Review question:

What is the effectiveness of pharmacotherapies for sleep disturbances in Alzheimer’s disease?

Nursing Implications:

People who have Alzheimer’s disease often have disturbed sleep which can burden family carers and increase the likelihood of institutionalisation. Treatment for this problem typically involves the use of pharmacotherapy. Nurses need to understand the benefits and risks of pharmacotherapy for sleep disturbances in Alzheimer’s disease given the frailty and vulnerability of patients with this disease.

Review Characteristics:

Five trials with 313 participants investigated the benefits and risks of any medication compared with a placebo. This included three trials that investigated the effects of melatonin and one trial each of trazodone and ramelteon. Melatonin, a hormone found in humans can be taken as a supplement to induce sleep and improve sleep quality. Trazodone is a tetracyclic antidepressant that has sedative effects found to be useful for the treatment of insomnia. Ramelteon is a melatonin receptor agonist used for the treatment of insomnia, particularly delayed sleep onset. The participants in the melatonin and trazodone trials had moderate to severe Alzheimer’s disease, whereas the ramelteon trial was conducted for people with mild to moderate Alzheimer’s disease. In all five studies, the participants had a variety of common sleep disturbances and the primary sleep outcomes were objectively measured with actigraphy.

Summary of Key Evidence:

• Melatonin: There was no evidence to indicate that either immediate or slow-release melatonin improved sleep (n=209). Data was synthesized for two outcomes: total night time sleep between 8.00 pm and 8.00 am (mean difference (MD) 10.68 minutes, 95% confidence interval (CI) -16.22 to 37.59, two studies n=184) and the ratio of daytime sleep to night-time sleep over 24 hours (MD -0.13 minutes, 95% CI -0.29 to 0.03, two studies n=184). No significant difference was found between the intervention and control groups for sleep efficiency (percentage of time spent sleeping in bed), time awake after sleep onset and before final awakening, night time awakenings, cognition or performance in activities of daily living (ADLs). No serious adverse effects were reported.
• Ramelteon: One trial of 74 participants reported on Ramelteon (8 mg) administered at night. There was no effect on night-time sleep and there were few significant differences from placebo for any sleep, behavioural or cognitive outcomes, but these were not of clinical significance. There were no serious adverse effects reported.
• Trazodone: A low dose of Trazodone (50mg) was administered at night for two weeks (n=30). Trazodone significantly improved total night-time sleep (MD 42.46 minutes, 95% CI 0.9 to 84.0) and sleep efficiency (MD 8.53, 95% CI 1.9 to 15.1). But there was no evidence for its effect on the amount of time spent awake after sleep onset and before final wakening (MD -20.41, 95% CI -60.4 to 19.6), or the number of night-time awakenings (MD -3.71, 95% CI -8.2 to 0.8). No effect was noted for daytime sleep, cognition or ADLs. No serious adverse effects were reported.

Best Practice Recommendations:

There is insufficient evidence that pharmacotherapies are effective for sleep disturbances in Alzheimer’s disease. Trazodone may be useful for people with moderate to severe Alzheimer’s disease, but larger trials are needed to support any recommendations. What is particularly concerning is the lack of evidence for other medications that are commonly prescribed for sleep disturbances in Alzheimer’s disease such as benzodiazepines and anti-psychotics, as these can have serious side effects such as drowsiness, amnesia and confusion leading to falls. Therefore extreme caution and vigilance must be exercised when any of these medications are in use.

Summary Author

Christine Neville, PhD, RN, FACMHN

Associate Professor
The University of Queensland, School of Nursing and Midwifery

A member of the Cochrane Nursing Care Field (CNCF)