Clinical pharmacology, efficacy, and safety of orexin receptor antagonists for the treatment of insomnia disorders

Expert Opin Drug Metab Toxicol. 2020 Nov;16(11):1063-1078. doi: 10.1080/17425255.2020.1817380. Epub 2020 Oct 4.


Introduction: The last two decades have witnessed a rapid increase in the knowledge about the role of the orexin system, particularly in the regulation of wakefulness and arousal. Dual orexin receptor antagonists (DORAs) have been approved for the treatment of insomnia disorders (suvorexant, lemborexant) and drugs with a distinctive profile (daridorexant) or orexin-2 receptor selectivity (seltorexant) are in development.

Areas covered: This review discusses pharmacokinetics (PK), pharmacodynamics (PD), efficacy, and safety properties of orexin receptor antagonists (ORAs).

Expert opinion: In general, the drugs described have a similar effect on sleep characteristics although their pharmacokinetic variables differ. ORAs have the potential to revolutionize the pharmacological treatment of insomnia because they not only improve sleep, but, in addition, appear to have no dependence - and tolerance-inducing effects, which makes them suitable for long-term-treatment. The safety and tolerability profile of ORAs clearly differ from those of more traditional sleep-promoting drugs. Further research is needed to demonstrate benefits to patients suffering from insomnia disorder, e.g., with respect to improving not only sleep but also daytime functioning. In addition, ongoing and future research will show whether ORAs may have beneficial effects in patients with various psychiatric and neurodegenerative disorders, including Alzheimer's disease.

Keywords: Efficacy; orexin; performance; pharmacodynamics; pharmacokinetics; receptor; review; safety; selectivity; sleep.

Publication types

  • Review

MeSH terms

  • Animals
  • Humans
  • Orexin Receptor Antagonists / administration & dosage*
  • Orexin Receptor Antagonists / adverse effects
  • Orexin Receptor Antagonists / pharmacology
  • Orexins / metabolism
  • Sleep Aids, Pharmaceutical / administration & dosage
  • Sleep Aids, Pharmaceutical / adverse effects
  • Sleep Aids, Pharmaceutical / pharmacology
  • Sleep Initiation and Maintenance Disorders / drug therapy*
  • Sleep Initiation and Maintenance Disorders / physiopathology


  • Orexin Receptor Antagonists
  • Orexins
  • Sleep Aids, Pharmaceutical