Repositioning Orexin in Sleep Medicine: From Wake Promotion to Sleep-State Control. A Treatment-Oriented Narrative Review

This review repositions orexin/hypocretin biology within sleep medicine from a primarily wake-promoting framework toward a treatment-oriented model centered on vigilance-state stability, REM-sleep boundary control, and orderly transitions among wakefulness, NREM sleep, and REM sleep.

Human and translational evidence indicates that orexin deficiency in narcolepsy type 1 produces not only sleepiness, but also cataplexy, sleep-onset REM periods, sleep paralysis, hallucinations, fragmented nocturnal sleep, and other dissociated-state phenomena. Human lumbar cerebrospinal fluid (CSF) data show only modest diurnal orexin variation, with a relative early-sleep peak and decline toward morning, a pattern not easily reducible to simple wake promotion and compatible with REM inhibition. Orexin receptor antagonists improve insomnia by attenuating wake-state stabilization rather than inducing nonspecific sedation, while generally preserving or enhancing REM sleep. Emerging orexin receptor agonists, and exploratory use of antagonists in disorders such as insomnia associated with restless legs syndrome, further expand the possible therapeutic relevance of this system.

Orexin should be viewed not only as a wake-promoting system but also as a stabilizer of vigilance states and REM boundaries. This framework better integrates narcolepsy, insomnia pharmacology, parasomnia vulnerability, CSF biomarker dynamics, and future orexin-targeted treatment development.