Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease

Abstract

IMPORTANCE Sleep-wake disorders are a common and debilitating nonmotor manifestation of Parkinson disease (PD), but treatment options are scarce.OBJECTIVE To determine whether nocturnal administration of sodium oxybate, a first-line treatment in narcolepsy, is effective and safe for excessive daytime sleepiness (EDS) and disturbed nighttime sleep in patients with PD. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, placebo-controlled, crossover phase 2a study carried out between January 9, 2015, and February 24, 2017. In a single-center study in the sleep laboratory at the University Hospital Zurich, Zurich, Switzerland, 18 patients with PD and EDS (Epworth Sleepiness Scale [ESS] score >10) were screened in the sleep laboratory. Five patients were excluded owing to the polysomnographic diagnosis of sleep apnea and 1 patient withdrew consent. Thus, 12 patients were randomized to a treatment sequence (sodium oxybate followed by placebo or placebo followed by sodium oxybate, ratio 1:1) and, after dropout of 1 patient owing to an unrelated adverse event during the washout period, 11 patients completed the study. Two patients developed obstructive sleep apnea during sodium oxybate treatment (1 was the dropout) and were excluded from the per-protocol analysis (n = 10) but included in the intention-to-treat analysis (n = 12).INTERVENTIONS Nocturnal sodium oxybate and placebo taken at bedtime and 2.5 to 4.0 hours later with an individually titrated dose between 3.0 and 9.0 g per night for 6 weeks with a 2-to 4-week washout period interposed. MAIN OUTCOMES AND MEASURESPrimary outcome measure was change of objective EDS as electrophysiologically measured by mean sleep latency in the Multiple Sleep Latency Test. Secondary outcome measures included change of subjective EDS (ESS), sleep quality (Parkinson Disease Sleep Scale-2), and objective variables of nighttime sleep (polysomnography).RESULTS Among 12 patients in the intention-to-treat population (10 men, 2 women; mean [SD] age, 62 [11.1] years; disease duration, 8.4 [4.6] years), sodium oxybate substantially improved EDS as measured objectively (mean sleep latency, +2.9 minutes; 95% CI, 2.1 to 3.8 minutes; P = .002) and subjectively (ESS score, −4.2 points ; 95% CI, −5.3 to −3.0 points; P = .001). Thereby, 8 (67%) patients exhibited an electrophysiologically defined positive treatment response. Moreover, sodium oxybate significantly enhanced subjective sleep quality and objectively measured slow-wave sleep duration (+72.7 minutes; 95% CI, 55.7 to 89.7 minutes; P < .001). Differences were more pronounced in the per-protocol analysis. Sodium oxybate was generally well tolerated under dose adjustments (no treatment-related dropouts), but it induced de novo obstructive sleep apnea in 2 patients and parasomnia in 1 patient, as detected by polysomnography, all of whom did not benefit from sodium oxybate treatment. CONCLUSIONS AND RELEVANCEThis study provides class I evidence for the efficacy of sodium oxybate in treating EDS and nocturnal sleep disturbance in patie...

Neurophysiological signature of gamma-hydroxybutyrate augmented sleep in male healthy volunteers may reflect biomimetic sleep enhancement: a randomized controlled trial

“…No significant effects of GHB on functional connectivity were found in the delta, alpha, sigma or beta ranges (results not shown). Clinically, GHB is the first-line treatment of excessive daytime sleepiness and cataplexy in narcolepsy type-1 and has recently been shown to be an effective novel treatment option for sleep-wake disturbances in Parkinson's disease (Büchele et al, 2018;Mamelak, 2018). Although it has been suggested that GHB may augment the regenerative functions of sleep (Mamelak, 2007b(Mamelak, , 2009 and activate similar physiological mechanisms as sleep deprivation (Morawska et al, 2016), the neurophysiological signature of GHB-augmented sleep has not yet been systematically investigated.…”

“…Mamelak, 2009). When administered at bedtime, GHB enhances sleep efficiency and electroencephalographic (EEG) slow waves in non rapid eye movement (NREM) sleep, and reduces pathological sleepiness in patients suffering from narcolepsy, Parkinson's disease and fibromyalgia (Huang and Guilleminault, 2009;Ondo et al, 2008;Swick, 2011;Van Cauter et al, 1997;Vienne et al, 2012;Büchele et al, 2018). Given the hypothesized importance of EEG slow waves in NREM sleep for cognition and emotions (Tononi and Cirelli, 2014;Walker, 2009), GHB's beneficial effects have primarily been assigned to its ability to promote slow wave sleep and to produce EEG slow oscillations during sleep (Godbout and Montplaisir, 2002;Morawska et al, 2016).…”

Excessive Daytime Sleepiness in Parkinson's Disease

“…This study used both objective and subjective assessments and showed that sodium oxybate improved mean sleep latency, ESS score, and slow-wave sleep duration. [ 80 ] Sodium oxybate should be taken in the evening and once again during the night. Its side effects are nausea, insomnia, headache, dizziness, vomiting, weight loss, psychiatric complications, and sleep apnea.…”

“…[ 81 ] It increased apnea-hypopnea index in PD patients[ 78 ] and induced de novo obstructive sleep apnea and parasomnia. [ 80 ] Efficacy conclusion for sodium oxybate is possibly useful. Evidence suggested that sodium oxybate might be efficacious for treating EDS in PD.…”

Sleep Symptoms Differentially Predict Cognition in Younger and Older-Onset Parkinson's Disease

“…Thus, the present study examines self-reported sleep data using the Parkinson's Disease Sleep Scale-Revised [22] to examine whether different aspects of self-reported sleep problems are differentially associated with memory and executive function (EF) in younger versus older-onset PD. Variants of the Parkinson's Disease Sleep Scales (PDSS [23]; PDSS-2 [24]) have been widely adopted by clinicians and integrated as outcome measures in clinical trials [25][26][27], therefore, understanding systematic differences in the antecedents and associations of sleep disturbances within PD subtype is critical.…”