Medication Summary
Before any medications are prescribed, the first priority should be to determine the underlying cause of the sleep disorder, rather than just treat insomnia symptomatically. Usually, treatment on a short-term basis together with sleep hygiene is appropriate for transient insomnia, such as insomnia secondary to bereavement or acute hospitalization. Medications used for insomnia in this population include antidepressants, nonbenzodiazepines, a melatonin agonist, and herbals. Medications, if used, should be started with a low dose and monitored for side effects. [40]
Medications for sundown syndrome
There are several medications used in the treatment of sundowning including melatonin, antipsychotics, antidepressants, benzodiazepines, and cannabinoids. While commonly used, there is little evidence to suggest benefits associated with the use of benzodiazepines and cannabinoids, and due to the significant negative side effects associated, the use of these agents should be avoided. [41, 42] Antipsychotics are commonly used and are recommended as possible treatments in national guidelines, yet there are only limited data that show minimal benefits for these patients. [43, 44] There have been few double-blind, randomized controlled trials evaluating the use of exogenous melatonin. [45] Overall, these studies show some behavioral improvement with extended use. [46] Melatonin dosage widely varied in these studies between 1.5 mg and 10 mg. Several non-pharmacological strategies have been used and have shown to have some beneficial impact on circadian rhythm and possibly nighttime behavioral disturbances in patients with dementia including physical exercise, [47, 48] aromatherapy, [49] music therapy, [50] and bright light therapy. [51] Three treatment principles are suggested when considering treatments for sundown syndrome: (1) the treatment process is a trial-and-error approach, (2) start with lower dosages and slowly titrate upwards, and (3) multi-component therapy (non-pharmacological and pharmacological) may be indicated. [52] Further investigation of non-pharmacological and pharmacological-targeted strategies would be of benefit. [53]
Sedative/Hypnotics
Class Summary
Barbiturates are not indicated for insomnia, and psychiatric consultation may become necessary for patients receiving barbiturates for many years. Barbiturates are effective only for short-term use, losing much of their effectiveness after 2 weeks of administration. According to the American Geriatrics Society (AGS) 2012 Updated Beers Criteria for Potentially Inappropriate Medications Use in Older Adults, barbiturates should be avoided because of the high risk of overdose, even at low dosages, and of physical dependence. [54] Chloral hydrate should also be avoided in older adults because of tolerance within just 10 days of treatment and risk of overdose with doses just 3 times the therapeutic dose.
Benzodiazepines remain the most commonly prescribed agents for sleep, although users of benzodiazepines tend to report poorer quality of sleep than nonusers. [55, 56] According to the 2012 AGS Beers criteria, [54] all benzodiazepines (short-, intermediate-, and long-acting) should not be used for insomnia in older adults. They can increase the risk of cognitive and psychomotor impairments, falls, fractures, and motor vehicle accidents. Use of benzodiazepines in older adults should be limited to other specific indications such as seizure disorders, REM sleep disorders, benzodiazepine or alcohol withdrawal, severe generalized anxiety disorder, periprocedural anesthesia, and end-of-life care. In 2006 Medicare part D excluded benzodiazepines from drug coverage.
The newer nonbenzodiazepine hypnotics zolpidem, zaleplon, and eszopiclone do not cause rebound insomnia or withdrawal symptoms at discontinuation but can have adverse effects similar to benzodiazepines (delirium, falls, and fractures). In a recent case-cross over study of nursing home residents the nonbenozdiazepine hypnotics were associated with increased risk of hip fracture (OR 1.66) and the risk was even higher for new user (OR 2.20) and residents with cognitive impairment (OR 1.86). [57] These hypnotics should we used with caution in older adults and for no longer than 90 days, [54] even if eszopiclone is approved for prolonged use.
Particular caution should be used in patient with dementia, according to a Cochrane systematic review, there is a lack of randomized controlled trials of benoziazepine or non-benzodiazepine hypnotics in patient with Alzheimer's dementia (AD). Studies of melatonin, either immediate- or slow-realese, did not show an improvement of sleep parameters in patients with AD while a small randomized trial of trazodone 50 mg qHS for two weeks improved nocturnal total sleep time and sleep efficency without serious side effects. [58]
Zolpidem (Ambien, Edluar, ZolpiMist)
Zolpidem is structurally dissimilar to benzodiazepines but similar in activity, with the exception of having reduced effects on skeletal muscle and seizure threshold. At recommended doses, it is as effective as triazolam. Adverse CNS effects (eg, nightmares, agitation, drowsiness) have been noted in 10% of patients. In May 2013 the FDA warned that patients taking zolpidem extended release (6.25 mg or 12.5 mg) should not drive or engage in other activities that require full alertness the day after taking the drug. As with benzodiazepine hypnotics, zolpidem is approved only for short-term use (maximum, 3-4 weeks); if used longer, they should be used for only 2-3 nights per week and for no more than 3 months.
According to the 2012 AGS Beers Criteria zolpidem should be avoided in patients with dementia and cognitive impairment because of adverse CNS effects.
Zaleplon (Sonata)
Zaleplon is a short-acting pyrazolopyrimidine hypnotic with full agonistic activity on central benzodiazepine receptors (B21 type). It has a short half life (1 hour) and at small doses, it is an effective sleep inducer. It is approved only for short-term use (maximum, 3-4 weeks); if used longer, it should be limited to only 2-3 nights per week and for no more than 3 months.
Eszopiclone (Lunesta)
Eszopiclone is a nonbenzodiazepine hypnotic pyrrolopyrazine derivative of the cyclopyrrolone class. The precise mechanism of action is unknown but is believed to be an interaction with the GABA-receptor at binding domains close to or allosterically coupled to benzodiazepine receptors. It is indicated for insomnia to decrease sleep latency and improve sleep maintenance. Eszopiclone has a short half-life, of 6 hours. Higher doses (ie, 2 mg for elderly adults and up to 3 mg for nonelderly adults) are more effective for sleep maintenance, whereas lower doses (ie, 1 mg) are suitable for difficulty in falling asleep.
Antidepressants
Class Summary
Sedating antidepressants like trazodone and mirtazapine in low doses are often prescribed at bedtime for insomnia. Little scientific evidence supports efficacy in the treatment of insomnia without associated depression; their use in patients with insomnia without depression is not FDA approved and should be considered off-label use. Doxepin is the only antidepressant, which, at a very low dose, is FDA approved for insomnia.
Doxepin (Silenor)
Doxepin at low doses (1, 3, and 6 mg) is a selective histamine antagonist (primarily H1 receptor) and is FDA approved for insomnia. Recent studies have shown that low-dose doxepin improves sleep parameters in older adults with a safety profile comparable to placebo. [25, 26] Higher doses of doxepin should be avoided in older adults because of high anticholinergic side effects. [22] Avoid in patients with glaucoma or urinary retention.
Mirtazapine (Remeron)
Mirtazapine exhibits both noradrenergic and serotonergic activity. In cases of depression associated with severe insomnia and anxiety, mirtazapine has been shown to be superior to other SSRIs.
Trazodone (Oleptro)
Trazodone is an antagonist at the 5-HT2 receptor and minimally inhibits the reuptake of 5-HT. It has negligible affinity for cholinergic and histaminergic receptors. Trazodone is not associated with tolerance or withdrawal effects but it may prolong the QTc interval. Associated orthostatic hypotension can be minimized by administration with food. Limited data exist regarding efficacy in patients who are not depressed, and the FDA has not approved trazodone as a hypnotic.
Melatonin Agonists
Class Summary
Melatonin agonists may promote sleep.
Ramelteon (Rozerem)
Ramelteon is a melatonin receptor agonist with high selectivity for human melatonin MT1 and MT2 receptors. MT1 and MT2 are thought to promote sleep and be involved in maintaining circadian rhythm and a normal sleep-wake cycle. Ramelteon does not cause rebound insomnia or withdrawal symptoms at discontinuation. It is approved for prolonged use. It is indicated for insomnia characterized by difficulty with sleep onset.
Orexin Receptor Antagonists
Class Summary
Orexin promotes wakefulness. Antagonism of the orexin receptor suppresses this action by orexin.
Suvorexant (Belsomra)
Suvorexant is an orexin receptor antagonist. The orexin neuropeptide signaling system is a central promoter of wakefulness. Blocking the binding of wake-promoting neuropeptides orexin A and orexin B to receptors OX1R and OX2R by suvorexant is thought to suppress wake drive. It is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance.
