Nabilone

Summary

Synopsis: Nabilone¹ is a new orally active cannabinoid for the treatment of severe gastrointestinal toxicity associated with cancer chemotherapy. The pharmacological profile of nabilone suggests that it acts primarily by preventing emesis controlled by the medulla oblongata, although its secondary mild anxiolytic activity may contribute to the overall efficacy. Nabilone 2mg twice daily starting 12 hours prior to, and continued for the duration of, chemotherapy produces significant reduction in the severity and duration of nausea and the frequency of vomiting in about 50 to 70% of patients with severe symptoms refractory to conventional therapy. Nabilone has proven to be more effective in controlling symptoms and preferred by more patients than prochlorperazine 10mg 2 to 4 times daily in a limited number of studies, despite a higher incidence of side effects. Comparative trials against other new antiemetic agents, such as high dose metoclopramide, and use of nabilone in combination with other antiemetics remain to be undertaken. The incidence of side effects is high with nabilone; drowsiness, dizziness and/or vertigo occur in 60 to 70% of patients, but rarely lead to drug withdrawal, although more troublesome effects, such as postural hypotension, ataxia, vision disturbance and toxic psychoses, may cause discontinuation of therapy. Thus, nabilone offers an effective alternative to the treatment options available in a difficult therapeutic area — those patients with severe gastrointestinal side effects from cancer chemotherapy who are refractory to conventional therapy.

Pharmacodynamic Studies: The antiemetic activity of nabilone has been demonstrated in anaesthetised and unanaesthetised cats. Nabilone was more potent than prochlorperazine in preventing emesis due to intravenous cisplatin (cis-diamminedichloroplatinum), nitrosureas. mechlorethamine and other emetogenic agents. Less activity was seen against apomorphine-induced emesis and no activity was seen against intravenous nicotine-induced emesis, suggesting these effects of nabilone may occur at the level of the vomiting control mechanism in the medulla oblongata. Nabilone usually produces marked reduction in blood pressure in cats, rabbits and rats (but not in monkeys or dogs). However, there is some evidence that cardiovascular and behavioural effects are intimately linked, and that repeated administration is associated with tolerance to the cardiovascular effects of nabilone. Mild anxiolytic activity has been seen with ‘lower’ doses both in animal models and in man, and at high doses nabilone is associated with locomotor disturbance and sedation. Nabilone possesses little or no opiate-like activity, does not induce development of a withdrawal syndrome and may be associated with a lower incidence of euphoria than Δ⁹-tetrahydrocannabinol, although evidence of abuse potential for nabilone has been demonstrated.

Pharmacokinetic Studies: Only very limited data are available on the disposition of nabilone in man. Oral doses are rapidly absorbed and the bioavailability is about 96%. Nabilone has an elimination half-life of about 2 hours and is extensively metabolised to a mixture of isomeric alcohols, with extended half-lives (up to 35 hours). Toxicity in dogs led to a withdrawal of nabilone from clinical trials until it was discovered that metabolism of the drug in dogs was different to that in man and other species.

Therapeutic Trials: Nabilone has been used as an oral antiemetic agent in the treatment of gastrointestinal toxicity in patients undergoing cancer chemotherapy. Significant reduction of the duration and severity of nausea and frequency of vomiting is usually seen after nabilone 2mg 2 or 3 times daily in about 50 to 70% of patients, many of whom have been refractory to conventional antiemetics. In a limited number of comparative studies, nabilone has produced significantly greater reduction of symptoms than prochlorperazine, and reduced the necessity for supplemental parenteral therapy. Despite a higher incidence of side effects, nabilone has also been preferred to prochlorperazine as treatment of choice in the majority of cases (40 to 75% vs 15 to 23%), although in 2 of 3 placebo-controlled studies less than 20% of patients elected to continue with nabilone therapy. Patients with more severe symptoms [induced by cisplatin, doxorubicin (adriamycin), cyclophosphamide] appear to respond equally well as those with less severe symptoms, and thus comprise the preferred treatment group for therapy with nabilone. Further therapeutic studies are needed with nabilone, particularly to clarify its efficacy compared with high dose metoclopramide and other antiemetic agents, and its use in combination with other antiemetic agents.

Side Effects: Nabilone is associated with a high incidence of mild or moderate side effects, the most common being drowsiness, dizziness and vertigo (60 to 70%), and dry mouth (29%). More severe effects such as postural hypotension, ataxia, visual disturbance and some toxic psychoses are occasionally seen, and may necessitate treatment withdrawal. Nabilone produces a higher incidence of side effects than prochlorperazine, but they may lessen in severity during continued therapy.

Dosage and Administration: The usual therapeutic dose of nabilone for use as an antiemetic agent in patients undergoing cancer chemotherapy is 2mg twice daily commencing 12 hours prior to, and continuing until one dose after, chemotherapy.