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Summary Clinicians and people with narcolepsy report varied access to higher‐cost narcolepsy treatments in England associated with variations in national and local commissioning. There are no publicly available data quantifying use of these drugs to support policy decisions. We therefore aimed to describe national, regional and local prescribing trends for higher‐cost narcolepsy drugs using new national databases. We used the English prescribing dataset and secondary care medicines data to quantify volumes of high‐cost narcolepsy drugs issued between 01 January 2019 and 31 December 2022. Volumes were converted to World Health Organisation defined daily doses, to estimate the monthly number of defined daily doses of sodium oxybate, pitolisant and solriamfetol issued by each integrated care board and region. We compared national, integrated care board, and regional level issuance of each drug over time. Analysis of almost 6000 primary care prescriptions and 2000 cumulative months of secondary care pharmacy stock data, issued across 41/42 integrated care boards in England, revealed a 49.1% increase in issuance of high‐cost narcolepsy drugs between 2019 and 2022. In 2022, sodium oxybate accounted for 52.66% of issuance, pitolisant 43.09% and solriamfetol 4.25%, with 22.31% of defined daily doses issued in primary care. Three integrated care boards (NHS Southeast London, NHS Cumbria and North‐East, NHS Cheshire and Merseyside) predominate, issuing 56.33% of all defined daily doses. Variations between integrated care boards and regions differ substantially by drug and route of issuance. Our findings describe substantial variation in the use of specialist narcolepsy drugs in England, and highlight the untapped potential of using large, public domain datasets to publicly review higher‐cost drug prescribing. [ABSTRACT FROM AUTHOR]

Background/Objectives: Narcolepsy is a chronic neurologic disorder associated with substantial challenges that affect the social, emotional, and financial quality-of-life domains. A social listening analysis and structured survey were conducted to better understand the candid perspective of people with narcolepsy (PWN) and their experience with twice-nightly sodium oxybate (SXB). Methods: To characterize conversations and experiences in narcolepsy communities where SXB was mentioned, a social media analysis was conducted from August 2011 to October 2022. A structured survey was administered to PWN taking oxybate therapy from October 2022 to November 2022. Results: From the social media analysis, the largest topic was related to "cataplexy", with 537 posts/comments. The most frequent term was "xyrem", with 22,200 mentions. Of the 87 survey respondents, 85 respondents had narcolepsy, 75.3% (64/85) reported missing their second dose of immediate-release SXB or mixed-salt oxybates, and 58.8% (50/85) of respondents reported that they took their second dose of oxybate > 4 h after the first dose. Respondents reported poor sleep quality as the greatest effect or issue experienced after missing their second oxybate dose. When respondents were asked whether they had ever been injured after waking to take their second oxybate dose, 31.8% (27/85) of respondents reported an injury. Conclusions: PWN taking twice-nightly oxybates often report inconsistent adherence to the prescribed dosing, which results in negative consequences in their lives. This research provided an anonymized forum for PWN to voice challenges with middle-of-the-night awakenings that they may be reluctant to explain to their clinician. [ABSTRACT FROM AUTHOR]

Objective: Narcolepsy, a rare neurological disorder believed to have an autoimmune etiology, necessitates lifelong management. This study aimed to provide evidence supporting the safety of pharmacological treatment for narcolepsy. Methods: Five-year data on pitolisant, sodium oxybate, solriamfetol, and modafinil were extracted from the FDA Adverse Event Reporting System (FAERS) self-reporting database for the period spanning from 2019 to 2023. Various statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network analysis (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to quantify the signals. Finally, a comparative analysis was conducted between demographic data, outcomes, and inherent associations among the medications and the signals. Results: After data analysis, we obtained 50 signals (a cumulative count of 762 cases) for pitolisant, 640 signals (corresponding to 46,962 cases) for sodium oxybate, 40 signals (equivalent to 1,228 cases) for solriamfetol, and finally, 72 signals (representing 632 cases) for modafinil. The majority of these patients were female. Psychiatric and nervous system disorders were identified as the predominant adverse drug events (ADEs). For sodium oxybate, it is crucial to consider psychiatric disorders (such as suicidal ideation), respiratory disorders (including sleep apnea syndrome and respiratory depression), and signs of pregnancy and congenital familial diseases. For solriamfetol, noteworthy new ADEs include drug inefficacy, suicidal ideation, restless legs syndrome, and somnambulism. Furthermore, a relationship has been observed between modafinil use and restricted fetal growth, spontaneous abortion, cognitive disorders, and drug inefficacy and abuse. Conclusion: The majority of observed adverse reactions in this study were consistent with those listed in the product instructions. However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy. [ABSTRACT FROM AUTHOR]

Background and Purpose: Narcolepsy is a chronic illness characterized by excessive daytime sleepiness and cataplexy. Recently, sodium oxybate (SXB) has been the only effective drug in treating multiple symptoms of narcolepsy. Our study aims to assess the effectiveness and safety of SXB in treating narcolepsy. Method: We searched four databases for eligible studies. Our primary outcome was to investigate the effectiveness of SXB through symptom improvement. For the secondary outcome, we assess its safety through the reported adverse events. Result: Five RCTs were included. The SXB group had significantly improved weekly cataplexy attacks better than the placebo (MD = -5.04, 95% CI [-6.35, -3.72], P < 0.00001), also the improvement in the Maintenance of Wakefulness Test, and ESS was better in the SXB group with (MD = 4.66, 95% CI: [2.24, 7.07], p = 0.0002), (MD = -1.93, 95% CI: [-2.73, -1.13], p < 0.00001) respectively. CGI-I was observed to be significantly better in the SXB group with (RR = 2.15, 95% CI: [1.69, 2.73], p < 0.00001). The weekly cataplexy attack was significantly improved by the doses (4.5, 6, and 9 gm) in comparison with the placebo, with the 9-gm dose having the most beneficial effect. The improvements were significant only in SXB 9 gm in ESS and 6 and 9 gm in CGI-I. Conclusion: SXB is an effective pharmacological treatment for the management of narcoleptic patients with cataplexy with an acceptable safety profile. Further studies with a large scale are needed to investigate and prove the efficacy and tolerability of SXB. [ABSTRACT FROM AUTHOR]

This document is a response to a letter to the editor regarding an article on the implications of oxybate dosing regimen for sleep in patients with narcolepsy. The authors acknowledge an error in Table 2 of the original article and provide a corrected version. They state that the correction does not affect the interpretation of the data or conclusions drawn in the article. The authors hope that these corrections, along with the original article's caveats related to cross-study comparisons, will allow readers to draw their own conclusions about the implications of oxybate dosing regimen on sleep in patients with narcolepsy. The authors also address a discussion on the potential benefits of increased exposure to oxybate in the second half of the night, suggesting that it may enhance slow-wave sleep. However, there is currently no evidence to support this speculation, highlighting the need for further research. The authors also disclose their conflicts of interest and funding sources for the publication of the letter. [Extracted from the article]

Long-term use of sodium oxybate (SXB), (also called gamma-hydroxybutyrate [GHB]) attenuates the cataplexy and sleepiness of human narcolepsy. We had previously found that chronic opiate usage in humans and long-term opiate administration to mice significantly increased the number of detected hypocretin/orexin (Hcrt) neurons, decreased their size, and increased Hcrt level in the hypothalamus. We also found that opiates significantly decreased cataplexy in human narcoleptics as well as in narcoleptic mice and that cessation of locus coeruleus neuronal activity preceded and was tightly linked to cataplectic attacks in narcoleptic dogs. We tested the hypothesis that SXB produces changes similar to opiates and now report that chronic SXB administration significantly increased the size of Hcrt neurons, the reverse of what we had seen with opiates in humans and mice. Levels of Hcrt in the hypothalamus were nonsignificantly lower, in contrast to the significant increase in hypothalamic Hcrt level after opiates. SXB decreased tyrosine hydroxylase levels in the locus coeruleus, the major descending projection of the hypocretin system, also the reverse of what we saw with opioids. Therefore despite some similar effects on narcoleptic symptomatology, SXB does not produce anatomical changes similar to those elicited by opiates. Analysis of changes in other links in the cataplexy pathway might further illuminate SXBs mechanism of action on narcolepsy.

Background: Once-nightly sodium oxybate (ON-SXB), an extended-release oxybate formulation, yielded significant (P

Background: In the REST-ON clinical trial (NCT02720744), mean sleep latency on the Maintenance of Wakefulness Test (MWT) was significantly improved with extended-release once-nightly sodium oxybate (ON-SXB) vs placebo (P 10 % remained awake for the entirety of the MWT. ON-SXB offers a once-at-bedtime treatment option for adults with narcolepsy.

Objective/Background: Preference for extended-release, once-nightly sodium oxybate (ON-SXB, FT218) vs twice-nightly immediate-release (IR) oxybate was assessed in participants switching from IR oxybate to ON-SXB in an open-label/switch study, RESTORE (NCT04451668). Patients/Methods: Participants aged ≥16 years with narcolepsy who completed the phase 3 REST-ON trial, were oxybate-naive, or were on a stable IR oxybate dose (≥1 month) were eligible for RESTORE. For participants who switched from twice-nightly dosing to ON-SXB, initial doses were closest or equivalent to their previous nightly IR oxybate dose. These participants completed a questionnaire at baseline about nocturnal adverse events associated with the middle-of-the-night IR oxybate dose in the preceding 3 months, a preference questionnaire after 3 months of stable-dose ON-SXB, and an end-of-study (EOS) questionnaire. Results: There were 130 switch participants; 92/98 (93.9 %) who completed the preference questionnaire preferred ON-SXB. At baseline, 69.2 % reported missing their second IR oxybate dose at least once; in these cases, 80 % felt worse the next day. Approximately 39 % reported taking a second nightly IR oxybate dose >4 h after the first dose, 51 % of whom felt somewhat to extremely groggy/unsteady the next morning; 120 participants (92 %) reported getting out of bed after their second oxybate dose. Of those, 9 (8 %) reported falls and 5 (4 %) reported injuries. Of the switch participants who completed the EOS questionnaire, 91.2 % felt better able to follow the recommended ON-SXB dosing schedule. Conclusions: The second nightly IR oxybate dose presents significant treatment burdens and adherence concerns. Participants overwhelmingly preferred the once-nightly dosing regimen of ON-SXB.

ObjectiveNarcolepsy, a rare neurological disorder believed to have an autoimmune etiology, necessitates lifelong management. This study aimed to provide evidence supporting the safety of pharmacological treatment for narcolepsy.MethodsFive-year data on pitolisant, sodium oxybate, solriamfetol, and modafinil were extracted from the FDA Adverse Event Reporting System (FAERS) self-reporting database for the period spanning from 2019 to 2023. Various statistical methods, including the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network analysis (BCPNN), and multi-item gamma Poisson shrinker (MGPS), were employed to quantify the signals. Finally, a comparative analysis was conducted between demographic data, outcomes, and inherent associations among the medications and the signals.ResultsAfter data analysis, we obtained 50 signals (a cumulative count of 762 cases) for pitolisant, 640 signals (corresponding to 46,962 cases) for sodium oxybate, 40 signals (equivalent to 1,228 cases) for solriamfetol, and finally, 72 signals (representing 632 cases) for modafinil. The majority of these patients were female. Psychiatric and nervous system disorders were identified as the predominant adverse drug events (ADEs). For sodium oxybate, it is crucial to consider psychiatric disorders (such as suicidal ideation), respiratory disorders (including sleep apnea syndrome and respiratory depression), and signs of pregnancy and congenital familial diseases. For solriamfetol, noteworthy new ADEs include drug inefficacy, suicidal ideation, restless legs syndrome, and somnambulism. Furthermore, a relationship has been observed between modafinil use and restricted fetal growth, spontaneous abortion, cognitive disorders, and drug inefficacy and abuse.ConclusionThe majority of observed adverse reactions in this study were consistent with those listed in the product instructions. However, potential novel or notable ADE signals were identified through real-world pharmacovigilance analysis. It is anticipated that this paper will offer additional information regarding safe and rational medication for narcolepsy.

What is this summary about? This is a plain language summary of a published article in the journal Sleep. Narcolepsy is a sleep condition that has 2 different subtypes: narcolepsy type 1 and narcolepsy type 2. These are called NT1 and NT2 for short. Sodium oxybate (SXB) is approved to treat excessive daytime sleepiness (EDS) and cataplexy. People with NT1 and NT2 both have EDS, but cataplexy is only present in people with NT1. Limited information is available about how SXB works in people with NT2. This is because previous trials have included only people with NT1 or people with unspecified narcolepsy. For more than 20 years, the only available formulation of this medicine had to be given twice during the night. Many people with narcolepsy find that chronically waking up in the middle of the night for a second dose of SXB is disruptive to themselves or others in their household. People have also reported sleeping through alarm clocks, missing their second dose, and feeling worse the next day. Some people have accidentally taken the second dose too early, putting them at risk for serious adverse effects. These adverse effects may include slow breathing, low blood pressure, or sedation. The US Food and Drug Administration (FDA) approved a medicine called LUMRYZ™ (sodium oxybate) for extended-release oral suspension in May 2023. LUMRYZ is a once-nightly formulation of SXB (ON-SXB for short) and is taken as a single dose before bedtime. This medicine treats EDS and muscle weakness (also known as cataplexy) in people with narcolepsy. A clinical trial called REST-ON studied ON-SXB to find out if it was better at treating narcolepsy symptoms than a medicine with no active ingredients (placebo). This summary describes a study that tested whether ON-SXB was better than placebo at treating narcolepsy symptoms in people with NT1 or NT2. What were the results? This study showed that compared to people who took placebo, people who took ON-SXB were able to stay awake longer during the day, felt less sleepy during the daytime, had less cataplexy, and had more improvements in their symptoms overall than people who took placebo. What do the results mean? ON-SXB has been proven effective for people with NT1 or NT2. Unlike prior formulations of SXB, ON-SXB is taken once at bedtime, without requiring waking up in the middle of the night for a second dose.

The deterioration of the brain's microvasculature, particularly in the hippocampus, appears to be a very early event in the development of Alzheimer's disease (AD), preceding even the deposition of amyloid-β. A damaged microvasculature reduces the supply of oxygen and glucose to this region and limits the production of energy, ATP. The damage may be a function of the rise with age in the expression and activity of NADPH oxidase (NOX) in these microvessels. This rise renders these vessels vulnerable to the effects of oxidative stress and inflammation. The rise in NOX activity with age is even more marked in the AD brain where an inverse correlation has been demonstrated between NOX activity and cognitive ability. Apocynin, a putative NOX inhibitor, has been shown to block the damaging effects of NOX activation. Apocynin acts as a strong scavenger of H2O2, and as a weak scavenger of superoxide. Like apocynin, sodium oxybate (SO) has also been shown to block the toxic effects of NOX activation. The application of SO generates NADPH and ATP. SO inhibits oxidative stress and maintains normal cerebral ATP levels under hypoxic conditions. Moreover, it acts epigenetically to attenuate the expression of NOX. SO may delay the onset and slow the progress of AD by suppling energy and maintaining an antioxidative environment in the brain throughout the night. The slow wave activity produced by SO may also activate the glymphatic system and promote the clearance of amyloid-β from the brain. [ABSTRACT FROM AUTHOR]

Many components of sleep are disrupted in patients with narcolepsy, including sleep quality, sleep architecture, and sleep stability (ie, frequent awakenings/arousals and frequent shifts from deeper to lighter stages of sleep). Sodium oxybate, dosed twice nightly, has historically been used to improve sleep, and subsequent daytime symptoms, in patients with narcolepsy. Recently, new formulations have been developed to address the high sodium content and twice-nightly dosing regimen of sodium oxybate: low-sodium oxybate and once-nightly sodium oxybate. To date, no head-to-head trials have been conducted to compare the effects of each oxybate product. This review aims to give an overview of the existing scientific literature regarding the impact of oxybate dose and regimen on sleep architecture and disrupted nighttime sleep in patients with narcolepsy. Evidence from 5 key clinical trials, as well as supporting evidence from additional studies, suggests that sodium oxybate, dosed once- and twice-nightly, is effective in improving sleep, measures of sleep architecture, and disrupted nighttime sleep in patients with narcolepsy. Direct comparison of available efficacy and safety data between oxybate products is complicated by differences in trial designs, outcomes assessed, and statistical analyses; future head-to-head trials are needed to better understand the advantage and disadvantages of each agent. • No head-to-head trials have compared different oxybate products or formulations. • Direct comparison of data is complicated by differences in trial designs. • Oxybate improves subjective and objective disrupted nighttime sleep in narcolepsy. • Improvements are observed for both formulations dosed once and twice nightly. [ABSTRACT FROM AUTHOR]

Background: Gamma hydroxybutyrate (GHB) is used illicitly for its sedative hypnotic effects, and those who take it regularly are at risk of developing a substance use disorder. Withdrawal from GHB can include severe symptoms that may require medical management. For GHB use and withdrawal during pregnancy, there are no evidence- or practice-based guidelines to follow, and there is only minimal research literature. Case Summary: We present the case of a 32-year-old woman, G1P0 at 29 weeks and 6 days of gestation, admitted to the perinatal unit at a tertiary hospital for GHB withdrawal management and stabilization. GHB withdrawal was managed with a combination of baclofen and diazepam. We report the dosing and tapering of these medications throughout her 14-day admission. Withdrawal symptoms were well managed with this medication protocol, and she did not experience any features of complicated withdrawal. The patient later presented to hospital in preterm labor and precipitously delivered a healthy, preterm infant male at 34 weeks and 5 days of gestation. At 7 months postpartum, the patient continued to engage with perinatal addiction service, reported no use of GHB since her admission, and was parenting her healthy son. Clinical Significance: There is a paucity of guidelines for managing GHB withdrawal in pregnancy. This case demonstrates good clinical outcomes administering a short-term combination of diazepam and baclofen during the third trimester of pregnancy. This case helps to fill a gap in the literature and may inform future research or clinical decision-making in similar situations. [ABSTRACT FROM AUTHOR]

PurposeCurrent US FDA-approved treatments for narcolepsy include sodium oxybate (SXB) and calcium, magnesium, potassium, and sodium oxybates (mixed-salt oxybates), which require 2 nightly doses, 1 at bedtime and another 2.5 to 4 hours later. Once-nightly SXB (ON-SXB; FT218) is under FDA review to treat adults with narcolepsy. This study quantitatively characterized attributes of SXB treatment preferred by individuals with narcolepsy via a discrete choice experiment (DCE) and evaluated preferences for the product profiles of once-nightly vs twice-nightly SXB treatment.Patients and methodsAdults with self-reported physician-diagnosed narcolepsy for ≥1 year and current or prior twice-nightly SXB treatment were eligible for this 30-minute, web-based study capturing patient experiences and a DCE. Participants responded to a survey instrument using 9-point scales; higher scores indicated greater severity/preference/satisfaction. In the DCE, hundreds of profiles were generated, each combining attributes of twice-nightly SXB and ON-SXB based on clinical trial data. The DCE was analyzed using a hierarchical Bayesian model.ResultsSeventy-five participants were surveyed (50 current and 25 past twice-nightly SXB users). Dosing frequency was the most important attribute of SXB treatment; once nightly was significantly preferred vs twice nightly. The most common reasons for overall product preference were lack of need to wake up in the middle of the night for a second dose (48%), fewer side effects (46%), and ease of administration (32%). Number of nightly doses was the most important driver of taking the medication exactly as directed and reduced anxiety/stress. Participants were significantly more likely to prefer the blinded product profile of once-nightly SXB over twice-nightly SXB (mean rating, 7.5 vs 4.3; P

Asim Roy,1 Diane Ito,2 Susan Morris,3 Shawn Candler,4 Judi Profant,3 Charles Bae5 1Ohio Sleep Medicine Institute, Dublin, OH, USA; 2Stratevi LLC, Santa Monica, CA, USA; 3Jazz Pharmaceuticals, Palo Alto, CA, USA; 4Jazz Pharmaceuticals, Philadelphia, PA, USA; 5Penn Sleep Center, University of Pennsylvania, Philadelphia, PA, USACorrespondence: Asim Roy, Ohio Sleep Medicine Institute, 4975 Bradenton Avenue, Dublin, OH, 43017, USA, Tel +1 614-766-0773, Fax +1 614-766-2599, Email aroy@sleepmedicine.comPurpose: Real-world data regarding divided nightly dosing of oxybate and individualized prescribing in patients with narcolepsy are limited. Study objectives were to understand oxybate prescribing practices, including optimizing dose regimens and adjusting dosing per occasional changes in patients’ routines, and physician recommendations for representative patient scenarios.Patients and Methods: A cross-sectional, web- and audio-based survey of physicians treating ≥ 2 patients with narcolepsy, prescribed nightly oxybate (sodium oxybate) dosing for ≥ 6 months, was conducted. Physicians were surveyed on patients’ usual oxybate dosing regimens, frequency of and reasons for oxybate dosing-related discussions, and preferred methods for and perceptions of adjusting oxybate dosing. Physicians provided dosing-related guidance for 4 representative scenarios.Results: Participating physicians (N=25) were neurologists (52%), psychiatrists (44%), and neuropsychiatrists (4%). Individualized oxybate prescribing practices were reflected by the variability of physicians’ reporting of the percentage of their patients being prescribed once-nightly, twice-nightly, and thrice-nightly dosing regimens. Most physicians (68%) reported discussing adjusting individualized treatment to accommodate occasional changes to patients’ routines; the most common reasons were consuming contraindicated beverages (alcohol; 65%) and travel (59%). Adjusting total nightly dose (68%) and dose timing (68%) were preferred adjustment methods. Most physicians (88%) felt the ability to individualize oxybate dosing was important and had a positive impact on ability to provide care. For each representative scenario, physicians provided several dose-adjustment recommendations, and physician responses encouraged patient participation in treatment decision-making.Conclusion: Physicians provided guidance supportive of oxybate dose adjustments to accommodate occasional changes in patients’ routines, and perceived individualized dosing as important in providing care.Plain Language Summary: Why was the research needed?Narcolepsy is an uncommon condition that causes individuals to feel sleepy throughout the day. Other symptoms may include sudden muscle weakness. There is no cure for narcolepsy, but there are several treatments, including medicines known as oxybates. This study focused on how doctors use oxybate to treat patients with narcolepsy.How was the research done?This study was an online survey of doctors who were treating 2 or more patients with narcolepsy. Patients had been taking oxybate for at least 6 months. The survey asked doctors about their patients’ normal oxybate usage, how often and why they discussed oxybate treatment, and which ways oxybate treatment was usually adjusted.What are the results?Twenty-five doctors took part in this study. Most doctors said they discuss personalized treatment to help with occasional changes in their patients’ daily lives. The most common reasons for making treatment changes were consuming alcohol and travel. The most common changes were total nightly amount and timing of oxybate. Most doctors said the ability to personalize oxybate treatment is important and has a positive impact.What does the research mean?This study provides valuable knowledge on real-world oxybate treatment patterns and the conditions when doctors make clinical decisions about treating patients with narcolepsy.Graphical Abstract: Keywords: sodium oxybate, low-sodium oxybate, calcium, magnesium, potassium, sodium oxybates, prescribing patterns, personalized dosing

Abstract 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, Xywav®; 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, have 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.

The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study assessed the real-world experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92 % less sodium than SXB). TENOR is a patient-centric, prospective, observational, virtual-format study. Eligible participants included US adults with narcolepsy transitioning from SXB to LXB (±7 days from LXB initiation). Longitudinal data were collected from baseline (taking SXB) through 21 weeks post-transition. TENOR included 85 participants with narcolepsy (type 1, n = 45; type 2, n = 40). Mean (SD) age was 40.3 (13.0) years; the majority (73 %) were female and White (87 %). At study completion, wake-promoting agents were the most common concomitant medications (47 %). Mean (SD) SXB treatment duration was 57.8 (52.1) months; 96 % took SXB twice nightly. After transitioning, 97 % continued on twice-nightly regimens. Mean (SD) dose of both total nightly SXB (n = 85) and baseline LXB (n = 84) was 7.7 (1.5) g; SXB-LXB dose conversions at baseline were gram-for-gram in 87 % of participants. The mean final total nightly dose of LXB was 7.9 g. The most common participant-reported reasons for transitioning included lower sodium content for improved long-term health (93 %), physician recommendation (47 %), to avoid cardiovascular issues (39 %), to avoid side effects (31 %), and to improve control of narcolepsy symptoms (18 %). Most participants transitioned from SXB to LXB using a gram-for-gram strategy. The most commonly cited reason for transition was long-term health benefits due to lower sodium. [Display omitted] • Transition from sodium oxybate to low-sodium oxybate for narcolepsy was evaluated. • Dosing and transition characteristics were examined via questionnaire over 21 weeks. • Most participants switched for long-term health reasons due to low sodium content. • Most switched gram-for-gram, and did not require low-sodium oxybate adjustments. • Dosing was generally maintained at twice-nightly equal dosing after transition. Registry: ClinicalTrials.gov ; Name: A Patient-Centric, Prospective, Observational, Non-Interventional Switch Study of XYWAV in Narcolepsy. URL: https://clinicaltrials.gov/ct2/show/NCT04803786 ; Identifier: NCT04803786. [ABSTRACT FROM AUTHOR]

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, Xywav®; 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, have 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. Plain Language Summary: Narcolepsy causes daytime sleepiness and difficulty sleeping (commonly called disrupted nighttime sleep). Sodium oxybate (Xyrem®) and low-sodium oxybate (Xywav®, 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 have 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. [ABSTRACT FROM AUTHOR]

Ca2+/calmodulin-dependent protein kinase II alpha subunit (CaMKIIα) is a key neuronal signaling protein and an emerging drug target. The central hub domain regulates the activity of CaMKIIα by organizing the holoenzyme complex into functional oligomers, yet pharmacological modulation of the hub domain has never been demonstrated. Here, using a combination of photoaffinity labeling and chemical proteomics, we show that compounds related to the natural substance γ-hydroxybutyrate (GHB) bind selectively to CaMKIIα. By means of a 2.2-Å x-ray crystal structure of ligand-bound CaMKIIα hub, we reveal the molecular details of the binding site deep within the hub. Furthermore, we show that binding of GHB and related analogs to this site promotes concentration-dependent increases in hub thermal stability believed to alter holoenzyme functionality. Selectively under states of pathological CaMKIIα activation, hub ligands provide a significant and sustained neuroprotection, which is both time and dose dependent. This is demonstrated in neurons exposed to excitotoxicity and in a mouse model of cerebral ischemia with the selective GHB analog, HOCPCA (3-hydroxycyclopent-1-enecarboxylic acid). Together, our results indicate a hitherto unknown mechanism for neuroprotection by a highly specific and unforeseen interaction between the CaMKIIα hub domain and small molecule brain-penetrant GHB analogs. This establishes GHB analogs as powerful tools for investigating CaMKII neuropharmacology in general and as potential therapeutic compounds for cerebral ischemia in particular.

Background: Essential tremor of voice (ETv) is characterized by involuntary oscillations of laryngeal and upper airway muscles, causing rhythmic alterations in pitch and loudness during both passive breathing and active laryngeal tasks, such as speaking and singing. Treatment of ETv is challenging and typically less effective compared with treatment of ET affecting extremities. Objective: We conducted a proof‐of‐concept, open‐label phase II study to examine the efficacy and central effects of sodium oxybate in patients with alcohol‐responsive ETv. Methods: All subjects received 1.0 to 1.5 g of oral sodium oxybate and underwent brain functional magnetic resonance imaging. The primary endpoint was the number of patients (% from total) with reduced ETv symptoms by at least 10% at about 40 to 45 minutes after sodium oxybate intake based on the combined visual analog scale score of ETv symptom severity. The secondary endpoint included changes in brain activity after sodium oxybate intake compared to baseline. Results: Sodium oxybate reduced ETv symptoms on average by 40.8% in 92.9% of patients. Drug effects were observed about 40 to 45 minutes after intake, lasting about 3.5 hours, and gradually wearing off by the end of the fifth hour. The central effects of sodium oxybate were associated with normalized activity in the cerebellum, inferior/superior parietal lobules, inferior frontal gyrus, and insula and re‐established functional relationships between these regions. Conclusions: Sodium oxybate showed high efficacy in ETv patients, with a likely central action on disorder pathophysiology. Sodium oxybate may be an effective novel oral drug for treatment of alcohol‐responsive ETv patients. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study was conducted to provide real-world insight into the experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92% less sodium than SXB). TENOR is a patient-centric, prospective, observational, virtual-format study. Participants were adults with narcolepsy (type 1 or 2) who were transitioning from SXB to LXB treatment (±7 days from LXB initiation). Effectiveness and tolerability data were collected online from baseline (taking SXB) through 21 weeks (taking LXB) via daily and weekly diaries and questionnaires, including the Epworth Sleepiness Scale (ESS), the Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and the British Columbia Cognitive Complaints Inventory (BC-CCI). TENOR participants (N = 85) were 73% female with a mean (SD) age of 40.3 (13.0) years. Mean (SD) ESS scores decreased numerically throughout the transition from SXB to LXB (baseline: 9.9 [5.2]; week 21: 7.5 [4.7]), with 59.5% and 75.0% of participants having scores in the normal range (≤10) at baseline and week 21, respectively. Mean (SD) FOSQ-10 scores (baseline: 14.4 [3.4]; week 21: 15.2 [3.2]) and BC-CCI scores (baseline: 6.1 [4.4]; week 21: 5.0 [4.3]) also remained stable. The most common symptoms related to tolerability reported by participants at baseline were sleep inertia, hyperhidrosis, and dizziness (45.2%, 40.5%, and 27.4%, respectively), which decreased in prevalence by week 21 (33.8%, 13.2%, and 8.8%, respectively). Findings from TENOR confirm maintenance of effectiveness and tolerability when transitioning from SXB to LXB treatment. [Display omitted] • Transition from high-sodium to low-sodium oxybate for narcolepsy was evaluated. • Effectiveness was maintained following the transition to low-sodium oxybate. • Symptoms related to tolerability remained mostly stable. • This real-world data informs expectations about transitioning to low-sodium oxybate. [ABSTRACT FROM AUTHOR]

Sodium oxybate (SO), the sodium salt of γ-hydroxybutyric acid, is one of the primary pharmacologic agents used to treat excessive sleepiness, disturbed nighttime sleep, and cataplexy in narcolepsy. The sodium content of SO ranges from 550 to 1640 mg at 3-9 g, given in two equal nightly doses. Clinicians are advised to consider daily sodium intake in patients with narcolepsy who are treated with SO and have comorbid disorders associated with increased cardiovascular (CV) risk, in whom sodium intake may be a concern. It remains unclear whether all patients with narcolepsy treated with SO should modify or restrict their sodium intake. No data are currently available specific to the sodium content or threshold of SO at which patients might experience increased CV risk. To appraise attributable risk, critical evaluation of the literature was conducted to examine the relationship between CV risk and sodium intake, narcolepsy, and SO exposure. The findings suggest that increased CV risk is associated with extremes of daily sodium intake, and that narcolepsy is associated with comorbidities that may increase CV risk in some patients. However, data from studies regarding SO use in patients with narcolepsy have shown a very low frequency of CV side effects (eg, hypertension) and no overall association with CV risk. In the absence of data that specifically address CV risk with SO based on its sodium content, the clinical evidence to date suggests that SO treatment does not confer additional CV risk in patients with narcolepsy.

Logan Douglas Schneider,1 Joanne Stevens,2 Aatif M Husain,3 Diane Ito,4 Douglas S Fuller,5 Phyllis C Zee,6 Wayne Macfadden2 1Stanford University Sleep Medicine Center, Stanford University School of Medicine, Stanford, CA, USA; 2Global Medical Affairs, Jazz Pharmaceuticals, Philadelphia, PA, USA; 3Department of Neurology, Duke University Medical Center, Durham, NC, USA; 4Stratevi, Santa Monica, CA, USA; 5Biostatistics, Jazz Pharmaceuticals, Philadelphia, PA, USA; 6Department of Neurology and Center for Circadian and Sleep Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USACorrespondence: Wayne Macfadden, Jazz Pharmaceuticals, 2005 Market Street, Philadelphia, PA, 19103, USA, Tel +1 215-832-3750, Email Wayne.Macfadden@jazzpharma.comObjective: Idiopathic hypersomnia is a debilitating sleep disorder characterized by excessive daytime sleepiness, sleep inertia, and prolonged sleep duration. The patient burden of idiopathic hypersomnia is poorly understood. The Real World Idiopathic Hypersomnia Outcomes Study (ARISE) evaluated symptoms and treatment effectiveness/satisfaction in participants with idiopathic hypersomnia.Methods: ARISE was a United States–based virtual cross-sectional survey. Participants were adults 21– 65 years of age with idiopathic hypersomnia recruited from social media, the Hypersomnia Foundation website, and a patient panel. Self-assessments included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Treatment Satisfaction Questionnaire for Medication, version II (TSQM-vII), and additional treatment questions. Data were analyzed for all participants and for subgroups with/without long sleep time (LST; ≥ 11 hours in 24 hours).Results: Of 75 participants enrolled, most were female (81.3%). The mean (SD) age was 34.1 (10.7) years and 49% had LST. Most participants took off-label prescription medications (89.3%) and/or used other measures (93.3%) to manage their symptoms. The mean (SD) ESS score was 14.5 (3.5) and the mean IHSS score was 35.2 (7.6). Treatment satisfaction was low (mean [SD] TSQM-vII score: overall, 61.9 [21.2]; with LST, 57.9 [21.4]; without LST, 66.7 [20.3]), primarily driven by dissatisfaction with treatment effectiveness. The most common classes of prescription medications used were stimulants (61.3%), wake-promoting agents (28.0%), and antidepressants (18.7%); non-prescription measures used to manage symptoms included caffeine (73.3%), planned naps (34.7%), and individual accommodations (32.0%).Conclusion: Overall, participants with idiopathic hypersomnia, with or without LST, had substantial symptom burden despite most of the study population taking off-label medications and using nonprescription measures to manage symptoms.Keywords: sleep disorder, sodium oxybate, wake-promoting agents, stimulants, antidepressants

Introduction: Immediate-release sodium oxybate (SXB) has been Food and Drug Administration (FDA)-approved to treat narcolepsy since 2002; in 2020, a mixed-salt oxybates formulation was also approved. Both are taken at bedtime with a second dose taken 2.5–4 h later. A third oxybate option, an investigational extended-release SXB, may soon be available. This study was undertaken to understand clinicians' preferences between these 3 different oxybate treatments. Methods: Clinicians in active clinical practice for 3–35 years and experience treating patients with narcolepsy were recruited. A 30-min web-based survey quantified narcolepsy disease-state attitudes, treatment perceptions, and satisfaction with oxybates on 9-point scales. A discrete choice experiment (DCE) of 12 choice sets, with 2 hypothetical treatment profiles in each, was used to capture clinician preferences about overall oxybate therapy preference, impact on patient quality of life (QoL), and patient anxiety/stress. Attributes associated with current therapies and those expected to be available in the near future were included in the design. Results: The clinicians surveyed (n = 100) indicated that narcolepsy has a negative impact on patient QoL (mean rating, 7.7) and rated impact on QoL and treatment efficacy as the most important aspects of a narcolepsy treatment (mean rating, 7.3–7.7). Clinicians with experience prescribing oxybates had moderately high satisfaction with SXB and mixed-salt oxybates efficacy (mean ratings, 6.5–6.9) and safety (mean ratings, 6.1–6.7) and lower satisfaction with nightly dosing frequency (mean rating, 5.9 and 6.3, respectively). In the DCE, dosing frequency was the most important attribute driving overall product choice, patient QoL, and reducing patient anxiety/stress (relative attribute importance, 46.1, 41.7, and 44.0, respectively), with once nightly preferred over twice nightly. Conclusion: Clinicians indicated a significantly higher preference for the once-at-bedtime dosing schedule versus twice nightly in selecting oxybate therapies overall and when aiming to improve patient QoL or reduce patient anxiety. Plain Language Summary: Current medications for narcolepsy include immediate-release sodium oxybate and mixed-salt oxybates. People taking these oxybates for narcolepsy take 1 dose at bedtime and must wake up 2.5–4 h later for the second dose. An investigational sodium oxybate, designed as a single bedtime dose, has been tentatively approved by the US Food and Drug Administration. This study used a 30-min web-based survey to learn what clinicians think about narcolepsy and narcolepsy medicines. A discrete choice experiment was used to identify which properties of current/future oxybate medicines are most important in a narcolepsy treatment. In this exercise, relevant properties of current/future oxybate medicines were mixed and matched to create hypothetical medicine profiles. Clinicians selected from these profiles which medication they preferred overall, which would improve patient quality of life, and which would reduce patient anxiety when thinking about taking the treatment. Clinicians were moderately satisfied with the effectiveness and safety of current narcolepsy medications. They strongly preferred oxybate treatments with fewer nightly doses and agreed that waking up for the second oxybate dose causes stress for patients. In the discrete choice experiment, the number of doses each night was the product characteristic that had the biggest impact on clinicians picking a medicine for narcolepsy. This was true for overall medicine choice, choosing a medicine that would improve patient quality of life, and choosing one that would reduce patient anxiety/stress. If granted marketing approval, extended-release sodium oxybate will be a once-at-bedtime option that may overcome challenges with current oxybate therapies. [ABSTRACT FROM AUTHOR]

Introduction: Narcolepsy Type 1 (NT1) is a rare hypersomnia of central origin linked to hypocretin deficiency, most frequently arising at pediatric age. NT1 could be associated with endocrine comorbidities involving the neuroendocrine axis, predominantly obesity, and Central Precocious Puberty (CPP). The primary aim of this study is the evaluation of endocrine and auxological parameters at diagnosis and during follow-up in patients with NT1, treated with Sodium Oxybate (SO) or not. Methods: We retrospectively evaluated the auxological, biochemical, and radiological parameters of 112 patients referred to our Center between 2004-2022. The design of our study is cross-sectional at the time of diagnosis followed by a longitudinal follow-up. Results: Our study confirms an increased frequency of CPP and obesity in patients with NT1. At first evaluation, obesity was found in 31.3% of patients, while overweight was found in 25.0%. A diagnosis of CPP was made in 19.6% of patients. Interestingly, this group showed a significantly lower level of CSF-hypocretin (hrct-1) at diagnosis compared to others. We found an improvement in BMI SDS in the SO-treated group compared to untreated patients, and this trend persisted also at 36 months of follow-up (0.0 ± 1.3 vs 1.3 ± 0.4; p<0.03). Sixty-three patients reached their final height, with a median SDS of 0.6 ± 1.1 in boys and 0.2 ± 1.2 in girls. Discussion: To our knowledge, these are the first results regarding the final height in a large series of pediatric patients with NT1, with a normal range of IGF1-SDS levels and stature SDS. [ABSTRACT FROM AUTHOR]

1,4-Butanediol (BDO)-used as solvent and abused for its euphoric effects-is converted to gamma-hydroxybutyrate (GHB) by the enzyme alcohol dehydrogenase. This double-blind, placebo-controlled crossover study with six healthy volunteers is the first to date investigating the role of the ADH inhibitor fomepizole (4-methylpyrazole (4MP)) in moderating this conversion in humans. Participants received on two different days either intravenous placebo or 15 mg/kg 4MP followed by oral administration of 25 mg/kg BDO. Pretreatment with 4MP resulted in significantly higher BDO maximal plasma concentration (P = 0.001) and area under the concentration-time curve (AUC; P = 0.028), confirming that ADH is the primary pathway for the conversion of BDO to GHB in humans. With 4MP, the mean arterial pressure was significantly lower at 105 minutes compared to baseline (P = 0.003), indicating that blood pressure lowering, observed not with a temporal relationship to 4MP administration but after the maximum BDO concentration was reached, may be an intrinsic effect of BDO.

IntroductionNarcolepsy Type 1 (NT1) is a rare hypersomnia of central origin linked to hypocretin deficiency, most frequently arising at pediatric age. NT1 could be associated with endocrine comorbidities involving the neuroendocrine axis, predominantly obesity, and Central Precocious Puberty (CPP). The primary aim of this study is the evaluation of endocrine and auxological parameters at diagnosis and during follow-up in patients with NT1, treated with Sodium Oxybate (SO) or not.MethodsWe retrospectively evaluated the auxological, biochemical, and radiological parameters of 112 patients referred to our Center between 2004-2022. The design of our study is cross-sectional at the time of diagnosis followed by a longitudinal follow-up. ResultsOur study confirms an increased frequency of CPP and obesity in patients with NT1. At first evaluation, obesity was found in 31.3% of patients, while overweight was found in 25.0%. A diagnosis of CPP was made in 19.6% of patients. Interestingly, this group showed a significantly lower level of CSF-hypocretin (hrct-1) at diagnosis compared to others. We found an improvement in BMI SDS in the SO-treated group compared to untreated patients, and this trend persisted also at 36 months of follow-up (0.0 ± 1.3 vs 1.3 ± 0.4; p

Jordan Dubow,1 Alon Y Avidan,2 Bruce Corser,3 Amod Athavale,4 David Seiden,1 Clete Kushida5 1Avadel Pharmaceuticals, Chesterfield, MO, USA; 2Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; 3Sleep Management Institute, Cincinnati, OH, USA; 4Trinity Life Sciences, Waltham, MA, USA; 5Department of Psychiatry and Behavioral Sciences, Stanford University Medical Center, Stanford Sleep Medicine Center, Redwood City, CA, USACorrespondence: David Seiden, Tel +1 954 600-4625, Fax +1 636-449-1850, Email dseiden@avadel.comPurpose: Current US FDA-approved treatments for narcolepsy include sodium oxybate (SXB) and calcium, magnesium, potassium, and sodium oxybates (mixed-salt oxybates), which require 2 nightly doses, 1 at bedtime and another 2.5 to 4 hours later. Once-nightly SXB (ON-SXB; FT218) is under FDA review to treat adults with narcolepsy. This study quantitatively characterized attributes of SXB treatment preferred by individuals with narcolepsy via a discrete choice experiment (DCE) and evaluated preferences for the product profiles of once-nightly vs twice-nightly SXB treatment.Patients and Methods: Adults with self-reported physician-diagnosed narcolepsy for ≥ 1 year and current or prior twice-nightly SXB treatment were eligible for this 30-minute, web-based study capturing patient experiences and a DCE. Participants responded to a survey instrument using 9-point scales; higher scores indicated greater severity/preference/satisfaction. In the DCE, hundreds of profiles were generated, each combining attributes of twice-nightly SXB and ON-SXB based on clinical trial data. The DCE was analyzed using a hierarchical Bayesian model.Results: Seventy-five participants were surveyed (50 current and 25 past twice-nightly SXB users). Dosing frequency was the most important attribute of SXB treatment; once nightly was significantly preferred vs twice nightly. The most common reasons for overall product preference were lack of need to wake up in the middle of the night for a second dose (48%), fewer side effects (46%), and ease of administration (32%). Number of nightly doses was the most important driver of taking the medication exactly as directed and reduced anxiety/stress. Participants were significantly more likely to prefer the blinded product profile of once-nightly SXB over twice-nightly SXB (mean rating, 7.5 vs 4.3; P< 0.05).Conclusion: Among the choices presented, dosing frequency was the most important attribute for overall product choice, likelihood to take medication exactly as directed, and reducing anxiety/stress. The ON-SXB blinded profile was significantly preferred over twice-nightly SXB.Keywords: narcolepsy, patient preference, adherence, sodium oxybate, discrete choice experiment, once-nightly