The Pharmaceutical Journal
Vol 276 No 7405 p714
17 June 2006

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Sleep aid without benzodiazepine side effects in Takeda's pipeline

Ramelteon (Rozerem; Takeda), a selective melatonin receptor agonist licensed in the US last year for the treatment of insomnia, is not likely to have benzodiazepine-like abuse or dependence problems, according to researchers.

They conducted three experiments in monkeys to compare the abuse and dependence profile of ramelteon with benzodiazepines.

In the first experiment, monkeys were trained only to press a lever when given the benzodiazepine midazolam. The monkeys were then give ramelteon and their behaviour observed. The monkeys did not press the lever associated with midazolam, which the researchers say indicates that they felt differently after receiving ramelteon than they did after receiving midazolam.

In the second experiment monkeys were given diazepam for at least one year. They were then given flumazenil, which reverses the effects of benzodiazepines. Subsequent administration of ramelteon in doses of up to 10mg/kg did not change the effects of flumazenil. This inability of ramelteon to attenuate the effects of flumazenil suggests that ramelteon does not share similar pharmacological mechanisms with benzodiazepines, say the researchers.

In the third experiment, monkeys who had received ramelteon for a year were monitored for signs of primary physical dependence through clinical behaviour, spontaneous behaviour and plasma concentration assessments.

Of the 33 withdrawal signs usually associated with dependence, 10 were never seen and all but one did not change in frequency. Withdrawal did not affect responses to obtain food or avoid shock.

“These findings suggest that ramelteon does not likely share subjective effects with benzodiazepines in humans and, thus, should not be expected to share abuse liability with benzodiazepines,” the researchers conclude.

The findings also indicate that ramelteon is not likely to produce physical dependence even after daily, long-term treatment, they add (Behavioural Neuroscience 2006;120:535, PDF (120K)).

Phase III studies required to obtain a license for ramelteon in Europe are currently ongoing and Takeda expects to seek approval within 18 months to two years.