Pharmacological treatment of insomnia

Oriana Sanchez MD (

Dr. Sanchez of University of Mississippi Medical Center has no relevant financial relationships to disclose.

Hrayr P Attarian MD (

Dr. Attarian, Director of the Northwestern University Sleep Disorders Program, received honorariums from Clearview, Eisai, and Insights for consulting work.

Antonio Culebras MD, editor. (

Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.

Originally released March 14, 2001; last updated April 20, 2019; expires April 20, 2022


The authors review the pharmacological means for the treatment of insomnia. This article includes information on benzodiazepines, imidazopyridines, antidepressants, anticonvulsants, herbal supplements including melatonin, and other over-the-counter medications. This current update includes the 2019 American Academy of Family Physicians guidelines in tapering older patients off zolpidem and similar benzodiazepine receptor agonists, as well as 2018 guidelines in treating insomnia in schizophrenia. In addition, new data are included in combination therapy with melatonin receptor agonist and dual orexin receptor antagonist for minimizing delirium.

Key points


• The pharmacological treatment of insomnia is an important therapeutic field that can significantly improve health and quality of life in patients with problems falling asleep or staying asleep.


• So far the most effective medications have been the GABAA agonists, either benzodiazepines or imidazopyridines.


• The newest FDA-approved medication for insomnia is the dual orexin receptor antagonist suvorexant, and research is underway to develop selective orexin receptor antagonists.


• Another medication currently being evaluated for the treatment of insomnia is the 5HT-2A and H1 receptor antagonist, esmirtazapine.

Historical note and terminology

In the late 1800s 2 compounds similar to alcohol were used to treat insomnia: (1) paraldehyde and (2) chloral hydrate. Synthesized by Justin Liebig in 1832, chloral hydrate is the oldest synthetic hypnotic agent. It has been used since 1869 as a hypnotic. It is still rarely used for this purpose. These 2 medications fell out of favor due to adverse effect profiles after the advent of the barbiturates in the early 20th century. The barbiturates were widely used as treatments of choice for insomnia for about half a century. In the 1950s problems with tolerance, addiction, withdrawal, and overdose became apparent. Meprobamate was introduced to solve these issues, but it and its congeners turned out to have the same problems of addiction, tolerance, and withdrawal as the barbiturates. In 1960 chlordiazepoxide was introduced as the first benzodiazepine. Since then, the safety and efficacy of this class has made the former methods of pharmacological treatment of insomnia obsolete. There is much controversy regarding the incidence of addiction, tolerance, and dependence with benzodiazepine use. Because of this, many natural products have been studied as insomnia drugs. In 1970 L-tryptophan, an amino acid precursor of serotonin, was found to be effective in the treatment of insomnia. By the 1990s it became obsolete because of its association with eosinophilia-myalgia syndrome. In the1990s the first benzodiazepine receptor agonist (imidazopyridines) was introduced, and in 2005, ramelteon, a melatonin receptor agonist, became available. In 2014, the first dual orexin receptor antagonist, a new class of pharmacotherapy for insomnia, was approved.

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