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Sleep impairment is a frequent condition in patients with epilepsy (PWE), and the relation between sleep and epilepsy has been considered bidirectional, as one can significantly influence the other, and vice versa. The orexin system was described more than 20\u2009years ago and is implicated in several neurobiological functions other than in controlling the sleep\u2013wake cycle. Considering the relation between epilepsy and sleep, and the significant contribution of the orexin system in regulating the sleep\u2013wake cycle, it is conceivable that the orexin system may be affected in PWE. Preclinical studies investigated the impact of the orexin system on epileptogenesis and the effect of orexin antagonism on seizures in animal models. Conversely, clinical studies are few and propose heterogeneous results also considering the different methodological approaches to orexin levels quantification (cerebrospinal\u2010fluid or blood samples). Because orexin system activity can be modulated by sleep, and considering the sleep impairment documented in PWE, the recently approved dual orexin receptor antagonists (DORAs) have been suggested for treating sleep impairment and insomnia in PWE. Accordingly, sleep improvement can be a therapeutic strategy for reducing seizures and better managing epilepsy. The present review analyzes the preclinical and clinical evidence linking the orexin system to epilepsy, and hypothesizes a model in which the antagonism to the orexin system by DORAs can improve epilepsy by both a direct and a sleep\u2010mediated (indirect) effect.<\/jats:p>","DOI":"10.1111\/epi.17661","type":"journal-article","created":{"date-parts":[[2023,5,22]],"date-time":"2023-05-22T14:04:31Z","timestamp":1684764271000},"page":"1991-2005","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Role of the orexin system in the bidirectional relation between sleep and epilepsy: New chances for patients with epilepsy by the antagonism to orexin receptors?"],"prefix":"10.1111","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4143-9445","authenticated-orcid":false,"given":"Chiara","family":"Berteotti","sequence":"first","affiliation":[{"name":"Physiological Regulation in Sleeping Mice Lab, Department of Biomedical and Neuromotor Sciences Alma Mater Studiorum\u2013University of Bologna Bologna Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4745-7281","authenticated-orcid":false,"given":"Carmen","family":"Calvello","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome Tor Vergata Rome Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2845-1332","authenticated-orcid":false,"given":"Claudio","family":"Liguori","sequence":"additional","affiliation":[{"name":"Department of Systems Medicine University of Rome Tor Vergata Rome Italy"},{"name":"Epilepsy Center, Neurology Unit University Hospital Tor Vergata Rome Italy"},{"name":"Sleep Medicine Center, Neurology Unit University Hospital Tor Vergata Rome 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