3 times as potent an analgesic on a weight basis as pentazocine, with a similar time until peak effect. The duration of action, however, appeared to be longer with nalbuphine. In the only published comparison with pethidine, nalbuphine was significantly less effective when administered intravenously for the discomfort associated with colonoscopy.
Subjective analgesia ratings were more frequently improved with subcutaneous nalbuphine when compared with subcutaneous morphine in cancer patients treated for at least 3 weeks. Only a small group of patients were studied however, under conditions where ideal control was not always possible, and these preliminary findings thus require confirmation.
Limited data suggest that orally administered nalbuphine is about 25% as potent as intramuscularly administered nalbuphine, and about 3 times as potent as orally administered codeine. When equianalgesic doses were compared in patients with moderate to severe pain nalbuphine was as effective as codeine with a rapid onset and about a 4-hour duration of analgesic effect.
Nalbuphine has been used as a premedication to anaesthesia and as a component of ‘balanced’ anaesthesia with generally favourable results. It has also been used to reverse respiratory depression after oxymorphone or hydromorphone ‘balanced’ anaesthesia, without apparent reversal of analgesia.
Side Effects: The most common side effect associated with nalbuphine administration is sedation (about 36% incidence). Nausea and vomiting may occur in about 6% of patients; less than 1% of patients experience psychomimetic reactions. The degree of respiratory depression after usual doses of nalbuphine is comparable to that with equianalgesic doses of morphine, although some evidence suggests that the incidence of postoperative respiratory depression after ‘balanced’ anaesthesia may be lower with nalbuphine than with morphine. Only very limited data on long term use of nalbuphine for chronic pain are available, and its side effect profile in this clinical setting needs further clarification.
Dosage and Administration: The recommended dose of nalbuphine is 10mg/70kg, repeated every 3 to 6 hours as needed, given by subcutaneous, intramuscular or intravenous routes. The maximum recommended single dose is 20mg, while the maximum recommended daily dose is 160mg. Withdrawal symptoms may be precipitated by nalbuphine in patients who have previously taken narcotics for long periods.
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