Nonbenzodiazepine Receptor Agonists for Insomnia

Abstract and Introduction

Abstract

Insomnia is a disorder due to inadequate sleep quantity and/or quality caused by impaired sleep initiation, maintenance, or duration. Understanding potential nonpharmacologic and pharmacotherapeutic treatment options for insomnia is a vitally important role for pharmacists. Many practitioners and patients are avoiding benzodiazepine receptor agonists (BZDRAs) due to their significant adverse-effect profiles, so pharmacists should understand the appropriate utility of the five FDA-approved non-BZDRA options. Diphenhydramine and doxylamine are generally not recommended due to efficacy and safety concerns, while doxepin, ramelteon, and suvorexant all appear to be efficacious options in the management of insomnia.

Introduction

Insomnia, the most common sleep-wake disorder, is generally defined as a lack of sleep due to insufficient sleep quality or quantity. It can be characterized by difficulty initiating sleep (also known as sleep latency), difficulty maintaining sleep, or inappropriate duration of sleep.^[1] The natural history of insomnia often changes with time; some patients initially have difficulty initiating sleep but later have difficulty maintaining sleep, or vice versa.^[2] Inadequate sleep is often accompanied by impaired daytime functioning, which can lead to performance difficulties at work and/or school.^[3]

Insomnia is commonly characterized as a disorder of nocturnal hyperarousal. This hyperarousal is a consequence of activation of the neuroendocrine system's stress response.^[4] High levels of cortisol and adrenocorticotropic hormones have been recorded in those with insomnia. Dysregulation of corticotropin-releasing factor also plays a role, and increased blood pressure, body temperature, heart rate, metabolic rate, and high-frequency electroencephalographic (EEG) activity during sleep may be present in insomniacs as well.^[5]

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ( DSM-5) criteria for a diagnosis of insomnia specify that symptoms must cause clinically significant functional distress or impairment and be present for at least 3 nights per week for at least 3 months. In addition, this must occur despite an adequate opportunity for appropriate sleep and cannot be explained via another sleeprelated disorder.^[1]

Table 1. FDA-Approved Non-BZDRAs for Insomnia
Drug	Standard Dose	Dosage Adjustment (Hepatic Impairment)	Special Dosing Considerations	Pregnancy Category
Diphenhydramine	50 mg once daily	No change	Peak effect is seen in about 2 h	B
Doxylamine	25 mg once daily	No change	Peak effect is not seen for 2–4 h	C
Doxepin	3 mg once daily Max: 6 mg once daily	Max: 3 mg once daily	Do not take within 3 h of a meal	C
Ramelteon	8 mg once daily	Not recommended in patients with severe hepatic impairment	Do not administer shortly after a high-fat meal	C
Suvorexant	10 mg once daily Max: 20 mg once daily	Not recommended in patients with severe hepatic impairment	Take at least 7 h before planned awakening; do not take with food as it delays onset of action	C