Therapeutic Use of γ-Hydroxybutyrate: History and Clinical Utility of Oxybates and Considerations of Once- and Twice-Nightly Dosing in Narcolepsy.

Narcolepsy is a rare and chronic hypersomnolence disorder characterized by excessive daytime sleepiness, disrupted nighttime sleep, sleep paralysis, and hypnagogic hallucinations and occurs with or without cataplexy. Orexin neuron loss has been implicated in the underlying pathophysiology of narcolepsy type 1 through dysregulation of sleep/wake patterns and rapid eye movement sleep. γ-Aminobutyric acid (GABA) has been shown to play a role in modulation of orexin neuronal activity during transitions from wakefulness to sleep. γ-Hydroxybutyrate (GHB), an endogenous analog of GABA, has demonstrated therapeutic benefit in treatment of narcolepsy through early investigations, but use has historically been limited owing to existing stigma related to illicit use and abuse risk. Initial regulatory approval of its sodium salt derivative, sodium oxybate (SXB), for cataplexy in patients with narcolepsy occurred in 2002, and additional formulations have been developed. The efficacy and safety of SXB in narcolepsy have been supported by decades of clinical use and research. This review discusses the history and clinical application of GHB and its SXB derivatives in the treatment of individuals with narcolepsy, including clinical safety and effect on sleep.