DENVER – The novel melatonin receptor agonist ramelteon was associated with significant reductions in the time it took to fall asleep in two phase III clinical trials totaling 1,234 adults with primary insomnia, investigators reported at the annual meeting of the Associated Professional Sleep Societies.
The recently approved drug accomplished this while maintaining a reassuring safety profile. Testing revealed no next-day effects on residual memory or psychomotor function, and no rebound insomnia upon discontinuation of ramelteon.
Moreover, unlike most sedative-hypnotics, which are classified as schedule IV controlled substances, ramelteon appears to lack abuse potential. It also lacks the generalized CNS depressant effects characteristic of traditional sedative-hypnotics, making it an attractive agent for treating insomnia in patients with chronic obstructive pulmonary disease (COPD), according to studies presented at the meeting.
Thomas Roth, Ph.D., explained that ramelteon differs from the endogenous hormone melatonin in that ramelteon is highly specific for the melatonin receptors MT1 and MT2 involved in the sleep-wake cycle; indeed, ramelteon has up to a 16-fold greater affinity for those sites than melatonin itself. And unlike melatonin, it has no serotoninergic metabolites. Ramelteon has low affinity for the MT3 receptor and other CNS binding sites, including the benzodiazepine, opioid, muscarinic, dopamine, and γ-aminobutyric acid receptors.
Dr. Roth presented a randomized, double-blind, placebo-controlled trial of ramelteon in 829 elderly patients with chronic insomnia. The results were similar to those seen in a separate phase III double-blind trial presented by Gary Zammit, Ph.D., involving 405 younger adults–mean age 39 years–with chronic insomnia. Both trials lasted for 5 weeks.
From the very beginning of both trials, the time it took for subjects to fall asleep was significantly less with ramelteon than with placebo, according to Dr. Zammit, director of the Sleep Disorders Institute at St. Luke's-Roosevelt Hospital, New York.
Headache, somnolence, and fatigue were roughly twice as common with ramelteon.
Takeda Pharmaceutical Co. filed for marketing approval of ramelteon with an insomnia indication last fall; in July it was approved by the Food and Drug Administration. But physicians will need a bit of experience with the drug to learn how to effectively use an agent with such subtle effects, according to Dr. Roth of Wayne State University, Detroit.
“Ramelteon has a significant effect upon sleep induction, yet it is not sedative. That's a unique thing in the sleep arena. It's going to be a clinical challenge, much like physicians faced when nonsedating antianxiety agents became available. People had treated anxiety for many, many years with sedating drugs, and one of the early clues an antianxiety agent was working was that the patient felt sleepy. The same issue arose when the nonsedating antihistamines came along,” he noted.
In another randomized double-blind study, Stephen Sainati, M.D., Ph.D., reported on 26 patients with mild to moderate COPD.
They received 16 mg of ramelteon or placebo ½ hour before bedtime and were monitored overnight using pulse oximetry and respiratory inductance plethysmography. Patients crossed over to the other study arm after a 5- to 12-day washout.
The primary end point was mean arterial oxygen saturation. It was unchanged throughout the night with ramelteon. That's welcome news, since traditional sedative-hypnotics have a respiratory-depressant effect. The clinical relevance of the absence of such an effect with ramelteon lies in the fact that insomnia is roughly threefold more prevalent in COPD patients than the general population, according to Dr. Sainati of the Takeda Global Research and Development Center, Lincolnshire, Ill.
All of these studies were sponsored by Takeda.