Substitution therapy for patients with alcohol dependence: Mechanisms of action and efficacy.

New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. Here, we explain the mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate, baclofen and benzodiazepines, NMDA receptor antagonists such as ketamine and memantine, or nAChRs agonists such as varenicline. All these compounds are already approved for other indications and we present clinical evidence for these drugs in the treatment of alcohol withdrawal syndrome (AWS) and in the long-term treatment of AD, and outline future steps for their acceptance as substitution treatment in AD. Finally, we discuss the substitution approach of managed alcohol programs for the most severely affected homeless populations. Results showed that sodium oxybate is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries. In conclusion, we argue that better AD treatment can be provided if substitution maintenance treatments for alcohol are implemented at a similar scale as for opioid and nicotine use disorder.

Effects of oxybate dose and regimen on disrupted nighttime sleep and sleep architecture.

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.

Dosing and transition characteristics in people with narcolepsy transitioning from sodium oxybate to low-sodium oxybate: Data from the real-world TENOR study.

OBJECTIVE: 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). METHODS: 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. RESULTS: 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 %). CONCLUSION: 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.

Consequences of 1,4-Butanediol Misuse: A Review.

Gamma-hydroxybutyrate (GHB), along with its precursors, 1,4-butanediol (1,4-BD) and gamma-butyrolactone (GBL), are potent central depressant agents widely illicitly used for their euphoric and relaxant effects. The article presents a review of the literature on the 1,4-BD misuse, the clinical picture of intoxication, development of addiction and delirium. The available evidence shows that 1,4-BD is a substance with its own psychoactive effects, a high addiction potential and potentially severe withdrawal symptoms.

GHB: a life-threatening drug complications and outcome of GHB detoxification treatment-an observational clinical study.

BACKGROUND: GHB (gammahydroxybutyrate) and its precursors are popular recreational drugs due to their sedative, anxiolytic and sexually stimulating effects. Their use has been steadily increasing in recent years. The detoxification process is complex and prone to high rates of complications while little is known about the pathophysiology. This study aims to elucidate the characteristics of GHB-addicted patients and to evaluate the risks and complications of GHB withdrawal treatment. METHODS: This observational study describes prospectively the socioeconomic status, clinical history and course of inpatient detoxification treatment of a group of 39 patients suffering from GHB substance use disorder. Detoxification treatment took place in a highly specialized psychiatric inpatient unit for substance use disorders. RESULTS: GHB patients were characterised by being young, well-educated and by living alone. More than 50% of the patients had no regular income. The patients were male and female in equal numbers. Detoxification treatment was complicated, with high rates of delirium (30.8%) and high need for intensive care (20.5%). CONCLUSIONS: In our sample, GHB users were young, well-educated people and male and female in equal number. Detoxification proved to be dangerous for GHB-addicted patients. The presence of delirium and the need for transfer to an intensive care unit during detoxification treatment was extraordinarily high, even with appropriate clinical treatment. The reasons for this remain unknown. Therefore an intensive care unit should be available for GHB detoxification treatment. Further studies are needed to evaluate the options for prophylactic treatment of delirium during detoxification.

[Withdrawal syndrome following chronic use of gamma-hydroxybutyric acid (GHB)]. / Syndrome de sevrage lors d'une consommation chronique d'acide gamma-hydroxybutyrique (GHB).

Chronic use of gamma-hydroxybutyric acid (GHB) and its precursors can rapidly lead to physical dependence with the emergence of a withdrawal syndrome. This complication is similar to the one linked to alcohol or benzodiazepines. The onset of symptoms and specially neuro-psychiatric symptoms is, however, more rapid in the case of the GHB and precursors. There is currently no consensus on the therapeutic management of GHB withdrawal syndrome. High-dose benzodiazepines are the most commonly used treatment. The use of GHB by titration and tapering could show fewer side effects and withdrawal symptoms. It appears necessary to reflect on and pursue research on the use of GHB and its precursors, which remains poorly understood, on the management of withdrawal syndrome due to the lack of protocol and on its probably underestimated impact on public health.

La consommation chronique d'acide gamma-hydroxybutyrique (GHB) et de ses précurseurs peut rapidement entraîner une dépendance physique avec l'émergence d'un syndrome de sevrage à l'arrêt des consommations. Ce syndrome de sevrage présente des similitudes avec celui lié à l'alcool ou aux benzodiazépines. On retrouvera, cependant, une apparition et une évolution plus brutales ainsi que l'émergence, plus précoce, de symptômes neuropsychiatriques. Il n'y a actuellement pas de consensus concernant la prise en charge thérapeutique de ce syndrome de sevrage. Dès lors, le recours aux benzodiazépines à hautes doses constitue le traitement le plus régulièrement utilisé. L'utilisation de GHB médical, titré et avec une posologie progressivement diminuée, pourrait démontrer moins d'effets secondaires et de symptômes de sevrage. Il apparaît nécessaire de réfléchir et de poursuivre les recherches sur la consommation du GHB et ses précurseurs, qui reste largement méconnue, ainsi que sur la prise en charge du sevrage, au vu de l'absence de protocole et de son impact en santé publique, probablement sous-estimé.

Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia.

STUDY OBJECTIVES: To evaluate 6-month efficacy and safety of low-sodium oxybate in people with idiopathic hypersomnia during an open-label extension period (OLE) of a phase 3 clinical trial. METHODS: Efficacy measures included the Epworth Sleepiness Scale (ESS), Idiopathic Hypersomnia Severity Scale (IHSS), Patient Global Impression of Change (PGIc), Functional Outcomes of Sleep Questionnaire, short version (FOSQ-10), and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI:SHP). Treatment-emergent adverse events were collected throughout the OLE. RESULTS: The OLE population included 106 participants. Most were female (71%) and White (83%), and the mean (SD) age was 41.0 (13.8) years. ESS scores decreased (improved) during the OLE (mean [SD], study baseline: 16.3 [2.8]; OLE week 2: 6.7 [4.7]; OLE end: 5.3 [3.7]), and IHSS total scores trended toward a decrease (study baseline: 32.6 [7.3]; OLE week 2: 16.2 [8.9]; OLE end: 14.8 [8.6]. Median (minimum, maximum) paired differences from OLE week 2 to OLE end were ESS, -1.0 (-20, 7; nominal P = .012); IHSS, -1.0 (-31, 19; nominal P = .086). The proportion of participants reporting PGIc ratings of "very much improved" increased from 36.7% at OLE week 2 to 53.8% at the OLE end. The FOSQ-10 and WPAI:SHP scores remained stable during OLE. The incidence of newly reported treatment-emergent adverse events decreased over the duration of the OLE. CONCLUSIONS: Efficacy and safety of low-sodium oxybate were maintained or improved during the 6-month OLE, supporting long-term treatment with low-sodium oxybate in adults with idiopathic hypersomnia. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) With an Open-label Safety Extension; URL: https://clinicaltrials.gov/study/NCT03533114; Identifier: NCT03533114 and Registry: EU Clinical Trials; Name: A Double-blind, Placebo-controlled, Randomized Withdrawal, Multicenter Study of the Efficacy and Safety of JZP-258 in the Treatment of Idiopathic Hypersomnia (IH) with an Open-label Safety Extension; URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-001311-79/results; Identifier: 2018-001311-79. CITATION: Morse AM, Dauvilliers Y, Arnulf I, et al. Long-term efficacy and safety of low-sodium oxybate in an open-label extension period of a placebo-controlled, double-blind, randomized withdrawal study in adults with idiopathic hypersomnia. J Clin Sleep Med. 2023;19(10):1811-1822.

Sodium Oxybate in Alcohol-Responsive Essential Tremor of Voice: An Open-Label Phase II Study.

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.

Effectiveness and tolerability in people with narcolepsy transitioning from sodium oxybate to low-sodium oxybate: Data from the real-world TENOR study.

OBJECTIVES: 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). METHODS: 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). RESULTS: 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). CONCLUSIONS: Findings from TENOR confirm maintenance of effectiveness and tolerability when transitioning from SXB to LXB treatment.

Clinician Preferences for Oxybate Treatment for Narcolepsy: Survey and Discrete Choice Experiment.

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.

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 2.5­4 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.

Calcium, magnesium, potassium, and sodium oxybates oral solution for cataplexy or excessive daytime sleepiness associated with narcolepsy.

INTRODUCTION: Lower-sodium oxybate (LXB) is a novel formulation that is approved by the US Food and Drug Administration (FDA) to treat cataplexy and excessive daytime sleepiness (EDS) in adult patients and children ≥7 years with narcolepsy. LXB contains 92% less sodium than sodium oxybate (SXB), which adds 550-1640 mg of sodium/day at usual doses of 3-9 g/day. The FDA has declared LXB to be clinically superior to SXB due to greater safety by reducing the chronic sodium load. Narcolepsy patients have high comorbidities for hypertension and cardiovascular disease conditions, which can be adversely affected by high sodium intake. AREAS COVERED: This drug review discusses narcolepsy, current and upcoming pharmacotherapy, and LXB chemistry, pharmacodynamics, pharmacokinetics, and metabolism. Published results from LXB's phase 1 studies, a phase 3 study, and two post-marketing studies are reviewed. Databases searched included PubMed, Google Scholar, Lexi-Comp, Scopus, Science, and Ovid. EXPERT OPINION: LXB is efficacious in treating daytime sleepiness and cataplexy in adults and children ≥7 years with narcolepsy. Using LXB instead of SXB formulations may benefit narcolepsy patients with cardiovascular comorbidities and hypertension, but long-term studies are needed to prove it.

Long-Term Safety and Tolerability During a Clinical Trial and Open-Label Extension of Low-Sodium Oxybate in Participants with Narcolepsy with Cataplexy.

BACKGROUND: The safety and efficacy of low-sodium oxybate (LXB; Xywav®) were established in a randomized, double-blind, placebo-controlled, phase 3 withdrawal study in adults with narcolepsy with cataplexy; however, the longer-term safety profile has not yet been examined. The aim of the current analysis was to assess the time of onset and duration of common treatment-emergent adverse events (TEAEs) for LXB throughout the open-label optimized treatment and titration period (OLOTTP) and the stable dose period (SDP) portions of the main study, and the subsequent 24-week open-label extension (OLE). METHODS: In a double-blind, placebo-controlled, randomized withdrawal trial of LXB, TEAEs were evaluated during the 12-week OLOTTP, the 2-week SDP, and the subsequent 24-week OLE. Eligible participants were aged 18-70 years with a diagnosis of narcolepsy with cataplexy. At study entry, participants were taking sodium oxybate (SXB) alone, SXB with other anticataplectics, other anticataplectics alone, or were anticataplectic-treatment naive; other anticataplectics were tapered and discontinued during the OLOTTP. All participants initiated LXB during week 1 of the OLOTTP, and their dose was individually titrated based on safety and efficacy. Following the main study period, participants entered the OLE after rescreening (re-entry) after discontinuing LXB treatment or directly after completing the main study (rollover). TEAEs were assessed in the safety population as of database lock. TEAE duration was defined as time from TEAE start date to end date (or end of SDP or OLE, if end date was unrecorded). RESULTS: The safety population included 201 participants (SXB alone, n = 52; SXB with other anticataplectics, n = 23; other anticataplectics alone, n = 36; anticataplectic-treatment naive, n = 90). During the OLOTTP/SDP, headache was the most common LXB-emergent TEAE overall (71 events; n = 42 (21%); median (range) duration = 1 (1-147) day), followed by nausea (31 events; n = 26 (13%); median (range) duration = 9 (1-54) days) and dizziness (26 events; n = 21 (10%); median (range) duration = 7 (1-117) days). Among the 74 participants in the OLE, the most commonly reported TEAEs were headache (14 events; n = 7, 9%; peak incidence month 3 (n = 5/72); median (range) duration = 1 (1‒25) day), dizziness (8 events; n = 5, 7%; peak incidence month 1 (n = 3/74); median (range) duration = 26 (1‒181) days), and nasopharyngitis (6 events; n = 6, 8%; peak incidence month 6 (n = 2/69); median (range) duration = 9 (1‒24) days). Overall, study discontinuations attributed to TEAEs were 21/65 (32%) during the OLOTTP and SDP and 3/7 (43%) during the OLE. CONCLUSIONS: In this long-term analysis, the safety and tolerability profile of LXB was generally consistent with the known safety profile of SXB. During the OLOTTP and SDP, most TEAEs occurred early and were generally of short duration. TEAE prevalence decreased throughout the duration of the OLE; the most common TEAEs reported during the OLE were headache, dizziness, and nasopharyngitis. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03030599 (25 January 2017).

Low-sodium oxybate (LXB) is a medicine for narcolepsy. LXB treats daytime sleepiness and cataplexy (sudden muscle weakness). LXB is like sodium oxybate (SXB) but has 92% less sodium. This study looked at side effects in people taking LXB for many months. Three study periods were looked at in this report. In period 1, people could change their LXB dose for 12 weeks. This was to find their best dose. In period 2, people took that same best dose for 2 weeks. In period 3, some people kept taking LXB for 24 weeks. This was to study the longer-term effects. Everyone knew that they were taking LXB. During periods 1 and 2, the most common side effect was headache. Nausea and dizziness were also common. During period 3, headache was also the most common side effect. Dizziness and nasopharyngitis were also common. Nasopharyngitis is a cold in the nose and throat. In periods 1 and 2, most side effects happened early on. They also ended quickly. Fewer side effects happened in period 3. Among people leaving the study early, 32% left because of side effects during periods 1 and 2. During period 3, 43% left because of side effects. Overall, long-term side effects in people taking LXB were similar to those seen with SXB.

Long-term follow-up on the effects of sodium oxybate on daytime sleepiness and sleep architecture in patients with narcolepsy type 1. / Efecto a largo plazo del oxibato de sodio en la somnolencia diurna y en la estructura del sueño en pacientes con narcolepsia de tipo 1.

INTRODUCTION: Sodium oxybate (SXB) was administered for the first time in 1979 in 16 patients with narcolepsy with cataplexy (NT1) that improved up to 20 months. AIMS: To evaluate the effect of SXB on daytime sleepiness and sleep architecture by video-polysomnography in a sample of 23 NT1 adult patients (13 men, 10 females) treated up to three years. Additional goal was to study the presence of sleep comorbidities. PATIENTS AND METHODS: NT1 patients were diagnosed according to International Classification of Sleep Disorders, third edition. We conducted a longitudinal observational study and a video-polysomnography comparing the sleep parameters of patients treated with an initial nocturnal dose of 4.5 g of SXB after six months (FU-1), one year (FU-2) and three years (FU-3) of uninterrupted treatment. Video-polysomnography parameters were analyzed including apnea-hypopnea and periodic leg movements indexes. RESULTS: Patients were HLA-DQB1*06:02 positive except a familial case. Thirteen patients (56%) discontinued SXB treatment over the three-year of the study. The two-nightly doses has been one of the reason for discontinuing treatment as well as insufficient compliance, mild or severe side effects, comorbidities and pregnancy. We found significant differences at FU-2 in sleep structure with an increased in stage N2 (p < 0.03) and a higher periodic leg movements index (p < 0.01). At FU-3 we found significant differences in sleep structure with an increase in stage N1 (p = 0.03) and in comorbidities (periodic leg movements and apnea-hypopnea indexes). There was not significant change on daytime sleepiness during the study. CONCLUSIONS: SXB was administered in low-medium doses. Two-nightly doses and sleep fragmentation linked to sleep comorbidities at long-term lead to drug withdrawal.

TITLE: Efecto a largo plazo del oxibato de sodio en la somnolencia diurna y en la estructura del sueño en pacientes con narcolepsia de tipo 1.Introducción. El oxibato de sodio (SXB) se utilizó en 1979 en 16 enfermos con narcolepsia-cataplejía (NT1) que mejoraron tras 20 meses de tratamiento. Objetivos. Evaluar el efecto del SXB en la somnolencia diurna y en la estructura del sueño mediante videopolisomnografía en una muestra de 23 enfermos de NT1 (13 hombres y 10 mujeres) tratados durante tres años. Investigamos adicionalmente la presencia de comorbilidad. Pacientes y métodos. Diagnosticamos a los enfermos de acuerdo con la Clasificación Internacional de Trastornos del Sueño, tercera edición. Realizamos un estudio longitudinal, observacional y de videopolisomnografía, comparando los parámetros de sueño y los índices de apnea-hipopnea y de movimientos periódicos de las piernas de los enfermos, tratados con una dosis nocturna inicial de 4,5 g de SXB al cabo de seis meses (C-1), un año (C-2) y tres años (C-3) de tratamiento ininterrumpido. Resultados. Todos los enfermos eran HLA-DQB1*06:02 positivos, excepto un caso familiar. Trece enfermos (56%) interrumpieron el tratamiento debido a las dos tomas nocturnas, así como a la presencia de efectos secundarios, comorbilidad y embarazo. Encontramos diferencias significativas en C-2 en la estructura del sueño con aumento del estadio N2 (p < 0,03) y del índice de movimientos periódicos de las piernas (p < 0,01). En el control C-3 encontramos diferencias significativas en la estructura del sueño con aumento del estadio N1 (p = 0,03), y de los índices de movimientos periódicos de las piernas y de apnea-hipopnea. Conclusiones. El SXB se administró en dos dosis nocturnas, lo que, unido a la fragmentación del sueño y a la aparición de comorbilidades, condujo a la interrupción del tratamiento a largo plazo.

Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration.

AIMS: The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients. METHODS: Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively. RESULTS: Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001. CONCLUSIONS: In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.

Inpatient GHB withdrawal management in an inner-city hospital in Sydney, Australia: a retrospective medical record review.

RATIONALE: Regular consumption of gamma-hydroxybutyrate (GHB) may result in a dependence syndrome that can lead to withdrawal symptoms. There are limited data on medications to manage GHB withdrawal. OBJECTIVES: To examine characteristics associated with delirium and discharge against medical advice (DAMA), in the context of implementing a GHB withdrawal management protocol at an inner-city hospital in 2020. METHODS: We retrospectively reviewed records (01 January 2017-31 March 2021), and included admissions that were ≥ 18 years of age, admitted for GHB withdrawal, and with documented recent GHB use. Admissions were assessed for demographics, medications administered, features of delirium, ICU admission, and DAMA. Exploratory analyses were conducted to examine factors associated (p < 0.2) with features of delirium and DAMA. RESULTS: We identified 135 admissions amongst 91 patients. Medications administered included diazepam (133 admissions, 98.5%), antipsychotics (olanzapine [70 admissions, 51.9%]), baclofen (114 admissions, 84%), and phenobarbital (8 admissions, 5.9%). Features of delirium were diagnosed in 21 (16%) admissions. Delirium was associated with higher daily GHB consumption prior to admission, while duration of GHB use, time from presentation to first dose of diazepam, and concomitant methamphetamine use were inversely associated with delirium. DAMA occurred amongst 41 (30%) admissions, and was associated with a longer time from presentation to first dose of baclofen, while being female and receiving a loading dose of diazepam were inversely associated. CONCLUSIONS: This study adds to the literature in support of the safety and feasibility of diazepam and baclofen for the management of GHB withdrawal. Prospective, randomised trials are required.

Characteristics of poisonings involving ketamine in the United States, 2019-2021.

BACKGROUND: The use of ketamine, a controlled dissociative anesthetic, has become more widespread in recent years with recreational/nonmedical use increasing and ketamine becoming more widely available in clinics to treat depression. AIMS: We examined recent trends in adverse effects related to ketamine use. METHODS: US National Poison Control data were examined, focusing on ketamine exposures among those aged ⩾13 between 2019 and 2021 (n = 758). We examined quarterly trends in exposure and delineated correlates of patients experiencing a major adverse effect or death. RESULTS: The number of reported exposures increased 81.1% from 2019 Quarter 1 through 2021 Quarter 4, from 37 to 67 (p = 0.018). The majority of patients were male (57.1%), and the plurality of cases involved intentional misuse or "abuse" (39.5%), followed by suspected suicide attempt (19.7%) and unintentional exposure (18.9%). A fifth (19.6%) experienced a major adverse effect or death. A third (33.4%) co-used other drugs; the drugs most commonly co-used were benzodiazepines (14.6%), alcohol (10.3%), and opioids (8.7%). Co-use of gamma-hydroxybutyrate (GHB; adjusted prevalence ratio (aPR) = 3.43, 95% confidence interval (CI): 1.57-7.46) and opioids (aPR = 2.44, 95% CI: 1.46-4.08) was associated with increased risk for a major adverse effect or death, as was injection-only administration (aPR = 2.68, 95% CI: 1.21-5.92). CONCLUSIONS: Although still rare, poisonings involving ketamine have increased in recent years. Polydrug use-particularly with opioids or GHB-appears to be a particular risk factor for more serious adverse effects. As prevalence of use increases, it is important to monitor adverse effects and co-occurring behaviors to inform timely prevention and harm reduction as needed.

Adverse outcomes of GHB use: Analysis of ambulance attendances in metropolitan and regional Victoria.

BACKGROUND: Gamma-hydroxybutyrate (GHB) use and attributable harms have been increasing in Australia, however changes over time, including the impact of COVID-19 lockdowns and restrictions on harms requiring an ambulance attendance, are unknown. This study utilised a novel population-based surveillance system to identify the types of GHB-related harms between January 2018 and 31 December 2021 in Victoria, Australia. METHODS: A cross-sectional, retrospective analysis of all GHB-related ambulance attendances between January 2018 and 31 December 2021 in Victoria, Australia was undertaken. Paramedic clinical notes and Glasgow Coma Scale scores were used to assess conscious state. Event codes were classified using dispatch information available in the database. Crude rates (per 100,000 population) and descriptive analyses were calculated for metropolitan and regional settings. Adjusted Odds ratios (aOR) with 95% confidence intervals [95% CI] were used to assess the relationship between GCS severity and polysubstance combinations with GHB. RESULTS: There were 6,836 ambulance attendances for GHB recorded during the study period. A statistically significant increase in GHB-related attendance numbers was observed State-wide in 2019 (n = 1,402, p<0.001) and 2020 (n = 2,622, p<0.001), when comparing year on year attendances. While both numbers and rates (per 100,000 population) of GHB-related attendances were significantly lower in regional areas, significant increases were evident in both metropolitan and regional areas in 2019 and 2020 (both p<0.001). Attendances involving GHB and alcohol had higher odds of a severe GCS score (aOR:1.25; 95%: 1.04-1.49; p<0.019). A high proportion of GHB-attendances involved harms of significant concern including: overdose (56%) and a loss of, or altered state of consciousness (45%). CONCLUSIONS: We observed increases in GHB-related ambulance attendances over time in both metropolitan and regional areas, placing a significant burden on ambulance services. Our study demonstrates the value of using ambulance surveillance to obtain representative data on acute GHB-related harms.

Randomized, crossover, open-label study of the relative bioavailability and safety of FT218, a once-nightly sodium oxybate formulation: Phase 1 study in healthy volunteers.

OBJECTIVES: Treatment for narcolepsy with sodium oxybate (SXB) has required twice-nightly dosing, at bedtime and 2.5-4 h later. This study evaluated the pharmacokinetics of FT218, an investigational, extended-release, once-nightly formulation of SXB (ON-SXB), vs twice-nightly SXB. METHODS: In this phase 1, open-label study, healthy volunteers were randomized (1:1) to ON-SXB 6 g or twice-nightly SXB (two 3-g doses administered 4 h apart); minimum 3-day washout before crossover. Doses were administered 2 h post-evening meal. Blood samples for pharmacokinetic assessments were collected predose and up to 14 h after the first dose during each treatment period. RESULTS: Twenty-eight participants were enrolled (mean age, 39.6 years; 54% women; 93% white). Mean ± SEM area under the concentration-time curve for ON-SXB was 282.7 ± 30.2  µg·h/mL vs 273.3 ± 27.8 µg·h/mL for twice-nightly SXB. Geometric mean ratio (GMR; 90% CI) was 102.9 (98.0-108.0). Maximum γ-hydroxybutyrate (GHB) plasma concentration (Cmax) was 65.8 ± 4.0 µg/mL for ON-SXB vs 77.1 ± 4.9 µg/mL for twice-nightly SXB (GMR [90% CI], 88.3 [80.5-97.0]). The GMR (90% CI) for GHB plasma concentrations 8 h post dose (C8h) for ON-SXB vs twice-nightly SXB was 61.7 (45.8-83.0). The most frequently reported adverse events were the same for ON-SXB and twice-nightly SXB (nausea, dizziness, somnolence, vomiting). CONCLUSIONS: GHB exposure and Cmax with one 6-g dose of ON-SXB were bioequivalent to those with two 3-g doses of twice-nightly SXB, whereas C8h was lower with ON-SXB. If approved, ON-SXB will provide a single bedtime oxybate option, with clinically relevant pharmacologic exposure during the entire sleep period.