Nalbuphine

Substance identification
Nalbuphirie (INN, CAS 20594-83-6), chemically 17-(cyclobutylmethyl)-4,5α-epoxymorphinan-3,6α-14-triol,, is also known as Nubain. Nalbuphine- is closely related in- structure. to hydromorphinol (controlled in Schedule I of the Single: Convention on Narcotic Drugs, 1961), but cannot easily be converted into it. There are five chiral carbon atoms in the molecule, so that 32 stereoisomeric forms plus racemic mixtures are possible, but only three stereoisomers: have been reported.

Similarity to known substances and effects on the CNS
Nalbuphine i is believed to be either a mu 1 antagonist or a partial mu agonist in humans; it also has high affinity for and agonist actions at kappa receptors. It produces analgesia and sedation, as well as respiratory depression with ceiling effects, as described in section 4.1.1. In contrast to pentazocine it rarely produces, even in high doses, psychotomimetic effects such as dysphoria and distortion of body image.

In both laboratory animals and humans nalbuphine has high systemic clearance and low oral bioavailability as a result of extensive first-pass metabolism, mainly by glucuronidation; the glucuronide conjugate is pharmacologically inactive. The plasma half-life of nalbuphine is about 5 hours.

Dependence potential
Rats, baboons and rhesus monkeys will self-administer nalbuphine. In non-withdrawn morphine-dependent mice, nalbuphine precipitates withdrawal signs similar to those observed after naloxone administration. Experienced morphine users usually identify nalbuphine as morphine-like, but occasionally as barbiturate- or amfetamine-like. After continuous administration of nalbuphine, administration of naloxone produces a withdrawal syndrome which is less severe than that produced by naloxone in morphine-dependent human subjects. As a mu-opioid antagonist, nalbuphine is approximately one-quarter as potent as nalorphine.

Actual abuse and or/evidence of likelihood of abuse
Infrequent abuse of nalbuphine has been reported, and the potential for abuse is rated as less than that of morphine. The producer of the drug has reported 77 individual abuse cases with an estimated incidence of one case per million therapeutic doses supplied. The majority of cases of abuse have occurred among health care personnel.

Therapeutic usefulness
Nalbuphine is indicated for the relief of moderate to severe pain. Unlike several other opioid agonist—antagonists, it produces minimal behavioural or autonomic effects in animals even in large doses. In humans, large doses of nalbuphine cause few psychotomimetic effects. The drug produces sedation, but rarely significant euphoria. The respiratory depression, gastrointestinal inhibition and cardiovascular effects are less marked than those produced by morphine. Nalbuphine antagonizes morphine strongly enough to reverse mu-agonist-induced respiratory depression and to produce withdrawal manifestations in mu-agonist-dependent subjects. Its limited effects on respiration mean that it can be used in burns patients with respiratory impairment and in patients with septic shock in whom morphine would be contraindicated.

Recommendation
On the basis of the available data concerning its pharmacological profile, dependence potential and actual abuse, the Committee rated the likelihood of abuse of nalbuphine as low to moderate, and the therapeutic usefulness as moderate to high. It considered that the degree of seriousness of the public health and social problems associated with the abuse of this substance was not great enough to warrant international control. The Committee did not recommend scheduling of nalbuphine.