Melatonin for delirium prevention in hospitalized patients: A systematic review and meta-analysis

Background and aims: Melatonin, a pineal gland hormone is reported to have a protective effect against delirium. This systematic review and meta-analysis explores the effect of melatonin and melatonin receptor agonist, ramelteon on delirium prevention in adult hospitalized patients.

Methods: Randomized Controlled trials of melatonin/ramelteon published up to May 7, 2020 were identified from MEDLINE, PREMEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled trials, PubMed, and Google Scholar. The primary outcome was delirium incidence. The secondary outcomes were sleep quality, sedation score, sedatives requirement, delirium duration, length of hospital stay, length of Intensive Care Unit (ICU) stay, mortality and adverse events. A meta-analysis with a random-effects models was performed. Estimates were presented as Risk Ratio (RR) or Mean Differences (MD) with 95% Confidence Interval (CI).

Findings: Fourteen studies with 1712 participants were included. Melatonin/ramelteon significantly reduced delirium incidence (RR 0·61, 95% CI 0·42-0·89, p 0·009) with risk reduction of 49% in surgical patients and 34% in ICU patients. Non-significant reduction was found in medical patients. Melatonin/ramelteon were associated with improvement in sleep quality, increased sedation score and lower sedatives consumption. However, they did not reduce delirium duration, length of hospital stay, length of ICU stay and mortality. Hallucinations, nightmares and gastrointestinal disorders were prevalent in melatonin group.

Interpretation: Melatonin/ramelteon are associated with reduction in delirium incidence in hospitalized patients. However, this effect seems confined to surgical and ICU patients. The optimum dosage and formulation of melatonin, and treatment duration remain uncleared and open to further studies with larger sample sizes.