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  • Updated 04.27.2024
  • Released 03.14.2001
  • Expires For CME 04.27.2027

Pharmacological treatment of insomnia



The authors review the pharmacological means for the treatment of insomnia. This article includes information on orexin receptor antagonists; benzodiazepines; imidazopyridines; antidepressants; anticonvulsants; herbal supplements, including melatonin; and other over-the-counter medications. This update includes new information on lemborexant and its safety in special populations as well as updates on herbal supplements for sleep.

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.

• Dual orexin receptor antagonists are emerging as safer alternatives to the GABAA agonists and as effective as them.

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

Historical note and terminology

In the late 1800s, two 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 two medications fell out of favor due to adverse effect profiles after the advent of barbiturates in the early 20th century. 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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