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Randomized Controlled Trial
, 33 (6), 825-31

Effects of the Melatonin MT-1/MT-2 Agonist Ramelteon on Daytime Body Temperature and Sleep

Affiliations
Randomized Controlled Trial

Effects of the Melatonin MT-1/MT-2 Agonist Ramelteon on Daytime Body Temperature and Sleep

Rachel R Markwald et al. Sleep.

Abstract

Study objectives: A reduction in core temperature and an increase in the distal-proximal skin gradient (DPG) are reported to be associated with shorter sleep onset latencies (SOL) and better sleep quality. Ramelteon is a melatonin MT-1/MT-2 agonist approved for the treatment of insomnia. At night, ramelteon has been reported to shorten SOL. In the present study we tested the hypothesis that ramelteon would reduce core temperature, increase the DPG, as well as shorten SOL, reduce wakefulness after sleep onset (WASO), and increase total sleep time (TST) during a daytime sleep opportunity.

Design: Randomized, double-blind, placebo-controlled, cross-over design. Eight mg ramelteon or placebo was administered 2 h prior to a 4-h daytime sleep opportunity.

Setting: Sleep and chronobiology laboratory.

Participants: Fourteen healthy adults (5 females), aged (23.2 +/- 4.2 y).

Measurements and results: Primary outcome measures included core body temperature, the DPG and sleep physiology (minutes of total sleep time [TST], wake after sleep onset [WASO], and SOL). We also assessed as secondary outcomes, proximal and distal skin temperatures, sleep staging and subjective TST. Repeated measures ANOVA revealed ramelteon significantly reduced core temperature and increased the DPG (both P < 0.05). Furthermore, ramelteon reduced WASO and increased TST, and stages 1 and 2 sleep (all P < 0.05). The change in the DPG was negatively correlated with SOL in the ramelteon condition.

Conclusions: Ramelteon improved daytime sleep, perhaps mechanistically in part by reducing core temperature and modulating skin temperature. These findings suggest that ramelteon may have promise for the treatment of insomnia associated with circadian misalignment due to circadian sleep disorders.

Figures

Figure 1
Figure 1
Protocol timeline Protocol events were scheduled according to habitual bed and wake times. The example shows a protocol for a participant with a habitual wake time of 07:00. Participants were admitted to the laboratory ∼1 h 50 min after their scheduled wake time. Pill administration is denoted by the arrow and occurred 2 h after admission and 2 h prior to the 4-h sleep opportunity.
Figure 2
Figure 2
Thermoregulatory effects of ramelteon on core body temperature, the DPG, and proximal and distal skin temperature sites. Values expressed as means ± SEM. The open circles represent the ramelteon condition and closed circles represent the placebo condition. The 0 point denotes time that ramelteon or placebo were administered. (A) The melatonin agonist, ramelteon significantly reduced core temperature by attenuating the normal daytime circadian rise as seen in placebo. (B) The DPG was increased after ramelteon ingestion relative to placebo. (C) Proximal skin temperature measured at the subclavian vein (Tsub) (D) Distal skin temperature measured at the dorsal foot (Tft).
Figure 3
Figure 3
Correlation between SOL and DPG. SOL (3 continuous epochs to sleep) and DPG were correlated such that a greater change in DPG was associated with a shorter SOL in the ramelteon condition (B) compared to placebo condition (A). The lines represent the best linear fit through the data.

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