FDA-approved Nonbenzodiazepine Receptor Agonists for the Management of Insomnia

Jon P. Wietholter, PharmD, BCPS; Renier Coetzee, BPharm, MPharm, PharmD

Disclosures

US Pharmacist. 2017;42(1):29-32. 

In This Article

FDA-approved Pharmacotherapy

Treatment goals of insomnia should center on improving sleep quality and quantity and minimizing insomniarelated impairments.[14] Knowledge of potential pharmacotherapeutic options is pertinent for every pharmacist. Previous guidelines mentioned benzodiazepine receptor agonists (BZDRAs; i.e., temazepam, zolpidem, eszopiclone, zaleplon) as potential first-line options for the management of insomnia.[14] However, other guidelines suggest only short-term use of these agents on a case-by-case basis due to their significant adverse-effect profiles.[15] BZDRAs are controlled substances and can lead to significant adverse effects that include but are not limited to cognitive impairment, falls/fractures, delirium/dementia, anterograde amnesia, altered sleep activities (e.g., sleep-eating, sleepdriving, sleep-walking), and carryover sedation.[2,11,15] Because of these concerns, many clinicians and patients prefer options that work outside the BZDRA mechanism of action. The following is a review of agents that work via non-BZDRA mechanisms and are FDA-approved for the management of insomnia. Dosing recommendations for each agent are contained in Table 1.

Diphenhydramine and Doxylamine

It is estimated that >60% of pharmacotherapy for insomnia is via nonprescription medications.[2] Diphenhydramine (e.g., Sominex) and doxylamine (e.g., Unisom SleepTabs) are firstgeneration antihistamines that work via competition with histamine at H1 receptors as inverse agonists. They exert their mechanism centrally, which leads to drowsiness and their potential effectiveness in the management of insomnia. Both OTC agents have carried historical FDA approval as safe and effective options for the management of insomnia for over 25 years, but their utility in this patient population is still controversial due to a dearth of large, well-designed trials.[11,16] Additionally, rapid tolerance to their sedative effects renders them ineffective for chronic use. Small studies of diphenhydramine have suggested significant improvements in overall sleep time, efficacy, latency, and nighttime awakenings, while others contradict these findings.[17–20]

Contrary to diphenhydramine, doxylamine lacks even small studies directly confirming its efficacy in the management of insomnia. From an adverse-effect standpoint, these agents can cause confusion, carryover sedation, urinary retention, and multiple other anticholinergic effects due to muscarinic receptor antagonism.[21] These effects are particularly concerning in the elderly, and the 2015 Beers criteria update gave a "strong" recommendation to avoid both agents in elderly patients.[22] Additionally, patients with glaucoma, thyroid disorders, chronic respiratory diseases, cardiovascular disease, benign prostatic hyperplasia (BPH), or significant urinary retention should use these agents cautiously or completely avoid their use. Due to the relative lack of efficacy data and significant adverse-effect profiles, diphenhydramine and doxylamine are not currently recommended as routine options in the management of insomnia.[14,15,21]

Doxepin

Doxepin (Silenor) is a tricyclic antidepressant with central H1-receptor antagonism that produces a sedative effect. While it has been utilized as an antidepressant for over 50 years, it only gained FDA approval for the treatment of insomnia in 2010.[23] The ability to use low doses (≤6 mg) for insomnia is derived from its high selectivity for histamine receptors.[21] Multiple studies evaluating doxepin's safety and efficacy in the management of insomnia have summarized that doxepin significantly improves Insomnia Severity Index (ISI) scores and also improves sleep duration, maintenance, and efficiency when compared to placebo.[11,21,23,24]

Regarding adverse effects, somnolence was the most commonly noted, with dizziness, nausea, upper respiratory tract infections, nasopharyngitis, hypertension, and headache all also being documented.[23,24] Additionally, doxepin is contraindicated in patients with glaucoma or severe urinary retention and should be used cautiously in patients with concomitant depression, cardiovascular disease, diabetes, seizures, chronic respiratory disease, or OSA. Of particular note is that anticholinergic effects are not seen frequently with ≤6 mg of doxepin, which provides a treatment benefit when compared to diphenhydramine, doxylamine, or the significantly higher doses of doxepin used to treat depression.[15,21,22] Doxepin could potentially cause a decrease in next-day psychomotor function, although a meta-analysis suggested no significant difference when compared to placebo.[23,24] Of note, neither rebound insomnia nor withdrawal symptoms seem to be of concern upon discontinuation of doxepin.[23] In summary, doxepin appears to be a safe and effective option for the management of insomnia at low doses.[11,15]

Ramelteon

Ramelteon (Rozerem) is a melatonin receptor agonist (MT1 and MT2) that gained FDA approval for the treatment of insomnia in 2005.[25] Ramelteon's activity at the MT1 receptor is thought to induce sleep, while its activity at the MT2 receptor is thought to influence the circadian rhythm. It is significantly more selective for these receptors when compared to melatonin itself. Clinical trials have primarily supported ramelteon's efficacy in improving sleep latency. Additional benefits on sleep quality, efficiency, and duration have been noted but are relatively minor when compared to placebo and may not carry clinical relevance.[26]

Ramelteon's adverse-effect profile includes somnolence, dizziness, nausea, myalgias, and upper respiratory tract infections. Interestingly, some patients (roughly 3%) reported a worsening of insomnia symptoms when using ramelteon. Other concomitant disease states that may be of concern are OSA, chronic obstructive pulmonary disease (COPD), severe hepatic impairment, and depression. Ramelteon does not appear to have any abuse potential and has a limited ability to cause carryover sedation, rebound insomnia, or withdrawal upon discontinuation. In summary, ramelteon appears to be a safe and effective option for the management of insomnia caused by difficulty falling asleep.[11,14,15]

Suvorexant

Suvorexant (Belsomra) is a schedule IV controlled substance and is the most recently FDA-approved agent for the management of insomnia, having garnered approval in 2014.[27] It works through inhibition of the binding of orexin-A and -B to the orexin receptors (OX1R and OX2R). Orexins are thought to be wake-promoting neurotransmitters, so that by blocking OX1R and OX2R, suvorexant essentially "turns off " wakefulness. Clinical trial data have summarized that suvorexant significantly improves sleep latency, sleep maintenance, sleep duration, and ISI scores when compared to placebo.[11,28]

Somnolence/excessive daytime sleepiness was the most commonly noted adverse effect (and was dose-dependent), with abnormal dreams and dry mouth also being documented more frequently than placebo.[27] Interestingly, most adverse effects appear more commonly in females (particularly obese females) due to higher drug exposure in this population. Suvorexant is contraindicated in patients with narcolepsy due to its unique ability to "turn off " wakefulness.[27]

Similar to ramelteon, concomitant OSA, COPD, or depression may be of concern when using suvorexant. Additionally, certain trials have suggested that suvorexant may cause impaired driving performance or balance deficits the morning after use.[27] However, no difference in rebound insomnia rates or withdrawal symptoms has been seen when compared to placebo.[28] In summary, clinical trial data support suvorexant as a safe and effective option for the management of insomnia.[28]

Other Therapies

Guidelines have also discussed other pharmacotherapeutic options that may have utility in the treatment of insomnia. Mirtazapine and trazodone may be beneficial in certain patient populations, particularly those with concomitant depression or unintentional weight loss.[14,15,21] Trazodone has little to no anticholinergic activity but may cause excessive daytime sleepiness and psychomotor impairment, while mirtazapine can lead to anticholinergic adverse effects and significant weight gain.[2,15,21,29] Because these medications do not have quality clinical trial data backing their efficacy and are not FDA-approved for the management of insomnia, they are not currently recommended for that purpose and should only be considered in patients who have concomitant diseases that may also benefit from their usage.

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