BOCA RATON, FLA. – The newly approved drug ramelteon significantly reduced sleep latency and increased total sleep time in a phase III study of elderly patients with chronic insomnia. In addition, researchers reported no evidence of next-day residual cognitive, psychomotor, or memory effects.
“There was really no problem with next-day psychomotor impairment that you can see with gamma-aminobutyric acid (GABA)-ergic agents. This study was done in an elderly population, so that is particularly important,” David Seiden, M.D., said in an interview at a poster presented at a meeting of the New Clinical Drug Evaluation Unit, sponsored by the National Institute of Mental Health. Use of sedative-hypnotic agents has been associated with increased risk of hip fractures from falls (J. Am. Geriatr. Soc. 1999;47:30–9).
Most agents approved by the Food and Drug Administration to treat insomnia work through the GABA-ergic system, including zolpidem (Ambien) or zaleplon (Sonata). But Dr. Seiden said ramelteon uses a novel approach and has a different mechanism of action through the melatonin system.
As a melatonin agonist, ramelteon has the ability to induce sleep and modulate circadian rhythm by binding to the same receptors, M1 and M2, targeted by endogenous melatonin, said Dr. Seiden, medical director of the Broward Research Group and Sleep-Wake Disorders Center of South Florida in Pembroke Pines.
Dr. Seiden and his associates studied 100 elderly patients with chronic insomnia in a crossover design. The mean age was 71 years, and 37 participants were men. Each participant took either ramelteon 4 mg/night, ramelteon 8 mg/night, or placebo for 5 weeks, followed by a 5- to 12-day washout period before switching. The drug was administered 30 minutes before the patient's usual bedtime.
The researchers used overnight polysomnography to assess efficacy. Patients also completed a postsleep questionnaire, Digital Symbol Substitution Test, and immediate and delayed memory recall tests.
“The major finding here is, there is an improvement in sleep latency,” he said.
Participants taking 4-mg/night ramelteon fell asleep faster than those taking a placebo (29 minutes versus 38 minutes), according to polysomnography. Similar improvements occurred with the higher dose of ramelteon (31 minutes). These differences were statistically significant.
Patients' subjective assessments of sleep latency were significantly different between those taking the 4-mg/night dose of ramelteon and those taking placebo (48 min vs. 58 min). However, patients taking the 8-mg/night dose reported it took them 51 minutes to fall asleep, which was not statistically different from results seen with placebo.
“Another positive finding was improvement in total sleep time. It could be an effect of them falling asleep quicker,” Dr. Seiden said. During the placebo phase, participants slept a mean of 350 total minutes, according to polysomnography. Total sleep time increased to 359 minutes at the 4-mg dose of ramelteon and 362 minutes at the 8-mg dose.
There were no consistent differences in wake time after sleep onset or number of nighttime awakenings between the two treatment groups.
“This drug has a really well tolerated side effect profile,” said Dr. Seiden, who has no financial affiliation with the company.
The most commonly reported adverse events were headache and nausea. Overall incidence of adverse events was similar between placebo (9%), ramelteon 4 mg (14%), and ramelteon 8 mg (7%) groups.
Dr. Seiden noted that the developer of ramelteon, Takeda Pharmaceuticals North America Inc., is currently looking at additional applications for the drug, including jet lag and shift work disorders.