Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson Disease: A Randomized Clinical Trial

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 measures: Primary 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 relevance: This study provides class I evidence for the efficacy of sodium oxybate in treating EDS and nocturnal sleep disturbance in patients with PD. Special monitoring with follow-up polysomnography is necessary to rule out treatment-related complications and larger follow-up trials with longer treatment durations are warranted for validation.

Trial registration: clinicaltrials.gov Identifier: NCT02111122.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Büchele received speaker honoraria from Hoffmann-La Roche Pharma. Dr Schreglmann received grants from the Swiss National Science Foundation, Swiss Neurological Society, the European Academy of Neurology, and the EMDO foundation, Zurich. Dr Werth received a grant from the Swiss National Science Foundation. Dr Hägele-Link received speaker honoraria from GE Healthcare, Zambon Pharma, Teva Pharma, and an unrestricted grant from AbbVie Pharma. Dr Baumann received grants from Swiss National Science Foundation, HSM-2 Grant Canton of Zurich, UCB Pharma, and AbbVie Pharma, and speaker honoraria from Hoffmann-La Roche Pharma, UCB Pharma, and Teva Pharma. No other conflicts were reported.

Figures

Figure 1.. CONSORT Flow Diagram and Study Design

AE indicates adverse event; SAS, sleep apnea syndrome.

Figure 2.. Effect of Placebo vs Sodium Oxybate on Excessive Daytime Sleepiness and Nighttime Sleep

A, Objective excessive daytime sleepiness measured by changes of mean sleep latency in the Multiple Sleep Latency Test (MSLT) (baseline vs treatment). B, Subjective excessive daytime sleepiness (measured by changes in the Epworth Sleepiness Scale (ESS). C, Objective nighttime sleep as measured by changes in durations of different sleep stages noted on polysomnography (PSG). D, Subjective nighttime sleep as measured by the Parkinson Disease Sleep Scale–2 (PDSS-2) questions 1 to 3 (Q 1-3), regarding general sleep quality and disturbances with initiation and maintenance of sleep. E, Cumulative slow-wave energy, plotted longitudinally over the course of the PSG night. The x-axis shows percentiles of individual sleep time; arrows indicate mean time points of sodium oxybate and placebo intake (ie, at lights off and 2.5-4.0 hours later). F, Correlation between change of slow-wave sleep duration and change of objective excessive daytime sleepiness (measured by mean sleep latency) during sodium oxybate treatment. Orange circles indicate 2 patients who developed a sleep apnea syndrome during sodium oxybate treatment and were excluded from the per-protocol analysis. Data are presented as means; error bars indicate SD (exception: SE for panel C for better overview). REM indicates rapid eye movement.