Narcolepsy is associated with disrupted nighttime sleep (DNS). Sodium oxybate (SXB; Xyrem®), administered twice nightly, is indicated for the treatment of cataplexy and excessive daytime sleepiness in patients 7 years or older with narcolepsy. Recently, low-sodium oxybate (LXB, Xyw®; for people 7 years of age and older), which contains 92% less sodium than SXB and is dosed twice nightly, and sodium oxybate for extended release (SXB-ER; Lumryz™; for adults), which contains equal sodium to SXB and is dosed once nightly, he also been approved to treat cataplexy or excessive daytime sleepiness in narcolepsy. This paper reviews the evidence regarding the overall impact of oxybate administration, and impact of different oxybate dosing regimens (once nightly, SXB-ER; twice nightly, SXB), on DNS in narcolepsy utilizing polysomnographic data from five clinical trials (three assessing SXB in adults [referred to here as SXB trials 1, 2, and 3], one assessing SXB in children [referred to as the pediatric SXB trial], and one assessing SXB-ER in adults [REST-ON]). Both once-nightly and twice-nightly oxybate regimens similarly improved symptoms of DNS. Regardless of dosing regimen, people with narcolepsy treated with oxybate experience roughly 42–53 arousals and 9–38 awakenings each night, with one of these awakenings on twice-nightly oxybate being due to the second dosing requirement in studies of SXB. Additionally, for SXB, but not SXB-ER, polysomnographic data has been analyzed by half of the night, demonstrating a greater positive impact on sleep architecture in the second half of the night, which might be related to its nonlinear pharmacokinetic profile. We conclude that while once-nightly and twice-nightly oxybate dosing regimens differ in their pharmacokinetic profiles, both improve DNS in patients with narcolepsy to a similar degree.
Keywords: Narcolepsy, Sodium oxybate, Low-sodium oxybate, Polysomnography, Disrupted nighttime sleep, Nocturnal
Plain Language SummaryNarcolepsy causes daytime sleepiness and difficulty sleeping (commonly called disrupted nighttime sleep). Sodium oxybate (Xyrem®) and low-sodium oxybate (Xyw®, which contains 92% less sodium than sodium oxybate), are taken twice nightly in patients with narcolepsy. Sodium oxybate for extended release (Lumryz™), which contains as much sodium as sodium oxybate, is taken once per night. All three medications improve narcolepsy symptoms and he the same active ingredient. It is important to understand how well they improve nighttime sleep.
This review examined results of five clinical studies looking at disrupted nighttime sleep in people with narcolepsy: three of twice-nightly sodium oxybate in adults (called SXB trials 1, 2, and 3 here), one of twice-nightly sodium oxybate in children (called the pediatric SXB trial here), and one of once-nightly sodium oxybate for extended release in adults (called REST-ON here). No studies specifically investigated disrupted nighttime sleep with twice-nightly low-sodium oxybate in people with narcolepsy. Although the trial designs for these studies were different, both twice-nightly and once-nightly oxybate medications improved sleep similarly, and neither eliminated arousals or awakenings. Certain aspects of sleep improved more during the second half of the night in SXB trials 1 and 3 compared with the first half of the night. Both once-nightly and twice-nightly oxybate medications similarly improve nighttime sleep in people with narcolepsy. Twice-nightly oxybate may be particularly helpful in improving sleep in the second half of the night.
Key Summary Points Why carry out this study? Multiple oxybate medications (sodium oxybate [SXB], sodium oxybate for extended release [SXB-ER], and low-sodium oxybate [LXB]) are approved to treat narcolepsy, a central hypersomnolence disorder. These medications differ in their dosing regimens (SXB and LXB are dosed twice nightly and SXB-ER is dosed once nightly), but there is no evidence that these different regimens he different effects on disrupted nighttime sleep (DNS) in narcolepsy. This commentary critically examines the effects of two different oxybate dosing regimens (once nightly or twice nightly) on sleep, sleep architecture, and sleep disruption in key clinical trials in narcolepsy. What was learned from the study? While no head-to-head trials exist and the impact of LXB on DNS has not been examined in narcolepsy, SXB and SXB-ER were found to similarly improve DNS across five key clinical trials. Although once-nightly dosing may be perceived as more convenient than twice nightly, the evidence suggests that once-nightly and twice-nightly oxybate regimens impart substantial and highly similar medical benefit on subjective and objective measures of sleep and daytime function. Open in a new tabIntroductionNarcolepsy is a central hypersomnolence disorder [1, 2]. Symptoms include excessive daytime sleepiness, cataplexy, disrupted nighttime sleep (DNS), hypnopompic/hypnagogic hallucinations, and sleep paralysis [3]. Excessive daytime sleepiness is experienced by all people with narcolepsy, and cataplexy and DNS are common [4]. There is no agreed upon definition of DNS, but it can be described both objectively, in terms of changes in polysomnographic (PSG) measures of sleep architecture and sleep stage transitions, and subjectively, in terms of self-report measures [5].
Sodium oxybate (SXB; Xyrem®), administered twice nightly and originally approved by the US Food and Drug Administration (FDA) in 2002, is an established and effective treatment for cataplexy and excessive daytime sleepiness in narcolepsy [6–8]. Recently, new oxybate therapies he been approved by the FDA for the treatment of these symptoms. Low-sodium oxybate (calcium, magnesium, potassium, and sodium oxybates; LXB; Xyw®; approved in 2020), which contains 92% less sodium than SXB and is dosed twice nightly, is indicated for patients 7 years of age and older with narcolepsy [9–12]. Sodium oxybate for extended release (SXB-ER; Lumryz™; approved in 2023), which is dosed once nightly but has the same high sodium content as SXB, is indicated for adults with narcolepsy [13].
Although head-to-head trials he not been conducted, clinical trial data from the individual clinical development programs demonstrate that once-nightly and twice-nightly oxybate regimens are associated with similar improvements in DNS (sleep architecture, stage shifts, arousals or awakenings, and patient-reported sleep quality) [14–20]. Importantly, no oxybate product is approved for the treatment of DNS, and approval of all oxybate products was based on clinically relevant endpoints of cataplexy rates and subjective and objective measures of excessive daytime sleepiness. Although waking one fewer time to take a second dose seems intuitively more convenient, there are no data to suggest that once-nightly regimens lead to a more forable effect on sleep architecture, nor are there any data to suggest that waking for a second dose has an adverse impact on daytime symptoms.
In this paper, we briefly review the scientific literature regarding the effects of oxybates on DNS in people with narcolepsy, critically examine these effects between two different oxybate dosing regimens (once nightly or twice nightly) in key clinical trials, and evaluate the impact of oxybate administration with both dosing regimens on sleep, sleep architecture, and sleep disruption. The ailable scientific evidence demonstrates an expected, highly similar, and substantial benefit on these parameters, without an identifiable additional benefit of a once-nightly regimen.
Disrupted Nighttime Sleep in Narcolepsy and Healthy IndividualsAlthough DNS is not included in the most recent diagnostic criteria for narcolepsy [21], nighttime sleep is dysregulated in many people with narcolepsy, commonly manifesting as early entry into rapid eye movement (REM) sleep after sleep onset, disordered sleep/wake stages, and sleep state instability, including frequent shifts from deeper to lighter stages of sleep and increased awakenings and arousals, resulting in poor sleep quality [5]. PSG studies of people with narcolepsy compared with healthy controls he shown that total sleep time is decreased [22–24], wake after sleep onset (WASO) is increased [22, 23, 25–28], awakenings are increased [25, 29], arousals are increased [29], N1 sleep is increased [22, 23, 25], N2 sleep is decreased [22, 23, 25], N3 sleep is decreased [29–31], sleep efficiency is lower [22, 23, 25], and transitions between sleep stages are increased [5]. No medications are currently indicated for the treatment of DNS in narcolepsy.
Brief disruptions in sleep are normal within a range of approximately 29–130 arousals and 4–40 awakenings per night, generally increasing in frequency with age, in people without diagnosed sleep disorders [29, 32]. It should be noted, however, that definitions of arousals and awakenings he changed over time, and may vary across studies; additionally, many studies fail to describe criteria used. Per American Sleep Disorders Association (ASDA) [33] criteria and, more recently, American Academy of Sleep Medicine (AASM) [34] criteria for PSG scoring, an arousal is defined as an abrupt shift in electroencephalogram (EEG) frequency lasting ≥ 3 s, which may include theta, alpha, and/or frequencies > 16 Hz, but not spindles, occurring after ≥ 10 continuous seconds of any sleep stage. Wakefulness was described as being characterized by EEG containing alpha activity and/or a low-voltage, mixed-frequency activity in the early ASDA scoring [35]; AASM criteria now define an awakening as alpha activity over the occipital region and/or other findings consistent with wake (eye blinks, REM associated with normal or high chin muscle tone, or reading eye movements) lasting ≥ 15 s [34].
In a study of untreated adults with narcolepsy, arousals and awakenings were found to be 2.7 and 9.3 times more common, respectively, than in healthy controls [29]. Specifically, people with narcolepsy experienced approximately 80 arousals and 35 awakenings (