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

Abstract

Study objectives: 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.

Methods: 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]).

Results: 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).

Conclusions: 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.

Figures

Figure 1

Changes from baseline in DLMoff during each of the 4 days of double-blind administration of study drug for placebo, ramelteon 8 mg, ramelteon 4 mg, ramelteon 2 mg, and ramelteon 1 mg. Values shown are the least-square means (SE) with standard error bars obtained from ANCOVA. The number of subjects with evaluable DLMoff data for each time point was: Day 1–placebo (9), 8 mg (10), 4 mg (13), 2 mg (14), 1 mg (11); Day 2–placebo (10), 8 mg (11), 4 mg (13), 2 mg (14), 1 mg (11); Day 3–placebo (10), 8 mg (11), 4 mg (11), 2 mg (13), 1 mg (11); Day 4–placebo (10), 8 mg (11), 4 mg (13), 2 mg (14), 1 mg (11).