Objective: To review the prospective controlled trials available for the use of melatonin receptor agonists for delirium prevention. Data Sources: A MEDLINE literature search (1946 to July 2016) was conducted using the search terms delirium, melatonin, ramelteon, tryptophan, and melatonin-receptor agonist. Prospective controlled clinical trials with delirium prevention as an outcome were included. The references of identified articles were reviewed to identify other relevant articles. Study Selection and Data Extraction: Controlled clinical trials in humans, limited to the English language, were reviewed. Five randomized and 1 nonrandomized prospective controlled clinical trial exploring the use of melatonin receptor agonists for delirium prevention were evaluated. Data Synthesis: Melatonin agonist therapy for delirium prevention has produced conflicting results in clinical trials. Delirium incidence ranged from no change to significant reductions of approximately 12% to 30%. Four trials were conducted with melatonin as the investigated agent, 1 with l-tryptophan, and 1 with ramelteon. The study setting also varied, with 4 trials being conducted in surgical patients and 2 trials in medical patients. Melatonin provided conflicting results, with 3 trials showing decreased delirium incidence and the largest randomized controlled trial showing no benefit. No benefit was found using l-tryptophan in delirium prevention. The single, small ramelteon trial showed decreased delirium incidence. Safety evaluations during trials were limited. Three trials found adverse effects similar to placebo, whereas the remaining 3 trials did not evaluate adverse effects. Conclusions: The routine use of melatonin receptor agonists for delirium prevention cannot be recommended at this time.
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