By: Dr. Geoffrey Modest
There have been a few articles looking at melatonin and one of its derivatives to decrease the development of delirium in hospitalized patients (thanks to my brother Andrew for bringing this to my attention). Delirium, from many studies, is common (30% of those hospitalized who are over 65 yo, 40% in those in ICU, and is often underdiagnosed). One article looked at ramelteon, a melatonin agonist with high affinity for the MT1 and MT2 receptors (more potent than melatonin by 6-fold and 3-fold, respectively, so that comparing 8mg of ramelteon has, for example, a 16- and 8-fold increased potency vs 3mg of melatonin) — see JAMA Psychiatry. 2014;71(4):397-403).
Details of this study:
–67 patients (mean age 78, 40% male, with most admitted with either stroke, infection, or fracture) from 4 university hospitals and 1 general hospital in Japan.
–24 patients in ICUs and 43 on hospital wards were randomly assigned to ramelteon 8mg/d vs placebo nightly for 7 nights
Results:
–-ramelteon was associated with a lower risk of delirium (1 vs 11 patients: 3% vs 32%, p=0.003) with RR 0.09 (0.01-0.69). the effect was evident within 2-3 days of admission
–controlling for risk factors (age, diagnosis of dementia, admission diagnosis of infection), ramelteon still significantly associated with decreased delirium risk [P=0.01, odds ratio 0.07 (0.008-0.54)]
–there were no differences in any of the sleep parameters in those on ramelteon (difficulty falling asleep, staying asleep, early awakening, sleep quality or duration), though more in the placebo group did get hydroxyzine, which has weak anticholinergic effects, for sleep (though, controlling for the use of hydroxyzine, there still was a significant benefit of ramelteon on delirium). so, it does not seem that sleep deprivation had a significant role in the occurrence of delirium
–subgroup analysis showed ramelteon’s benefits were even in those without prior history of delirium. (too few patients in sample with history of delirium to see any difference)
–adverse events potentially attributable to drug: zero — though other studies on ramelteon have shown slight increases in somnolence (5% vs 3%), dizziness (5% vs 3%) and fatigue (4% vs 2%)
This was a pretty benign intervention in a small number of patients but with pretty dramatic outcome, especially since the only other medications showing any benefit in some studies are antipsychotics that have lots of adverse effects. Trials of cholinesterase inhibitors (eg donepezil) mostly produce just adverse effects. other studies on ramelteon confirm its benefit in sleep-promotion in the elderly, at both the 4 and 8mg dosages (likely related to restoring the otherwise decreasing endogenous melatonin levels with aging). Other small RCTs have found some benefit of melatonin at doses of 3mg, 5mg, and 10mg in restoring circadian rhythms in ICU patients and decreasing delirium in medical or elective surgical patients. The main issues with this ramelteon study is the small sample size, some differences in those with baseline dementia (24% in the placebo group and 15% in those on ramelteon), and lack of breakdown of which patients were in the ICU vs the wards (though there was no difference in the APACHE scores, Charlson comorbidity index, or performance status of the randomized patients)
Bottom line:
–there seems to be some utility of melatonin or derivatives (ramelteon) in restoring circadian rhythm, sleep and preventing delirium in hospitalized patients
–the big issue to me with melatonin is that it is a “supplement”, not subject to the FDA regulation, and there have been dramatic differences found in the actual amount of melatonin in the advertised doses.
–the average wholesale price of ramelteon (which is not available as a generic) is $333 for 30 pills and requires a prior approval from medicaid …. so, will stick with melatonin for now.