Is sodium oxybate superior to placebo in improving electrophysiologic measures of daytime sleepiness and sleep disturbance in Parkinson disease?
In this double-blind, placebo-controlled crossover trial including 12 patients with Parkinson disease, sodium oxybate, compared with placebo, significantly improved sleepiness and disturbed nighttime sleep both subjectively and objectively. However, it induced de novo obstructive sleep apnea in 2 patients and parasomnia in 1 patient.
The study provides class I evidence for the efficacy of sodium oxybate for sleep-wake disturbances in patients with Parkinson disease, but stringent monitoring is necessary and larger follow-up trials with longer treatment durations are warranted for validation.
Sleep-wake disorders are a common and debilitating nonmotor manifestation of Parkinson disease (PD), but treatment options are scarce.
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).
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).
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.
clinicaltrials.gov Identifier: NCT02111122
Fabian Büchele, Marc Hackius, Sebastian R. Schreglmann, Wolfgang Omlor, Esther Werth, Angelina Maric, Lukas L. Imbach, Stefan Hägele-Link, Daniel Waldvogel, Christian R. Baumann. Sodium Oxybate for Excessive Daytime Sleepiness and Sleep Disturbance in Parkinson DiseaseA Randomized Clinical Trial. JAMA Neurol. Published online November 06, 2017. doi:10.1001/jamaneurol.2017.3171