An orexin receptor antagonist, or orexin antagonist, is a drug that inhibits the effect of orexin by acting as a receptor antagonist of one (selective orexin receptor antagonist or SORA) or both (dual orexin receptor antagonis or DORA) of the orexin receptors, OX1 and OX2.[1] Medical applications include treatment of sleep disorders such as insomnia.[2][3]
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).[17][18][19][20][21]
Orexin receptor antagonists are not currently used as first-line treatments for insomnia due to cost and concerns about possible misuse liability.[22]
Suvorexant appears to be effective in the prevention of delirium.[9][10]
Side effects of orexin receptor antagonists include somnolence, daytime sleepiness and sedation, headache, abnormal dreams, fatigue, and dry mouth.[17][18][19][21][20]
Rates of somnolence or fatigue with orexin receptor antagonists in clinical trials were 7% (vs. 3% with placebo) for suvorexant 15 to 20 mg,[23] 7 to 10% (vs. 1.3% for placebo) for lemborexant 5 to 10 mg,[24] and 5 to 6% (vs. 4% with placebo) for daridorexant 25 to 50 mg.[25]
Narcolepsy, a neurological disorder caused by orexin deficiency, is a contraindication to the use of orexin antagonists.[26]
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.[8] 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.[8][27]
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.[28]
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.[29][28][30] In patients with moderate to severe hepatic impairment, dose adjustments of these medications may be necessary.[31]
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.[32][33][34] Seltorexant is under development for treatment of major depressive disorder however and is in phase 3 trials for this indication.[35] 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.[35][36][37]
