Orexin antagonist

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Orexin antagonist
Drug class
Other namesHypocretin antagonist

Orexin receptor antagonist, or orexin antagonist, is class of medication used to treat trouble sleeping.[1][2] They result in people falling asleep nearly 10 minutes faster and sleeping nearly 20 minutes longer.[3]

Common side effects include increased next day sleepiness from 2% to 8%.[3] Other side effects may include sleep paralysis and complex sleep behavior.[3] It works by blocking the effect of orexin by acting as a receptor antagonist of one or both of the orexin receptors, OX1 and OX2.



  • Daridorexant (nemorexant; Quviviq) – dual OX1 and OX2 antagonist – approved for insomnia in January 2022, formerly under development for sleep apnea[4] – half-life 8 hours
  • Lemborexant (Dayvigo) – dual OX1 and OX2 antagonist – approved for insomnia in December 2019 and released June 1 2020, under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea – half-life 17–55 hours
  • Suvorexant (Belsomra) – dual OX1 and OX2 antagonist – approved for insomnia in August 2014, under development for delirium – half-life 12 hours

Under development

  • Seltorexant (MIN-202, JNJ-42847922, JNJ-922) – selective OX2 antagonist – under development for major depressive disorder, insomnia, and sleep apnea, up to phase 3 – half-life 2–3 hours [5]
  • Vornorexant (ORN-0829, TS-142) – dual OX1 and OX2 antagonist – under development for insomnia and sleep apnea, up to phase 2 – half-life 1.5–3 hours[6]

Not marketed

  • ACT-335827 – selective OX1 antagonist
  • Almorexant (ACT-078573) – dual OX1 and OX2 antagonist – development of the drug was abandoned in January 2011 [7]
  • EMPA – selective OX2 antagonist
  • Filorexant (MK-6096) – dual OX1 and OX2 antagonist – development was discontinued in 2015 [8]
  • GSK-649868 (SB-649868) – dual OX1 and OX2 antagonist – was in development for potential use in sleep disorders
  • JNJ-10397049 – selective OX2 antagonist
  • RTIOX-276 – selective OX1 antagonist
  • SB-334867 – first non-peptide selective OX1 antagonist – has been shown to produce sedative and anorectic effects in animals[9]
  • SB-408124 – selective OX1 antagonist
  • TCS-OX2-29 – first non-peptide selective OX2 antagonist

Medical uses

Trouble sleeping

Orexin receptor antagonists dose-dependently improve sleep parameters including latency to persistent sleep (LPS), wake after sleep onset (WASO), sleep efficiency (SE), total sleep time (TST), and sleep quality (SQ).[10][11][12][13][14]

They decrease time to falling asleep by about 9 minutes and total duration of sleep by about 19 minutes.[15] It however does not change the number of people who feel refreshed the next day.[15]

Orexin receptor antagonists are more effective in the treatment of insomnia than other sleep aids including benzodiazepines, Z-drugs, antihistamines, antidepressants, anticonvulsants, and melatonin receptor agonists (e.g., melatonin, ramelteon).[16][14][10]

Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.[16]


Suvorexant appears to be effective in the prevention of delirium.[17][18]

Side effects

Side effects of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.[10][11][12][14][13]

Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20 mg,[19] 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10 mg,[20] and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50 mg.[21]



The elimination half-lives of clinically used orexin receptor antagonists are 12 hours for suvorexant, about 17 to 19 hours ("effective" half-life) or 55 hours (terminal elimination half-life) for lemborexant, and 6 to 10 hours for daridorexant.[22] The elimination half-lives of investigational orexin receptor antagonists are 2 to 3 hours for seltorexant and about 1.5 to 3 hours for vornorexant.[22][23]


Filorexant was studied for but was not found to be effective in the treatment of diabetic neuropathy, migraine, and major depressive disorder in phase 2 clinical trials.[24][25][26] Seltorexant is under development for treatment of major depressive disorder however and is in phase 3 trials for this indication.[27] Also, suvorexant is in a phase 4 trial for use as an adjunct to antidepressant therapy in people with major depressive disorder and residual insomnia.[27][28][29]


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