Background: Insomnia is a common sleep disorder with a significant potential for deleterious effects on activities of daily living, productivity, and overall quality of life. Ramelteon, a highly selective agonist for melatonin subtypes 1 and 2 receptors, is a hypnotic agent approved by the US Food and Drug Administration (FDA) for the treatment of insomnia characterized by difficulty falling asleep.
Objective: This article reviews the pharmacokinetic properties, efficacy, and tolerability of ramelteon in the treatment of insomnia characterized by difficulty falling asleep.
Methods: Relevant articles were identified through searches of MEDLINE (1966 to July 2006), International Pharmaceutical Abstracts (January 1970 to July 2006), EMBASE Drugs and Pharmacology (1980 to third quarter 2006), and Current Contents/Clinical Medicine (2005 week 32 to 2006 week 31). Search terms included ramelteon, TAK-375, melatonin agonist, melatonin receptor agonist, insomnia, and sleep disorders/drug therapy (MeSH).
Results: A literature search revealed 12 randomized, controlled clinical trials that examined the efficacy or tolerability of ramelteon. In addition, 17 studies were reviewed for pharmacology and pharmacokinetic data. The references of the clinical trials and recent review articles were examined to ensure the comprehensiveness of the literature search. In 2 trials of patients with primary insomnia, patients treated with ramelteon 4 to 32 mg had significant reductions in latency to persistent sleep (LPS) compared with placebo (P < 0.001). Additionally, improvements in total sleep time (TST) were observed (P < 0.001), although increases in TST were noted only on nights 1-2 of the second study. Similarly, improvement in sleep efficiency was reported only on nights 1-2 of the second trial (P < 0.001). In elderly patients with primary insomnia, significant reductions in subjective LPS were observed with ramelteon 4 and 8 mg (P = 0.008); however, average subjective LPS was >70 minutes. Mean reported TST was significantly increased in the 4-mg group (P = 0.004). A second study in elderly patients found decreases in LPS with ramelteon 4 mg (P < 0.001) and 8 mg (P < 0.01), as well as significant increases in TST (P < 0.05 and P < 0.01, respectively). Sleep efficiency improved for patients treated with 4 mg (P < 0.05) and 8 mg (P < 0.01). Overall, the mean decrease in LPS reported in trials of ramelteon ranged from 10 to 19 minutes, and the mean increase in TST was 8 to 22 minutes. The most common adverse events observed with ramelteon included headache (7%), dizziness (5%), somnolence (5%), fatigue (4%), and nausea (3%). No evidence of cognitive impairment, rebound insomnia, withdrawal effects, or abuse potential was noted.
Conclusions: Based on this review, ramelteon, the first FDA-approved melatonin receptor agonist, represents a pharmacologic option for the treatment of insomnia characterized by difficulty falling asleep. In patients with insomnia, treatment with ramelteon was generally well tolerated and resulted in modest but statistically significant decreases in LPS. In the absence of published trials comparing ramelteon with other sedative-hypnotic agents, it is not yet possible to determine its efficacy relative to other therapeutic options for insomnia.