Circadian phase-shifting effects of repeated ramelteon administration in healthy adults

To assess the ability of repeated daily oral ramelteon to facilitate re-entrainment of human circadian rhythms after an imposed phase advance of the sleep-wake cycle. A total of 75 healthy adult volunteers aged 18-45 years remained in a sleep laboratory for 6 days and 5 nights; a 5-h phase advance i...

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Bibliographic Details
Published in:Journal of clinical sleep medicine 2008-10, Vol.4 (5), p.456-461
Main Authors: Richardson, Gary S, Zee, Phyllis C, Wang-Weigand, Sherry, Rodriguez, Laura, Peng, Xuejun
Format: Article
Language:English
Subjects:
Administration, Oral
Adolescent
Adult
Circadian Rhythm - drug effects
Dose-Response Relationship, Drug
Double-Blind Method
Female
Humans
Indenes - adverse effects
Indenes - pharmacology
Male
Melatonin - blood
New Research
Polysomnography - drug effects
Sleep - drug effects
Young Adult
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Summary:To assess the ability of repeated daily oral ramelteon to facilitate re-entrainment of human circadian rhythms after an imposed phase advance of the sleep-wake cycle. A total of 75 healthy adult volunteers aged 18-45 years remained in a sleep laboratory for 6 days and 5 nights; a 5-h phase advance in their sleep-wake cycle was imposed under dim-light conditions. Oral ramelteon (1,2, 4, or 8 mg once daily for 4 days) or placebo was administered 30 min before bedtime. The primary endpoint was the phase of the circadian rhythm as assessed by the time at which salivary melatonin concentrations declined below 3 pg/mL after morning awakening (dim-light melatonin offset [DLMoff]). After 4 days of once-daily treatment, participants receiving 1, 2, or 4 mg ramelteon exhibited statistically significant phase shifts in DLMoff of -88.0 (16.6), -80.5 (14.8), and -90.5 (15.2) minutes respectively, versus -7.1 (18.6) minutes for placebo (least-squares mean(SEM), p = 0.002, p = 0.003, p = 0.001, respectively). Change in DLMoff for the 8 mg dose of ramelteon, -27.9 (16.4) minutes, was not significantly different than that for placebo (p = 0.392). Ramelteon (1, 2, or 4 mg per day) administered before bedtime significantly advanced the phase of the circadian rhythm after a 5-h phase advance in the sleep-wake cycle. These findings suggest that ramelteon has potential as a specific therapy for circadian rhythm sleep disorders.
ISSN:1550-9389
1550-9397
DOI:10.5664/jcsm.27282