Effect of Administration of Ramelteon, a Melatonin Receptor Agonist, on the Duration of Stay in the ICU

A Single-Center Randomized Placebo-Controlled Trial

Mitsuaki Nishikimi, MD; Atsushi Numaguchi, MD; Kunihiko Takahashi, PhD; Yasuhiro Miyagawa, PhD; Kota Matsui, MA; Michiko Higashi, MD; Go Makishi, MD; Shigeyuki Matsui, PhD; Naoyuki Matsuda, MD, PhD


Crit Care Med. 2018;46(7):1099-1105. 

In This Article

Abstract and Introduction


Objectives: Occurrence of delirium in the ICU is associated with a longer stay in the ICU. To examine whether the use of ramelteon, a melatonin agonist, can prevent delirium and shorten the duration of ICU stay of critically ill patients.

Design: A single-center, triple-blinded, randomized placebo-controlled trial.

Setting: ICU of an academic hospital.

Patients: Eligible patients were ICU patients who could take medicines orally or through a nasogastric tube during the first 48 hours of admission.

Interventions: The intervention group received ramelteon (8 mg/d), and the control group received placebo (1 g/d of lactose powder) at 20:00 hours every day until discharge from the ICU.

Measurements and Main Results: A total of 88 subjects were randomized to the ramelteon group (45 subjects) or the placebo group (43 subjects). As the primary endpoint, there was a trend toward decrease in the duration of ICU stay (4.56 d) in the ramelteon group compared with the placebo group (5.86 d) (p = 0.082 and p = 0.028 before and after adjustments). As the secondary endpoints, statistically significant decreases in the occurrence rate (24.4% vs 46.5%; p = 0.044) and duration (0.78 vs 1.40 d; p = 0.048) of delirium were observed in the ramelteon group. The nonintubated patients of the ramelteon group showed statistically significantly fewer awakenings per night and a higher proportion of nights without awakenings.

Conclusions: Ramelteon tended to decrease the duration of ICU stay as well as decreased the occurrence rate and duration of delirium statistically significantly.


Melatonin, a substance synthesized in the pineal gland, exhibits pleiotropic physiologic actions,[1] and several recent studies have demonstrated a variety of effects of melatonin in vivo, including antioxidant and anti-inflammatory effects, as well as an effect on regulation of the circadian rhythm. Although the melatonin secretion rhythm has been shown to be severely depressed in patients admitted to the ICU because of various environmental factors as well as factors related to the patients' life-threatening conditions themselves and the drugs used,[2–4] few studies have been conducted yet to determine whether exogenous melatonin administration in the ICU can improve the outcomes in critically ill patients.[5,6]

One of the most well-known functions of melatonin is to prevent delirium in critically ill patients.[7,8] Delirium is an undesirable, but frequently encountered manifestation in ICU patients,[9] and is known to be associated with worse outcomes,[9,10] including longer ICU stay,[11] higher mortality rate,[12] longer time on the ventilator,[13] and higher ICU and hospital costs.[14] Considering that recent randomized controlled clinical trials have indicated that melatonin can prevent delirium,[15–17] we considered that prophylactic administration of melatonin or melatonin agonists may shorten the duration of ICU stay and improve the outcomes in critically ill patients.

Therefore, we performed this single-center, triple-blinded, randomized placebo-controlled trial to examine whether prophylactic administration of ramelteon, a selective melatonin receptor agonist, is effective for shortening the duration of ICU stay in critically ill patients. As secondary endpoints, we measured the mortality rate and the occurrence rate and duration of delirium in ICU patients. To the best of our knowledge, this is the first randomized controlled clinical trial conducted exclusively in ICU patients to determine whether prophylactic administration of ramelteon can shorten the duration of ICU stay and decrease the occurrence rate of delirium in ICU patients.