Insomnia Treatment Update With a Focus on Orexin Receptor Antagonists

Nicholas Monkemeyer, PharmD; Stanley V. Thomas, DO; Daniel E. Hilleman, PharmD, FCCP, FCCP; Mark A. Malesker, PharmD, FCCP, FCCP, FCCM, FASHP, BCPS


US Pharmacist. 2022;47(5):43-49. 

In This Article

Abstract and Introduction


Insomnia is a common condition that can have negative effects on cognition, productivity, and quality of life. A number of different types of insomnia have been identified. Recent studies suggest that insomnia is a risk factor for mood disorders, hypertension, and relapse of depression and alcoholism. Cognitive-behavioral therapy is considered the first-line treatment for insomnia. Pharmacotherapy involves the use of sedative-hypnotics, with traditional targets of these agents being gamma-aminobutyric acid, histamine, and melatonin receptors. Alternative medications, such as antidepressants and antipsychotics, may be used in patients with certain comorbidities. Herbal supplements also have been used to treat insomnia. Orexin receptor antagonists are a novel class of sedative-hypnotics for sleep-onset and sleep-maintenance insomnia, and currently three agents have been approved by the FDA.


Most adults need about 7 to 9 hours of sleep per day.[1] Insomnia, a common sleep disorder characterized by difficulty falling asleep or maintaining sleep, affects from 10% to 50% of the population worldwide.[2] Insomnia is associated with adverse effects on cognition, productivity, and quality of life, and recent studies suggest that it is a risk factor for mood disorders, hypertension, and relapses of depression and alcoholism. Patients with insomnia are more likely to be absent from work and are at increased risk for occupational and motor-vehicle accidents.[3]

Insomnia is defined as difficulty initiating or maintaining sleep that results from daytime circumstances and is not attributable to environmental factors or inadequate opportunity to sleep.[4] Different types of insomnia have been identified. Transient insomnia has a duration of less than 1 week and is caused by acute situational or environmental stressors, such as sleeping in a hotel room. Short-term insomnia has a duration of less than 3 months and is related to personal stressors, such as moving into a new house or the death of a spouse. Chronic insomnia, in which symptoms last longer than 3 months, is related to psychiatric illness, substance-abuse disorders, medical issues, or behavioral factors. Insomnia may be further divided into sleep-onset and sleep-maintenance insomnia. Sleep-onset insomnia is defined as difficulty initiating sleep, and sleep-maintenance insomnia refers to difficulty staying asleep through the night.

Cognitive-behavioral therapy (CBT) is the first-line treatment for insomnia.[2] Pharmacotherapy for insomnia should be considered mainly in patients who are unable to participate in CBT for insomnia (CBT-I) or as an adjunct to CBT-I. Medications for insomnia have historically targeted gamma-aminobutyric acid (GABA), histamine, and melatonin receptors (Table 1). The newest class of medications works by antagonizing orexin receptors. The purpose of this article is to update the pharmacist on guideline-directed pharmacotherapy for insomnia and to characterize the role of orexin receptor antagonists in treatment.