Laboratory studies of the effects of ramelteon suggest that the drug’s targeting of the brain’s melatonin receptors rather than its benzodiazepine receptors make its subjective side effects unlike other sedative hypnotics. The research is reported in the June issue of Behavioral Neuroscience, which is published by the American Psychological Association (APA).
At the University of Texas Health Science Center in San Antonio, pharmacology researchers led by Charles P. France, PhD, assessed whether ramelteon instigated the same kinds of broad cognitive effects as other more commonly prescribed sleep aids. That other group includes traditional hypnotics and newer drugs such as zaleplon (Sonata) and zolpidem (Ambien), all of which bind to the brain’s benzodiazepine receptors and may result in impaired thinking, hangover, withdrawal symptoms, and rebound insomnia.
Laboratory tests and clinical studies also show that even low-dose benzodiazepines, especially in long-term use, create the potential for dependence and abuse. “Although medication might not always be indicated for insomnia, when they are prescribed, it is essential to limit the adverse side effects as much as possible,” France said.
The U.S. Food and Drug Administration (FDA) approved the use of ramelteon (brand name Rozerem) in July of 2005. Prior to FDA approval, France and his colleagues researched drug side effects, capitalizing on the fact that monkeys—just like humans—can be trained to recognize the specific effects of a drug class, presumably by how they feel. “Those experienced with the ‘feeling’ of a particular drug can easily recognize when they have received that drug and can reliably detect when they have been given a drug from a different pharmacologic class,” France said.
In one experiment, the researchers trained monkeys to press a lever only when given a benzodiazepine called midazolam (Versed). Then the team gave the monkeys ramelteon. The animals did not press the lever associated with midazolam, their lack of response indicating that they felt different after receiving ramelteon than they did after receiving midazolam.
In a second experiment, the researchers determined that ramelteon and the benzodiazepines have different pharmacologic mechanisms. The team gave monkeys diazepam (Valium) for at least a year. Then they administered flumazenil (Romazicon), which reverses the effects of benzodiazepines. The subsequent administration of ramelteon did not change the effects of flumazenil, further evidence that ramelteon works altogether differently.
In a third experiment, the team carefully watched how monkeys who’d been given ramelteon for a year behaved when the drug was withdrawn. To assess whether the monkeys had come to depend on the drug, France and his colleagues measured clinical behavior, operant (learned) behavior, and blood levels of the drug. The first type of measure was the most revealing: Of the 33 usual withdrawal-related signs of dependence, such as teeth grinding, rubbing lips on bars, nose rubbing, scratching, biting fingernails, shakes, and tremors, 10 were never seen; all but one of the other behaviors didn’t change in frequency.
The authors say that, together, the findings highlight significant differences between ramelteon and the prototypical benzodiazepines studied. They say their results, “suggest that ramelteon does not likely share subjective effects with benzodiazepines in humans and, thus, should not be expected to share abuse liability with BZRAs [benzodiazepine receptor agonists].” The findings also indicate that ramelteon will not produce benzodiazepine-like physical dependence in humans. Thus the authors say these findings are potentially important for the treatment of sleep problems.
This study was conducted at the University of Texas Health Science Center and funded by Takeda Pharmaceutical Company Limited, which markets ramelteon under the brand name Rozerem.