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Insomnia is associated with an abnormal state of hyperarousal (increased somatic, cognitive, and cortical activation) and orexin has been identified as a key promotor of arousal and vigilance. The current standards of care for the treatment of insomnia recommend non\u2010pharmacological interventions (cognitive behavioural therapy) as first\u2010line treatment and, if behavioural interventions are not effective or available, pharmacotherapy. In contrast to most sleep medications used for decades (benzodiazepines and \u2018Z\u2010drugs\u2019), the new orexin receptor antagonists do not modulate the activity of \u03b3\u2010aminobutyric acid receptors, the main inhibitory mechanism of the central nervous system. Instead, they temporarily block the orexin pathway, causing a different pattern of effects, e.g., less morning or next\u2010day effects, motor dyscoordination, and cognitive impairment. The pharmacokinetic\/pharmacodynamic properties of these drugs are the basis of the different characteristics explained in the package inserts, including the recommended starting dose. Orexin receptor antagonists seem to be devoid of any dependence and tolerance\u2010inducing effects, rendering them a viable option for longer\u2010term treatment. Safety studies did not show exacerbation of existing respiratory problems, but more real\u2010world safety and pharmacovigilance experience is needed. This review provides an overview of the orexin history, the mechanism of action, the relation to insomnia, and key features of available drugs mediating orexin signalling.<\/jats:p>","DOI":"10.1111\/jsr.13902","type":"journal-article","created":{"date-parts":[[2023,4,22]],"date-time":"2023-04-22T04:19:53Z","timestamp":1682137193000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":117,"title":["The orexin story and orexin receptor antagonists for the treatment of insomnia"],"prefix":"10.1111","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0788-3788","authenticated-orcid":false,"given":"Clemens","family":"Muehlan","sequence":"first","affiliation":[{"name":"Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Roch","sequence":"additional","affiliation":[{"name":"Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric","family":"Vaillant","sequence":"additional","affiliation":[{"name":"Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4083-5817","authenticated-orcid":false,"given":"Jasper","family":"Dingemanse","sequence":"additional","affiliation":[{"name":"Idorsia Pharmaceuticals Ltd  Allschwil Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,22]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1111\/jgs.15767"},{"key":"e_1_2_11_3_1","volume-title":"Diagnostic and statistical manual of mental disorders","author":"APA","year":"2013"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2021.105053"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.241422"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms2461"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-018-2559-5"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/sleep\/zsaa275"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.congress-2020.2149"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2021.11.015"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/JM801296D"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm1544"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881118822258"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11606-007-0251-z"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddmod.2011.07.002"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00213-018-4887-7"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2018.08.005"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01509-2015"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81973-X"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1111\/jsr.13021"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543770903567085"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm100541c"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(07)60237-2"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201907-1284OC"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1177\/0269881118773745"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-59489-1.00003-3"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.1.322"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-31591-y"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.109.152009"},{"key":"e_1_2_11_30_1","unstructured":"EMA. 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