Anorexin receptor antagonist, ororexin antagonist, is a drug that inhibits the effect oforexin by acting as areceptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonist or DORA) of theorexin receptors,OX₁ andOX₂.^[1] Medical applications include treatment ofsleep disorders such asinsomnia.^[2][3]

• Daridorexant (nemorexant; Quviviq) – dual OX₁ and OX₂ antagonist – approved for insomnia in January 2022,^[4] formerly under development for sleep apnea^[5] – half-life 8 hours^[6]
• Lemborexant (Dayvigo) – dual OX₁ and OX₂ antagonist – approved for insomnia in December 2019^[4] and released June 1 2020, under development for circadian rhythm sleep disorders, chronic obstructive pulmonary disease, and sleep apnea – half-life 17–55 hours^[7][8]
• Suvorexant (Belsomra) – dual OX₁ and OX₂ antagonist – approved for insomnia in August 2014,^[4] under development for delirium^[9][10] – half-life 12 hours^[7][11]

• Fazamorexant (YZJ-1139) – dual OX₁ and OX₂ antagonist – under development for insomnia, up to phase 3 – half-life 2–4 hours^[12][13]
• Nivasorexant (ACT-539313) – selective OX₁ antagonist – under development for binge eating disorder and previously for anxiety disorders, up to phase 2 – half-life 3–7 hours^[14]
• 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^[15]
• Tebideutorexant (JNJ-61393215, JNJ-3215) – selective OX₁ antagonist – under development for major depressive disorder, no development reported for anxiety disorders and panic disorder, up to phase 2 – half-life 14–25 hours^[16][17]
• Vornorexant (ORN-0829, TS-142) – dual OX₁ and OX₂ antagonist – under development for insomnia and sleep apnea, up to phase 3 in Japan – half-life 1.5–3 hours^[18]

• ACT-335827 – selective OX₁ antagonist
• Almorexant (ACT-078573) – dual OX₁ and OX₂ antagonist – half-life 13–19 hours – development of the drug was abandoned in January 2011^[19]
• EMPA – selective OX₂ antagonist
• Filorexant (MK-6096) – dual OX₁ and OX₂ antagonist – half-life 3–6 hours – development was discontinued in 2015^[20]
• 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 producesedative andanorectic effects in animals^[21]
• SB-408124 – selective OX₁ antagonist
• TCS-OX2-29 – first non-peptide selective OX₂ antagonist

Orexin receptor antagonistsdose-dependently improve sleep parameters includinglatency to persistent sleep (LPS),wake after sleep onset (WASO),sleep efficiency (SE),total sleep time (TST), andsleep quality (SQ).^{[22][23][24][25][26]}

Orexin receptor antagonists are not currently used asfirst-line treatments for insomnia due to cost and concerns about possiblemisuse liability.^[27]

Suvorexant appears to be effective in the prevention ofdelirium.^[9][10]

Side effects of orexin receptor antagonists includesomnolence,daytime sleepiness and sedation,headache,abnormal dreams,fatigue, anddry mouth.^{[22][23][24][26][25]}

Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20 mg,^[28] 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10 mg,^[29] and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50 mg.^[30]

Narcolepsy, a neurological disorder caused by orexin deficiency, is acontraindication to the use of orexin antagonists.^[31]

Theelimination half-lives of clinically used orexin receptor antagonists are 12 hours forsuvorexant, about 17 to 19 hours ("effective" half-life) or 55 hours (terminal elimination half-life) forlemborexant, and 6 to 10 hours for daridorexant.^[8] The elimination half-lives of investigational orexin receptor antagonists are 2 to 3 hours forseltorexant and about 1.5 to 3 hours forvornorexant.^[8][32]

The pharmacokinetics of suvorexant are significantly affected by age, sex, and other factors, leading to increased blood concentrations in female, obese, and older patients.^[7] These factors do not significantly affect the pharmacokinetics of lemborexant^[7] or daridorexant.^[33]

All three marketed orexin antagonists do not need to be dose adjusted in patients with reduced renal function, as the pharmacokinetic profiles of these medications are not significantly affected.^[34][33][35] In patients with moderate to severe hepatic impairment, dose adjustments of these medications may be necessary.^[36]

Filorexant was studied for but was not found to be effective in the treatment ofdiabetic neuropathy,migraine, andmajor depressive disorder inphase 2clinical trials.^[37][38][39]Seltorexant is under development for treatment of major depressive disorder however and is inphase 3 trials for this indication.^[40] Also, suvorexant is in aphase 4 trial for use as anadjunct toantidepressant therapy in people with major depressive disorder and residual insomnia.^[40][41][42]

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