sodium-oxybate and Narcolepsy

Idiopathic hypersomnia is a central hypersomnolence disorder of unknown origin characterized by excessive daytime sleepiness despite normal or long sleep time, and frequent severe sleep inertia. Management strategies have been largely derived from expert consensus, due to a lack of disease-specific assessments and reliance on case series and rare randomized controlled studies. Guidelines recommend treatment with off-label medications. Modafinil, which was approved for idiopathic hypersomnia until 2011 in Europe, is the most commonly used treatment and improved sleepiness in two recent randomized placebo-controlled trials. In 2021, low-sodium oxybate (LXB) was approved in the United States for idiopathic hypersomnia. In a placebo-controlled, double-blind, randomized withdrawal study, LXB reduced daytime sleepiness and sleep inertia, and improved daily functioning. Here, treatment options are reviewed considering the authors' professional experience, current guidelines, and the latest research developments. The choice of pharmacotherapy should be guided by symptom profile, age, comorbidities (eg, depressive symptoms, cardiovascular problems), and concomitant medications (eg, oral contraceptives). Nonpharmacologic approaches have a role in management. An instrument (idiopathic hypersomnia severity scale) has been validated in idiopathic hypersomnia specifically, opening a path to better assessment of symptoms, impact, and response to treatment. Continued research on idiopathic hypersomnia is needed to support treatment algorithms.

Topics: Disorders of Excessive Somnolence; Expert Testimony; Humans; Idiopathic Hypersomnia; Modafinil; Narcolepsy; Randomized Controlled Trials as Topic; Sleep; Sodium Oxybate

This article provides a comprehensive review of pediatric sleep disorders including the clinical features, diagnosis, and treatment of sleep-disordered breathing, insomnia, parasomnias, restless sleep disorder, restless legs syndrome, narcolepsy in childhood, and Kleine-Levin syndrome.. Our understanding of pediatric sleep pathophysiology continues to evolve, and diagnostic and treatment modalities have expanded. A low-sodium oxybate formulation was approved in July 2020 in the United States to treat cataplexy and excessive daytime sleepiness in patients 7 years old and older with narcolepsy. A validated pediatric hypersomnolence survey for pediatric narcolepsy and idiopathic hypersomnia with high sensitivity, specificity, and interrater reliability is now available.. The clinical presentation, diagnostics, and treatment of children with sleep disorders differ from those of adults. Untreated sleep disorders in childhood can lead to adverse physical and psychological consequences in adults. Correctly diagnosing and treating sleep disorders in youth can prevent a significant burden of disease in adulthood.

Topics: Adolescent; Adult; Cataplexy; Child; Disorders of Excessive Somnolence; Humans; Narcolepsy; Parasomnias; Reproducibility of Results; Sodium Oxybate

This is a plain language summary of a published article in the journal. Compared to people who took placebo, people who took ON-SXB had fewer number of changes from deeper to lighter sleep stages and woke up less during the night. They also reported that they slept better at night and felt more refreshed when waking up in the morning. People with narcolepsy sometimes take alerting agents to help with sleepiness during the day, but alerting agents can cause difficulty sleeping at night. This study showed that people who took ON-SXB had better nighttime sleep even if they were taking alerting agents during the day. The most common side effects of ON-SXB included dizziness, nausea (feeling sick to your stomach), vomiting, headache, and bedwetting.. A once-nightly bedtime dose of ON-SXB is a narcolepsy treatment option for people without the need for a middle-of-the-night dose of sodium oxybate.

Topics: Adult; Cataplexy; Humans; Narcolepsy; Sleep; Sodium Oxybate; United States; United States Food and Drug Administration

This review aimed to summarize current knowledge about disrupted nighttime sleep (DNS) and sleep instability in narcolepsy, including self-reported and objective assessments, potential causes of sleep instability, health consequences and functional burden, and management.. One hundred two peer-reviewed publications from a PubMed search were included.. DNS is a key symptom of narcolepsy but has received less attention than excessive daytime sleepiness and cataplexy. There has been a lack of clarity regarding the definition of DNS, as many sleep-related symptoms and conditions disrupt sleep quality in narcolepsy (eg, hallucinations, sleep paralysis, rapid eye movement sleep behavior disorder, nightmares, restless legs syndrome/periodic leg movements, nocturnal eating, sleep apnea, depression, anxiety). In addition, the intrinsic sleep instability of narcolepsy results in frequent spontaneous wakings and sleep stage transitions, contributing to DNS. Sleep instability likely emerges in the setting of orexin insufficiency/deficiency, but its exact pathophysiology remains unknown. DNS impairs quality of life among people with narcolepsy, and more research is needed to determine its contributions to cardiovascular risk. Multimodal treatment is appropriate for DNS management, including behavioral therapies, counseling on sleep hygiene, and/or medication. There is strong evidence showing improvement in self-reported sleep quality and objective sleep stability measures with sodium oxybate, but rigorous clinical trials with other pharmacotherapies are needed. Treatment may be complicated by comorbidities, concomitant medications, and mood disorders.. DNS is a common symptom of narcolepsy deserving consideration in clinical care and future research.. Maski K, Mignot E, Plazzi G, Dauvilliers Y. Disrupted nighttime sleep and sleep instability in narcolepsy.

Topics: Cataplexy; Humans; Narcolepsy; Quality of Life; Sleep; Sodium Oxybate

Sodium oxybate is a medicine for narcolepsy symptoms. It contains a high level of sodium. Should people taking sodium oxybate and their doctors worry about the sodium increasing their risk of heart or cardiovascular problems? This is a summary of an article that reviewed 20 years of published data to answer that question.. We found that sodium oxybate was not linked to cardiovascular risks, such as heart attacks or strokes.. This suggests that the sodium in sodium oxybate may not add cardiovascular risk for people with narcolepsy. People currently taking sodium oxybate should talk to their doctor to ask if they need to be concerned about the sodium in their medicine. People who take sodium oxybate are unlikely to need to change their sodium oxybate medicine because of the sodium.

Topics: Humans; Language; Narcolepsy; Sodium; Sodium Oxybate

Idiopathic hypersomnia (IH) includes a clinical phenotype resembling narcolepsy (with repeated, short restorative naps), and a phenotype with an excess of sleep, sleep drunkenness, drowsiness, and infrequent long, nonrestorative naps. Sleep tests reflect this heterogeneity. MSLTs are greater than 8 min in 2/3 of the cases and poorly repeatable. Sleep excess is better captured by extended monitoring identifying 11 to 16h of sleep/24 h. Patients with IH are young and more often female. Possible mechanisms of IH include deficiencies in arousal systems, inappropriate stimulation of sleep-inducing systems, and long biological night. Treatments now include robust studies of modafinil, clarithromycin, and sodium oxybate.

Topics: Clarithromycin; Disorders of Excessive Somnolence; Female; Humans; Idiopathic Hypersomnia; Modafinil; Narcolepsy; Precision Medicine; Sodium Oxybate

Narcolepsy is a chronic sleep disorder characterized by a pentad of excessive daytime sleepiness (EDS), cataplexy, sleep paralysis, hypnagogic/hypnopompic hallucinations, and disturbed nocturnal sleep. Treatment of narcolepsy remains challenging and current therapy is strictly symptomatically based.. The present manuscript is based on an extensive Internet and PubMed search from 1990 to 2020. It is focused on the clinical and pharmacological properties of pitolisant in the treatment of narcolepsy.. Currently there is no cure for narcolepsy. Although efforts have been made, current treatments do not always allow to obtain an optimal control of symptoms. Pitolisant is an antagonist/inverse agonist of the histamine H3 autoreceptor. Its mechanism of action is novel and distinctive compared to the other available therapies for narcolepsy. Clinical trials suggest that pitolisant administered at a dose of ≤36 mg/day is an effective treatment option for narcolepsy, reducing EDS and cataplexy. Pitolisant is available as oral tablets and offers a convenient once-daily regimen. Pitolisant is generally well tolerated and showed minimal abuse potential in animals and humans. Long-term studies comparing the effectiveness and tolerability of pitolisant with active drugs (e.g. modafinil, sodium oxybate) are needed.

Topics: Animals; Cataplexy; Humans; Modafinil; Narcolepsy; Piperidines; Sleep; Sodium Oxybate; Treatment Outcome

Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.. The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.. A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.. The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Topics: Adult; Cataplexy; Child; Humans; Modafinil; Narcolepsy; Sleep; Sodium Oxybate

Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children.. The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach.. A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions.. The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

Topics: Adult; Cataplexy; Child; Humans; Modafinil; Narcolepsy; Sleep; Sodium Oxybate

Topics: Adult; Cataplexy; Humans; Methylphenidate; Modafinil; Narcolepsy; Sodium Oxybate

Narcolepsy is a central disorder of hypersomnolence with symptoms of excessive daytime sleepiness, sleep paralysis, and cataplexy. Cataplexy is the sudden loss of muscle tone in either the face, neck, trunk, and/or limbs, leading to a loss of voluntary muscle control. This article reviews recent research on the clinical characteristics of cataplexy.. Longitudinal research in adults suggests that there may be a remission of cataplectic severity after symptom stabilization. First-line treatment options for cataplexy include sodium oxybate and pitolisant, with many drugs such as AXS-12, FT218, and JZP258 under investigation. Patients with cataplexy reported greater limitations of daily activities such as driving and exercise compared to patients without cataplexy. Cataplexy remains a challenge for children and adults with narcolepsy and can interfere with daily activities. There is no cure for narcolepsy, but cataplexy can be well-managed with current and promising new treatment options on the horizon.

Topics: Adult; Cataplexy; Child; Disorders of Excessive Somnolence; Humans; Narcolepsy; Sodium Oxybate

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.

Topics: Cataplexy; Disorders of Excessive Somnolence; Humans; Narcolepsy; Sodium; Sodium Oxybate

Narcolepsy is a chronic and debilitating sleep disorder characterized by cataplexy and excessive daytime sleeping. Gamma-hydroxybutyrate (GHB) has been widely used to treat narcolepsy, and new findings have been published in recent years.. A meta-analysis was conducted to assess the efficacy and tolerability of GHB treatment in adults with narcolepsy.. A systematic search of PubMed, Cochrane, Embase, Web of Science, and clinical-trials.gov from inception to June 2018 was performed. Change in daily diaries and polysomnographic data of narcoleptic patients were defined as the efficacy outcomes. The tolerability and acceptability outcomes were the rates of adverse events and dropping out for adverse effects or other reasons.. Fifteen randomized controlled trials involving 2104 participants were identified. GHB was found to improve cataplexy attacks (P = 0.001), subjective daytime sleepiness (P < 0.0001), daytime sleep latency (P < 0.0001), inadvertent naps/sleep attacks (P < 0.00001), effective rates (Clinical Global Impression of change) (P < 0.00001), hypnagogic hallucinations (P = 0.004), sleep paralysis (P = 0.004), stage 1 sleep (P = 0.04), slow wave sleep (P = 0.003), REM sleep (P = 0.0006), sleep shifts (P = 0.005), nocturnal awakenings (P = 0.004), quality of nocturnal sleep (P < 0.00001), chin muscle activity, and quality of life, but had no effect on stage 2 sleep (P = 0.88). GHB was less well tolerated than placebo because of side effects that occurred in a dose-dependent fashion (RR = 6.08; 95% CI = 2.18 to 16.97; P = 0.0006).. GHB was effective in improving narcolepsy-cataplexy and related symptoms in adults but was less well tolerated than placebo because of dose-dependent side effects.

Topics: Adult; Cataplexy; Humans; Narcolepsy; Quality of Life; Randomized Controlled Trials as Topic; Severity of Illness Index; Sodium Oxybate; Treatment Outcome

Topics: Adjuvants, Anesthesia; Antidepressive Agents; Antidepressive Agents, Tricyclic; Cataplexy; Central Nervous System Stimulants; Drug Therapy; Humans; Immunogenetics; Intracellular Signaling Peptides and Proteins; Modafinil; Narcolepsy; Neurobiology; Sodium Oxybate

Topics: Adolescent; Adult; Antidepressive Agents; Cataplexy; Central Nervous System Stimulants; Child; Humans; Narcolepsy; Quality of Life; Randomized Controlled Trials as Topic; Sleep; Sodium Oxybate; Wakefulness-Promoting Agents

Narcolepsy type 1 (NT1) is a chronic neurologic disorder defined by excessive daytime sleepiness, cataplexy, sleep paralysis, hallucinations and disrupted nocturnal sleep, typically with onset during childhood/ adolescence. Pediatric NT1 is associated with limitations on children's activities and achievements, especially poor performance at school, difficulty with peers due to disease symptoms and comorbidities including depression, obesity, and precocious puberty. Sodium oxybate (SO) is a sodium salt of γ-hydroxybutyric (GHB) acid and is greatly effective in treating cataplexy and excessive daytime sleepiness in NT1 and it can be helpful also for sleep disruption, hypnagogic hallucination and sleep paralysis in these patients.. We conducted a research of literature into bibliographic databases regarding NT1 features in childhood and the possible option treatment with SO in this kind of patient population.. We reported sixteen papers focusing on symptom presentation and on clinical and metabolic features of children affected with NT1. Furthermore, we reported 24 manuscripts focusing on SO biological actions and pharmacological properties and on the few but important available studies (8) conducted in NT1 children under SO therapy.. Although in the majority of patients develop NT1 during childhood, there are no approved treatments for pediatric NT1. However, SO has been widely used off-label to treat narcolepsy symptoms in children and adolescents with NT1 in non-controlled studies, showing a similar safety profile and therapeutic response to adult patients. Ongoing pediatric therapy is based only on observational data shared among sleep disorders clinicians.

Topics: Animals; Body Weight; Child; Drug Interactions; Growth Hormone; Humans; Narcolepsy; Sodium Oxybate

Randomized controlled trials (RCTs) that compared the safety and efficacy of medical treatments for narcolepsy were analyzed using network meta-analysis.. The RCTs in narcolepsy were searched. Network meta-analysis compared efficacy and safety of multiple treatments, multi-arm studies, and multi-criteria treatment decisions, based on a random model that assumed heterogeneity between studies, with corrections for multi-arm studies.. Fourteen RCTs, three drug treatments, and six doses were identified: sodium oxybate (6 and 9 g/d), modafinil (between 200 and 400 mg/d), and pitolisant (up to 20 and up to 40 mg/d). Significant heterogeneity (>50%) between studies was found in 12/14 studies for almost all endpoints, but between-design consistency was present. For ESS and MWT, sodium oxybate 9 g/d, modafinil, and pitolisant up to 40 mg/d had similar efficacy. Pitolisant 40 mg/d and sodium oxybate 9 g/d in two nightly doses had similar efficacy in reducing cataplexy. A good safety profile characterized by a TEAE incidence risk ratio (IRR) <1.5 was found for all the compared treatments, except for sodium oxybate 9 g/d. Although no significant difference was found, Pitolisant 40 mg was shown with the best P scores for the benefit/risk (BR) ratio.. Modafinil (200-400 mg/d), sodium oxybate 9 g/d, and pitolisant up to 40 mg/d had similar efficacy in reducing excessive day time sleepiness. Only sodium oxybate 9 g/d and pitolisant up to 40 mg/d were shown with a comparable beneficial effect on cataplexy. Overall, Pitolisant was found with the best P score on the BR ratio.. PROSPERO 2017 CRD42017054686. Efficacy, safety, and benefit-risk comparison of alternative treatments in narcolepsy: a network multiple comparisons of treatment meta-analysis. http://www.crd.york.ac.uk/PROSPERO/display_record.php?ID=CRD42017054686.

Topics: Adult; Cataplexy; Humans; Modafinil; Narcolepsy; Network Meta-Analysis; Odds Ratio; Piperidines; Risk Assessment; Sleepiness; Sodium Oxybate

Narcolepsy is an orphan neurological disease and presents with sleep-wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life. Areas covered: This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies. First- and second-line options are discussed as well as combination therapies. In addition, treatment options for frequent coexisting co-morbidities and different phenotypes of narcolepsy are presented. Finally, this review considers potential future management strategies. Non-pharmacological approaches are important in the management of narcolepsy but will not be covered in this review. Expert opinion: Concise evaluation of symptoms and type of narcolepsy, coexisting co-morbidities and patients´ distinct needs is mandatory in order to identify a suitable, individual pharmacological treatment. First-line options include Modafinil/Armodafinil (for excessive daytime sleepiness, EDS), Sodium Oxybate (for EDS and/with cataplexy), Pitolisant (for EDS and cataplexy) and Venlafaxine (for cataplexy (off-label) and co-morbid depression). New symptomatic and causal treatment most probably will be completed by hypocretin-replacement and immune-modifying strategies.

Topics: Adult; Benzhydryl Compounds; Cataplexy; Drug Therapy, Combination; Humans; Modafinil; Narcolepsy; Neuropeptides; Off-Label Use; Orexins; Piperidines; Quality of Life; Sleep; Sodium Oxybate; Venlafaxine Hydrochloride; Wakefulness-Promoting Agents

Narcolepsy is a chronic sleep disorder that has a typical onset in adolescence and is characterized by excessive daytime sleepiness, which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2), both of which have similar clinical profiles, except for the presence of cataplexy, which occurs only in patients with narcolepsy type 1. The pathogenesis of narcolepsy type 1 is hypothesized to be the autoimmune destruction of the hypocretin-producing neurons in the hypothalamus; this hypothesis is supported by immune-related genetic and environmental factors associated with the disease. However, direct evidence in support of the autoimmune hypothesis is currently unavailable. Diagnosis of narcolepsy encompasses clinical, electrophysiological and biological evaluations, but simpler and faster procedures are needed. Several medications are available for the symptomatic treatment of narcolepsy, all of which have quite good efficacy and safety profiles. However, to date, no treatment hinders or slows disease development. Improved diagnostic tools and increased understanding of the pathogenesis of narcolepsy type 1 are needed and might lead to therapeutic or even preventative interventions.

Topics: Adjuvants, Anesthesia; Benzhydryl Compounds; Biomarkers; Cataplexy; Genetic Predisposition to Disease; HLA-DQ beta-Chains; Humans; Modafinil; Narcolepsy; Orexins; Quality of Life; Risk Factors; Serotonin and Noradrenaline Reuptake Inhibitors; Sleep Wake Disorders; Sodium Oxybate; Wakefulness-Promoting Agents

Narcolepsy type 1 and narcolepsy type 2 are central disorders of hypersomnolence. Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy and is associated with hypocretin-1 deficiency. On the other hand, in narcolepsy type 2, cerebrospinal fluid hypocretin-1 levels are normal and cataplexy absent. Despite major advances in our understanding of narcolepsy mechanisms, its current management is only symptomatic. Treatment options may vary from a single drug that targets several symptoms, or multiple medications that each treats a specific symptom. In recent years, narcolepsy treatment has changed with the widespread use of modafinil/armodafinil for daytime sleepiness, antidepressants (selective serotonin and dual serotonin and noradrenalin reuptake inhibitors) for cataplexy, and sodium oxybate for both symptoms. Other psychostimulants can also be used, such as methylphenidate, pitolisant and rarely amphetamines, as third-line therapy. Importantly, clinically relevant subjective and objective measures of daytime sleepiness are required to monitor the treatment efficacy and to provide guidance on whether the treatment goals are met. Associated symptoms and comorbid conditions, such as hypnagogic/hypnopompic hallucinations, sleep paralysis, disturbed nighttime sleep, unpleasant dreams, REM- and non REM-related parasomnias, depressive symptoms, overweight/obesity, and obstructive sleep apnea, should also be taken into account and managed, if required. In the near future, the efficacy of new wake-promoting drugs, anticataplectic agents, hypocretin replacement therapy and immunotherapy at the early stages of the disease should also be evaluated.

Topics: Animals; Antidepressive Agents; Central Nervous System Stimulants; Humans; Methylphenidate; Narcolepsy; Neuropeptides; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) is a short chain fatty acid endogenously produced within the central nervous system (CNS) and acts as a precursor and metabolite of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Although, it is an illegal recreational drug of abuse, its sodium salt (sodium oxybate) has been utilized as a medication for a number of medical conditions. The first aim of this review was to focus on current applications of sodium oxybate for the treatment of narcolepsy, with a particular emphasis on the key symptoms of this disorder: cataplexy and excessive daytime sleepiness (EDS). Secondly, the effectiveness of sodium oxybate therapy for the treatment of alcohol withdrawal syndrome (AWS) and the maintenance of alcohol abstinence has been assessed. Nowadays, sodium oxybate is the first-line treatment for narcolepsy and it is highly effective in meliorating sleep architecture, decreasing EDS and the frequency of cataplexy attacks in narcoleptic patients. Sodium oxybate currently finds also application in the treatment of AWS and the maintenance of alcohol abstinence in alcoholics. Most of the studies evaluating the efficacy of GHB in the treatment of AWS use a dosage of 50 mg/kg divided in three or four administrations per day. Human studies showed that GHB (dose of 50 mg/kg, divided in three administrations per day) is capable to increase the number of abstinent days, reduce alcohol craving and decrease the number of drinks per day. However, there is limited randomized evidence and, thus, GHB cannot be reliably compared to clomethiazole or benzodiazepines. Some randomized data suggest that GHB is better than naltrexone and disulfiram regarding abstinence maintenance and prevention of craving in the medium term i.e. 3-12 months. It is recommended that GHB should be used only under strict medical supervision, since concerns about the abuse/misuse of the drug and the addiction potential have been arisen.

Topics: Alcohol Withdrawal Delirium; Alcohol Withdrawal Seizures; Female; gamma-Aminobutyric Acid; Humans; Illicit Drugs; Male; Narcolepsy; Prodrugs; Sleep; Sodium Oxybate

The medications used to treat narcolepsy are targeted toward alleviating symptoms such as excessive sleepiness and cataplexy. The cause of this neurological sleep disorder is still not completely clear, though a destruction of hypocretin/orexin neurons has been implicated. The destruction of these neurons is linked to inactivity of neurotransmitters including histamine, norepinephrine, acetylcholine, and serotonin, causing a disturbance in the sleep/wake cycles of narcoleptic patients. Stimulants and MAOIs have traditionally been used to counteract excessive daytime sleepiness and sleep attacks by inhibiting the breakdown of catecholamines. Newer drugs, called wake-promoting agents, have recently become first-line agents due to their better side-effect profile, efficacy, and lesser potential for abuse. These agents similarly inhibit reuptake of dopamine, but have a novel mechanism of action, as they have been found to increase neuronal activity in the tuberomamillary nucleus and in orexin neurons. Sodium oxybate, a sodium salt of gamma-hydroxybutyrate (GHB), is another class that is used to treat many symptoms of narcolepsy, and is the only U.S. Food and Drug Administration (FDA)-approved medication for cataplexy. It has a different mechanism of action than either stimulants or wake-promoting agents, as it binds to its own unique receptor. Antidepressants, like selective serotonin re-uptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), have also been used, as similar to stimulants, they inhibit reuptake of specific catecholamines. In this article, we seek to review the mechanisms behind these classes of drugs in relation to the proposed pathophysiology of narcolepsy. Appropriate clinical strategies will be discussed, including specific combinations of medications that have been shown to be effective.

Topics: Antidepressive Agents; Antidepressive Agents, Tricyclic; Cataplexy; Central Nervous System Stimulants; Dopamine Uptake Inhibitors; Humans; Intracellular Signaling Peptides and Proteins; Monoamine Oxidase Inhibitors; Narcolepsy; Neuropeptides; Orexins; Sodium Oxybate; Wakefulness-Promoting Agents

Gamma-hydroxybutyrate (GHB) is currently authorized by the European Medicines Agency (EMA) to treat narcolepsy with cataplexy in adults, and by the Food and Drug Administration (FDA) to treat cataplexy in patients with narcolepsy, with an expanded indication for the treatment of excessive daytime sleepiness. This study meta-analyses and reviews the effectiveness of GHB on the clinical features of narcolepsy and its neurophysiological correlates.. A systematic review of the literature using Medline, Embase, Web of Science, Cochrane reviews, clinical-trials.gov, Scopus, Scirus, and a subsequent meta-analysis were performed. Considered outcomes were: cataplexy attacks, subjective daytime sleepiness, sleep attacks, clinical global impression change (CGI-c), quality of life (QoL), hypnagogic hallucinations, sleep paralysis, mean sleep latencies on the multiple sleep latency test (MSLT) and maintenance of wakefulness test (MWT), nocturnal polysomnographic data.. Nine randomized controlled trials reporting data on the effectiveness of GHB on narcolepsy were identified, for a total of 1,154 patients (771 patients in the GHB-treated group and 383 in the placebo group). The meta-analysis showed that GHB reduced cataplexy attacks both on a daily (weighted mean difference (WMD) -1.10; 95% confidence interval (CI) -1.29/-0.90, p < 0.00001) and a weekly basis (WMD -7.04; 95% CI -12.45/-1.63, p = 0.01), subjective nocturnal awakenings (WMD -1.33; 95% CI -1.78/-0.88, p < 0.00001), daytime sleep attacks on a weekly basis (WMD -9.30; 95% CI -15.92/-2.68, p = 0.006), subjective daytime sleepiness (WMD -2.81; 95% CI -4.13/-1.49, p < 0.0001) and sleep stage shifts (WMD -9.69; 95% CI -17.14/-2.24, p = 0.01). GHB increased sleep stages 3 + 4 (WMD 4.11; 95% CI 0.07/8.16, p = 0.05) and improved the CGI-c score (odds ratio (OR) 3.45; 95% CI 2.47/4.80, p < 0.00001). No significant changes were observed in night sleep latency, total sleep time, rapid-eye movement (REM) sleep and sleep stages 1 and 2.. This meta-analysis demonstrates the effectiveness of GHB in treating major, clinically relevant narcolepsy symptoms and sleep architecture abnormalities.

Topics: Adult; Cataplexy; GABA-B Receptor Agonists; Humans; Narcolepsy; Polysomnography; Randomized Controlled Trials as Topic; Sleep; Sleep Stages; Sodium Oxybate

Narcolepsy is a life-long neurodegenerative disorder that causes considerable impairment to quality of life. Until the 1970s, the treatment for one of the main symptoms, excessive daytime sleepiness, was restricted to stimulants, whereas the second core symptom, cataplexy, was treated with antidepressants, and the resultant fragmented night-time sleep with hypnotics. Sodium oxybate (Xyrem(®), UCB Pharma, Brussels, Belgium) is an efficacious drug for all three symptoms which improves the quality of life of narcoleptic patients. Owing to its metabolic pathway, there is very little pharmacokinetic interaction with other drugs. In combination with modafinil, some of its therapeutic benefits are enhanced. Adverse events and side effects are moderate when taken according to indication and as recommended. Essential limitations have to be considered before starting the treatment (sleep-related breathing disorders, alcohol intake, hypnotic and sedative comedication, and epilepsy). This article gives an overview of sodium oxybate, which has been US FDA approved for the treatment of cataplexy and excessive daytime sleepiness in patients with narcolepsy, and EMA approved for the treatment of narcolepsy-cataplexy.

Topics: Adjuvants, Anesthesia; Animals; Clinical Trials as Topic; Humans; Narcolepsy; Quality of Life; Sodium Oxybate

Narcolepsy is an emblematic, unique disease within sleep disorders that is characterised by excessive daytime sleepiness, cataplexy and other abnormal manifestations of REM sleep. In the last 14 years truly spectacular progress has been made in our knowledge of this disease, since the discovery of its cause, i.e. a loss of the hypothalamic neurons that synthesise hypocretin, a previously unknown neurotransmitter, and its probable aetiopathogenic mechanisms, i.e. an autoimmune process in a patient with very precise immunological characteristics - a specific type of HLA and a specific type of T-cell receptor. The cause of this autoimmune process remains unknown. The definitive treatment - the administration of hypocretin, which is the substance missing in the organism - is still unavailable, but there are powerful drugs for treating its main symptoms, the sleepiness and the cataplexy. Some of these are classic compounds (methylphenidate, clomipramine), while others are more recent (modafinil, venlafaxine, sodium oxybate), but together they allow many patients to experience significant improvements. Lack of knowledge about the disease, both on the part of patients and their relatives as well as physicians, is the reason for the great delay in its diagnosis, with even more dramatic consequences when the disease begins in infancy.

Topics: Adolescent; Adult; Age of Onset; Animals; Autoimmune Diseases; Benzhydryl Compounds; Cataplexy; Child; Clomipramine; Cyclohexanols; Delayed Diagnosis; Disease Models, Animal; Dogs; Genetic Predisposition to Disease; Histamine Agonists; HLA-DQ Antigens; HLA-DQ beta-Chains; Humans; Hypothalamus; Immunoglobulins, Intravenous; Intracellular Signaling Peptides and Proteins; Methylphenidate; Modafinil; Narcolepsy; Neuropeptides; Orexins; Polysomnography; Receptors, Antigen, T-Cell; Sodium Oxybate; Venlafaxine Hydrochloride

To assess the efficacy and safety of sodium oxybate (SXB) in narcolepsy-cataplexy patients.. Systematic review and meta-analysis.. Adults with narcolepsy-cataplexy.. SXB.. Electronic databases (e.g., MEDLINE) and references of included studies were searched to identify randomized controlled trials (RCTs) assessing the efficacy and safety of SXB for patients with narcolepsy-cataplexy. Risk of bias was appraised using the Cochrane risk of bias tool. Meta-analysis was conducted in Review Manager Version 5. Six RCTs and 5 companion reports were included after screening 14 full-text articles and 483 citations. All were private-industry funded. SXB (usually 9 g/night) was superior to placebo for reducing mean weekly cataplexy attacks (n = 2 RCTs, mean difference [MD]: -8.5, 95% CI: -15.3, -1.6), increasing maintenance wakefulness test (MWT) (n = 2, MD: 5.18, 95% CI: 2.59-7.78), reducing sleep attacks (n = 2, MD: -9.65, 95% CI: -17.72, -1.59), and increasing Clinical Global Impression scores (n = 3, relative risk, RR: 2.42, 95% CI: 1.77-3.32). SXB did not significantly increase REM sleep versus placebo (n = 2, MD: -0.49, 95% CI: -3.90, 2.92). Patients receiving SXB had statistically more adverse events versus placebo, including nausea (n = 3, relative risk [RR]: 7.74, 95% CI: 3.2, 19.2), vomiting (n = 2, RR: 11.8, 95% CI: 1.6, 89.4), and dizziness (n = 3, RR: 4.3, 95% CI: 1.1, 16.4). Enuresis was not significantly different from placebo (n = 2, RR: 2.6, 95% CI: 0.8, 9.8). All meta-analyses had minimal statistical heterogeneity (p-value > 0.1).. Narcolepsy patients on SXB have significant reductions in cataplexy and daytime sleepiness. SXB is well tolerated in patients with narcolepsy, and most adverse events were mild to moderate in severity.

Topics: Adult; Female; Humans; Male; Narcolepsy; Polysomnography; Sodium Oxybate; Treatment Outcome

Studies examining GABA(B) receptor agonists have reported effects on sleep including decreased sleep onset latency (SOL), increased sleep consolidation and increases in slow wave sleep (SWS). γ-hydroxybutyrate (GHB) is proposed to act as a GABA(B) receptor agonist; however, the mechanism of action of GHB is controversial. In addition, the GABA(B) receptor agonist, baclofen, has also been proposed to exert similar effects on sleep. The aim of this paper is to provide a review of the human clinical studies of sodium oxybate and baclofen regarding sleep and the treatment of sleep disorders including narcolepsy and insomnia, as well as other disorders involving disrupted sleep such as fibromyalgia.

Topics: Animals; Baclofen; GABA-B Receptor Agonists; Humans; Narcolepsy; Sleep; Sleep Initiation and Maintenance Disorders; Sleep Wake Disorders; Sodium Oxybate

While the symptoms of narcolepsy are often amenable to treatment with sodium oxybate (SXB), the respiratory effects of long-term SXB treatment have not been systematically studied. Recent reports have implicated SXB with several cases of worsening sleep-related breathing disturbances and accidental death. In addition, these patients are at risk for obesity, which may aggravate co-morbid obstructive sleep apnea.. Based on a review of the literature and the clinical experience of the author, recommendations for the use of SXB in patients with sleep-disordered breathing have been developed.. Among narcolepsy patients with evidence of sleep disordered breathing during baseline polysomnography, SXB should be prescribed only to those patients who fully comply with nasal continuous positive airway pressure therapy. The respiratory status of other SXB-treated patients should be periodically evaluated with nocturnal oximetry.. Based on the currently available data, physicians prescribing SXB should remain vigilant for the possible development of sleep-disordered breathing during long-term treatment with SXB.

Topics: Adjuvants, Anesthesia; Drug Monitoring; Humans; Narcolepsy; Sleep Apnea Syndromes; Sleep, REM; Sodium Oxybate

Narcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness (EDS), cataplexy, hypnagogic hallucinations, sleep paralysis and nocturnal sleep disruption. Non-pharmacological treatments (i.e., behavioral modification) are often helpful for the clinical management of narcoleptic patients. As these symptoms are often disabling, most patients need life-long treatments. Over 90% of diagnosed narcoleptic patients are currently prescribed medications to control their symptoms; however, available treatments are merely symptomatic.. This review presents a description of the clinical symptoms of narcolepsy, followed by a discussion of the state-of-the-art knowledge regarding the disorder and related emerging treatments. In preparing this review, an extensive literature search was conducted using Pubmed. Only selected references from 1970 to 2008 are cited.. This review focuses on emerging treatments for human narcolepsy, and the reader will gain significant knowledge of current and future treatment for this and related disorders. Traditionally, amphetamine-like stimulants (i.e., dopaminergic release enhancers) have been used for clinical management to improve EDS, and tricyclic antidepressants have been used as anticataplectics. However, treatments have recently evolved which utilize better tolerated compounds, such as modafinil (for EDS) and adrenergic/serotonergic selective reuptake inhibitors (as anticataplectics). In addition, night time administration of a short-acting sedative, gamma-hydroxybutyrate, has been used for the treatment for EDS and cataplexy. As a large majority of human narcolepsy is hypocretin peptide deficient, hypocretin replacement therapy may also be a new therapeutic option; yet, this option is still unavailable. In addition to the hypocretin-based therapy, a series of new treatments are currently being tested in animal and/or humans models. These potential options include novel stimulant and anticataplectic drugs as well as immunotherapy, based on current knowledge of the pathophysiology of narcolepsy with cataplexy.. We expect that more pathophysiology-based treatments, capable of curing and/or preventing narcolepsy and related diseases, will be available in near future. As cases of EDS, associated with other neurological conditions (i.e., symptomatic narcolepsy or narcolepsy due to medical conditions), are often linked with hypocretin deficiency, these novel therapeutic options may also be applied to treatment of these disabling conditions.

Topics: Animals; Antidepressive Agents; Cataplexy; Cell Transplantation; Central Nervous System Stimulants; Drugs, Investigational; Genetic Therapy; Hallucinations; Humans; Immunologic Factors; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Sleep Initiation and Maintenance Disorders; Sleep Paralysis; Sodium Oxybate; Wakefulness

Narcolepsy is a neurodegenerative disorder resulting in the instability of the sleep-wake cycle and marked by low levels of hypocretin in cerebrospinal fluid. Sleep instability is marked by brisk, sleep-onset REM periods and sleep fragmentation, while the waking state is interrupted by the intrusion of REM sleep and sometimes accompanied by cataplectic attacks.. Current pharmacologic interventions that aim to address three primary features of this disorder; excessive daytime sleepiness (EDS), cataplexy and automatic behaviors, and sleep fragmentation. We review and compare the use of traditional and new stimulants in the treatment of EDS. For the treatment of cataplexy and automatic behaviors, serotonergic and noradrenergic agents are considered. The role of gamma-hydroxybutyrate (GHB) is also explored in its ability to reduce daytime sleepiness and catapletic attacks and to consolidate sleep. Findings are based on a PubMed literature search of clinical and basic science research papers spanning 1977-2009.. A comprehensive understanding of the various existing and promising future treatments for narcolepsy. For each of these treatments, we evaluate risks versus benefits of treatment, and proposed pharmacologic mechanisms of action. We conclude with a review of new treatment approaches, including thyrotropin-releasing hormone (TRH), histamine agonists, immunotherapy and hypocretin replacement therapies.. Narcolepsy is an autoimmune, neurodegenerative disorder that results in significant sleep-wake instability with or without cataplectic attacks. Current treatments aim symptomatically to reconsolidate the sleep and waking states and to reduce daytime attacks of cataplexy. Future treatments aim primarily towards correcting the causal deficiency of hypocretin or preventing the autoimmune response that results in the loss of hypocretin cells.

Topics: Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Caffeine; Central Nervous System Stimulants; Humans; Hypnotics and Sedatives; Immunotherapy; Intracellular Signaling Peptides and Proteins; Modafinil; Narcolepsy; Neuropeptides; Orexins; Selective Serotonin Reuptake Inhibitors; Sodium Oxybate

Gamma-hydroxybutyric acid (GHB) is a neurotransmitter that occurs naturally in the brain and is increasingly being used as a 'party drug' because of its relaxing and euphoria-inducing effects. GHB has a limited medical use in the treatment of narcolepsy. GHB-intoxications occur often in non-medical use, and generally result in a coma of short duration. GHB use several times a day can lead to tolerance and dependence. After sudden cessation or reduction of intensive GHB use, a severe withdrawal syndrome may occur with symptoms varying from tremor, anxiety and agitation to autonomic instability, hallucinations and delirium. Treatment of the GHB withdrawal syndrome consists of supportive care and benzodiazepines, often in high doses. The controlled detoxification of GHB using pharmaceutical GHB in an adjusted dose is currently being investigated in the Netherlands. There is no literature concerning the treatment of patients following GHB intoxication or after detoxification.

Topics: Adjuvants, Anesthesia; Coma; Drug Tolerance; Humans; Narcolepsy; Sodium Oxybate; Substance Withdrawal Syndrome; Substance-Related Disorders

Narcolepsy is a disorder of children and adolescence, but until recently it was often not identified until adulthood, with a reported time from onset to diagnosis of about a decade. This disorder affects approximately 0.05% of the population and starts in childhood and adolescence about half of the time. With narcolepsy, the boundaries between wake, sleep, and dreams are blurred. The cardinal features of narcolepsy-cataplexy are daytime somnolence, cataplexy (sometimes occurring long after onset of sleepiness), sleep paralysis, and hypnagogic hallucinations. Weight gain, disturbed nocturnal sleep, and social/school functional changes are common; reactive substance use to maintain wakefulness during the day may also be seen. Males and females are equally affected. It is classically associated with HLA DQB1*0602, the most specific genetic marker for narcolepsy across all ethnic groups. CSF hypocretin has recently been found to be depleted in this disorder, and late-breaking data support that the disease is caused by autoimmune destruction of hypocretin-producing neurons in the hypothalamus. There is no known cure for narcolepsy. Therapies include behavioral/ scheduling modification, medications to combat daytime sleepiness and cataplexy, and treatment of concomitant disorders leading to daytime sleepiness. The differential diagnosis for this disorder should include other disorders of excessive daytime sleepiness with a proclivity toward onset in adolescence, such as delayed sleep phase syndrome, obstructive sleep apnea, and insufficient sleep time; substance use; and less commonly neurologic disorders such as Klein Levin syndrome, Prader-Willi syndrome, and others. Immunomodulator therapy and hypocretin replacement are proposed therapies that hold promise for the future.

Topics: Adolescent; Cataplexy; Central Nervous System Stimulants; Humans; Narcolepsy; Polysomnography; Sodium Oxybate

GHB is used therapeutically and recreationally, although the precise mechanism of action responsible for its different behavioral effects is not entirely clear. The purpose of this review is to summarize how behavioral procedures, especially drug discrimination procedures, have been used to study the mechanism of action of GHB. More specifically, we will review several different drug discrimination procedures and discuss how they have been used to qualitatively and quantitatively study different components of the complex mechanism of action of GHB. A growing number of studies have provided evidence that the behavioral effects of GHB are mediated predominantly by GABAB receptors. However, there is also evidence that the mechanisms mediating the effects of GHB and the prototypical GABAB receptor agonist baclofen are not identical, and that other mechanisms such as GHB receptors and subtypes of GABAA and GABAB receptors might contribute to the effects of GHB. These findings are consistent with the different behavioral profile, abuse liability, and therapeutic indications of GHB and baclofen. A better understanding of the similarities and differences between GHB and baclofen, as well as the pharmacological mechanisms of action underlying the recreational and therapeutic effects of GHB, could lead to more effective medications with fewer adverse effects.

Topics: Animals; Baclofen; Behavior, Animal; Discrimination Learning; GABA-B Receptor Agonists; Humans; Illicit Drugs; Narcolepsy; Receptors, GABA-A; Receptors, GABA-B; Reinforcement, Psychology; Sodium Oxybate

There are distinct differences in the accessibility, purity, dosing, and misuse associated with illicit gamma-hydroxybutyrate (GHB) compared to pharmaceutical sodium oxybate. Gamma-hydroxybutyrate sodium and sodium oxybate are the chemical and drug names, respectively, for the pharmaceutical product Xyrem (sodium oxybate) oral solution. However, the acronym GHB is also used to refer to illicit formulations that are used for non-medical purposes. This review highlights important differences between illicit GHB and sodium oxybate with regard to their relative abuse liability, which includes the likelihood and consequences of abuse. Data are summarized from the scientific literature; from national surveillance systems in the U.S., Europe, and Australia (for illicit GHB); and from clinical trials and post-marketing surveillance with sodium oxybate (Xyrem). In the U.S., the prevalence of illicit GHB use, abuse, intoxication, and overdose has declined from 2000, the year that GHB was scheduled, to the present and is lower than that of most other licit and illicit drugs. Abuse and misuse of the pharmaceutical product, sodium oxybate, has been rare over the 5 years since its introduction to the market, which is likely due in part to the risk management program associated with this product. Differences in the accessibility, purity, dosing, and misuse of illicit GHB and sodium oxybate suggest that risks associated with illicit GHB are greater than those associated with the pharmaceutical product sodium oxybate.

Topics: Chemistry, Pharmaceutical; Humans; Illicit Drugs; Narcolepsy; Rape; Risk Management; Sodium Oxybate; Substance-Related Disorders

Narcolepsy is a neurological disorder characterized, in its classical form, by excessive daytime sleepiness (EDS) with irresistible episodes of sleep, cataplexy, disrupted nocturnal sleep, hypnagogic/hypnopompic hallucinations and sleep paralysis. It is often under-diagnosed, however, if it is suitably diagnosed, symptoms can be well treated by means of targeted drugs, such as modafinil to treat EDS, sodium oxybate for cataplexy, as well as EDS and disrupted nocturnal sleep, and tricyclic and newer antidepressants for cataplexy. Hallucinations and sleep paralysis can be treated with the same drugs used for cataplexy. Amphetamines and amphetamine-like stimulants are used less nowadays. Behavioral measures are also important and useful. The discovery of hypocretin deficiency in narcoleptic patients opens new perspectives for the development of newer therapeutic approaches for both EDS and cataplexy. Therapy for narcolepsy is chronic, hence symptomatic. However, the correct use of available drugs enables patients to gain a better quality of life, keeping the symptoms under control, which, mainly from a social point of view, are heavily disabling.

Topics: Antidepressive Agents, Tricyclic; Behavior Therapy; Central Nervous System Stimulants; Humans; Narcolepsy; Sodium Oxybate; Sympathomimetics

A voluminous literature describes the relationship between disturbed sleep and depression. The breakdown of sleep is one of the cardinal features of depression and often also heralds its onset. Frequent arousals, periods of wakefulness and a short sleep onset REM latency are typical polysomnographic features of depression. The short latency to REM sleep has been attributed to the combination of a monoaminergic deficiency and cholinergic supersensitivity and these irregularities have been proposed to form the biological basis of the disorder. A similar imbalance between monoaminergic and cholinergic neurotransmission has been found in narcolepsy, a condition in which frequent awakenings, periods of wakefulness and short sleep onset REM latencies are also characteristic findings during sleep. In many cases of narcolepsy, this imbalance appears to result from a deficiency of hypocretin but once established, whether in depression or narcolepsy, this disequilibrium sets the stage for the dissociation or premature appearance of REM sleep and for the dissociation of the motor inhibitory component of REM sleep or cataplexy. In the presence of this monoaminergic/cholinergic imbalance, gammahydroxybutyrate (GHB) may acutely further reduce the latency of REM sleep and induce cataplexy, in both patients with narcolepsy or depression. On the other hand, the repeated nocturnal application of GHB in patients with narcolepsy improves the continuity of sleep, prolongs the latency to REM sleep and prevents cataplexy. Evidence to date suggests that GHB may restore the normal balance between monoaminergic and cholinergic neurotransmission. As such, the repeated use of GHB at night and the stabilization of sleep over time makes GHB an effective treatment for narcolepsy and a potentially effective treatment for depression.

Topics: Anesthetics, Intravenous; Animals; Depression; gamma-Aminobutyric Acid; Humans; Intracellular Signaling Peptides and Proteins; Motor Activity; Narcolepsy; Neurobiology; Neuropeptides; Neurotransmitter Agents; Orexins; Polysomnography; Quality of Life; Reaction Time; Receptors, GABA; Sleep, REM; Sodium Oxybate

Narcolepsy is a serious neurological condition in which patients are overcome by persistent, excessive feelings of fatigue and drowsiness. In addition to chronic fatigue, patients with narcolepsy often succumb to intermittent, uncontrollable periods where they abruptly fall asleep during waking hours. In addition to episodic bouts of daytime sleeping, narcoleptics also exhibit cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations. Unfortunately, many individuals with narcolepsy remain undiagnosed and therefore, untreated, posing a risk to themselves and those around them. There is currently no cure for this lifelong disease. Nonetheless, narcolepsy can be effectively managed with medications, lifestyle changes, and the peripheral support of individuals such as family members, coworkers, and other casual relations.

Topics: Benzhydryl Compounds; Biomarkers; Cataplexy; Central Nervous System Stimulants; Decision Making; Diagnosis, Differential; Drug Approval; Hallucinations; Humans; Intracellular Signaling Peptides and Proteins; Life Style; Methylphenidate; Modafinil; Narcolepsy; Neuropeptides; Orexins; Physicians, Family; Polysomnography; Primary Health Care; Quality of Life; Respiration; Risk Factors; Sleep Paralysis; Sleep Stages; Sodium Oxybate; United States; United States Food and Drug Administration

Sodium oxybate is the sodium salt of gamma- hydroxybutyrate, an endogenous cerebral inhibitory neurotransmitter. It is licensed in the United States for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy and in the European Union for the treatment of narcolepsy with cataplexy. Its mode of action is uncertain, but it increases 5-hydroxytryptamine turnover, interacts with opioid systems and may act as a gamma-aminobutyric acid B receptor agonist (GABA(B)). It is rapidly absorbed and eliminated, having a mean elimination half-life of 30-60 minutes. In controlled trials in narcolepsy without cataplexy, it decreased excessive daytime sleepiness and increased several quality of life domains. In combination with modafinil, it exerted an additive effect in diminishing daytime sleepiness. Both acute (four to eight weeks) and chronic (12 months) studies have demonstrated sodium oxybate's efficacy in decreasing cataplectic attack frequency. It is well tolerated with adverse event withdrawal rates of approximately 3-10% after acute and chronic administration. There is no clear evidence of a withdrawal syndrome after abrupt cessation of therapeutic doses. Sodium oxybate appears to be an effective and well-tolerated treatment for all the key symptoms of the two forms of narcolepsy.

Topics: Adjuvants, Anesthesia; Drug Interactions; Humans; Narcolepsy; Sodium Oxybate

Narcolepsy is a rare chronic sleep disorder classically characterized by excessive daytime sleepiness. Other symptoms of the disease, including cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep, may follow later. The disease can be incapacitating and frequently results in impaired psychosocial interaction. In the absence of a cure for narcolepsy, medical therapy is directed at symptom control.. The aim of this study was to review the current approach to the treatment of narcolepsy.. A search of three bibliographic databases (MEDLINE/PubMed, EMBASE and the Cochrane Library Database) was conducted from 1966 to January 2008 using the National Library of Medicine MeSH search terms narcolepsy and cataplexy. Relevant studies, case reports, review articles, editorials, short communications and chapters from selected textbooks were then extracted and manually cross-referenced.. Traditionally, stimulants have been used to improve the symptoms of excessive daytime sleepiness. However, the treatment of narcolepsy has evolved recently with the widespread use of newer drugs, including modafinil for daytime sleepiness, newer antidepressants for cataplexy and gamma-hydroxybutyrate (sodium oxybate) for both excessive daytime sleepiness and cataplexy.

Topics: Cataplexy; Central Nervous System Stimulants; Clinical Trials as Topic; Humans; Monoamine Oxidase Inhibitors; Narcolepsy; Selective Serotonin Reuptake Inhibitors; Smoking Cessation; Socioeconomic Factors; Sodium Oxybate

Narcolepsy is a disabling disease with a prevalence of 0.05%. It is characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnogogic hallucinations, automatic behavior, and disrupted nocturnal sleep. The presentation can be very variable, making diagnosis difficult. Loss of hypocretin containing neurons in the lateral hypothalamus has been noted in autopsy studies, and the cerebrospinal fluid level of hypocretin is reduced in patients with narcolepsy with cataplexy. New treatment options are available for the many symptoms of this disease. Early recognition and treatment can greatly improve the quality of life of patients with narcolepsy. A detail review of the epidemiology, pathophysiology, and management of narcolepsy in children is presented.

Topics: Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Child; Dextroamphetamine; Ghrelin; Hallucinations; Humans; Intracellular Signaling Peptides and Proteins; Leptin; Methylphenidate; Modafinil; Narcolepsy; Neuropeptides; Orexins; Polysomnography; Randomized Controlled Trials as Topic; Sleep, REM; Sodium Oxybate

Sleep is a physiologic state that performs an essential restorative function and facilitates learning and memory consolidation. When sleep is disrupted for more than a short time, normal daily functions decline. Mood, attention, and behavior deteriorate. Sleepiness and disrupted sleep can result from a large number of pathological disorders. Currently, 88 sleep disorders are listed in the International Classification of Sleep Disorders, as established by the American Academy of Sleep Medicine, and sleep disorders adversely affect more than an estimated 70 million Americans. Most of these disorders can be classified as causing insomnia and/or hypersomnia. Insomnia results from disorders that cause difficulty with falling asleep and staying asleep; examples are hyperarousal, circadian dysrhythmia, and homeostatic dysregulation. In contrast, hypersomnia refers to difficulty in staying awake and is characterized by recurrent episodes of excessive daytime sleepiness or prolonged nighttime sleep. Hypersomnia can result from several primary sleep disorders, including narcolepsy, sleep apnea, restless legs syndrome, idiopathic hypersomnia, and periodic limb movement disorder. The effects of some of these sleep disorders and other chronic illnesses on daytime sleepiness are measured using the Epworth Sleepiness Scale. Narcolepsy was found to cause some of the highest measures of excessive sleepiness. This supplement uses a case-based approach to describe the underlying pathology and symptoms of narcolepsy. Differential diagnosis of narcolepsy and current treatment options will be discussed.

Topics: Benzhydryl Compounds; Central Nervous System Stimulants; Female; Humans; Male; Modafinil; Narcolepsy; Polysomnography; Quality of Life; Sodium Oxybate

Sodium oxybate (Xyrem) is the sodium salt of the CNS depressant gamma-hydroxybutyric acid (GHB) and is therefore subject to prescription restrictions. It is approved in the US for the treatment of cataplexy and excessive daytime sleepiness (EDS) in patients with narcolepsy, and in the EU for the treatment of narcolepsy with cataplexy. Sodium oxybate is generally well tolerated and effective in the treatment of symptoms of narcolepsy with cataplexy. While its short half-life necessitates twice-nightly administration, it is highly effective in reducing the frequency of cataplexy, improving sleep architecture and reducing EDS in patients with narcolepsy. Sodium oxybate therefore offers a valuable alternative or addition to the use of TCAs, SSRIs and stimulants in the treatment of the symptoms of narcolepsy including cataplexy and EDS.

Topics: Anesthetics, Intravenous; Clinical Trials as Topic; Databases, Factual; Guidelines as Topic; Humans; MEDLINE; Narcolepsy; Sodium Oxybate

The 5 classic symptoms of narcolepsy are excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. The presence of cataplexy is strongly associated with a deficiency of the neuropeptide hypocretin. This discovery has led to new diagnostic subclassifications: narcolepsy without cataplexy, which can be demonstrated by a multiple sleep latency test, and narcolepsy with cataplexy, which can be confirmed with a multiple sleep latency test or a cerebrospinal fluid deficiency of hypocretin I. Various treatment options are available, including psychostimulants and gamma hydroxybuterate.

Topics: Cataplexy; Central Nervous System Stimulants; Diagnosis, Differential; Humans; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Sleep, REM; Sodium Oxybate

Narcolepsy treatment has changed dramatically over the last century. For the treatment of sleepiness in narcolepsy, we have progressed from the early use of caffeine. We have available a variety of different stimulants, and a wake-promoting agent, modafinil, which is widely regarded as the first-line medication for narcolepsy. Cataplexy is managed by medications whereas behavioral treatment, such as avoidance of emotion, was the only treatment available in the past. Following the widespread use of antidepressant medications for cataplexy, we now have sodium oxybate, which works by an unknown mechanism but is the only Food and Drug Administration (FDA)-approved medication for cataplexy. We also recognize that other sleep disorders can occur in narcolepsy, such as obstructive sleep apnea syndrome or rapid eye movement sleep behavior disorder, and new treatments allow these comorbid conditions to be effectively treated. However, although we cannot cure narcolepsy, the current treatments for excessive sleepiness and cataplexy can be effective for many patients. We are improving the quality of life for our patients without producing clinically significant adverse effects. We need new therapeutic advances and several medications that work, though different mechanisms are likely to be available in the near future.

Topics: Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Humans; Immunotherapy; Methylphenidate; Modafinil; Narcolepsy; Quality of Life; Selective Serotonin Reuptake Inhibitors; Selegiline; Sodium Oxybate

The purpose of this paper is to summarize current knowledge about treatment of narcolepsy and other hypersomnias of central origin.. The task force performed a systematic and comprehensive review of the relevant literature and graded the evidence using the Oxford grading system. This paper discusses the strengths and limitations of the available evidence regarding treatment of these conditions, and summarizes key information about safety of these medications. Our findings provide the foundation for development of evidence-based practice parameters on this topic by the Standards of Practice Committee of the American Academy of Sleep Medicine.. The majority of recent papers in this field provide information about use of modafinil or sodium oxybate for treatment of sleepiness associated with narcolepsy. Several large randomized, placebo-controlled studies indicate that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy. We identified no studies that report direct comparison of these newer medications versus traditional stimulants, or that indicate what proportion of patients treated initially with these medications require transition to traditional stimulants or to combination therapy to achieve adequate alertness. As with the traditional stimulants, modafinil and sodium oxybate provide, at best, only moderate improvement in alertness rather than full restoration of alertness in patients with narcolepsy. Several large randomized placebo-controlled studies demonstrate that sodium oxybate is effective for treatment of cataplexy associated with narcolepsy, and earlier studies provide limited data to support the effectiveness of fluoxetine and tricyclic antidepressants for treatment of cataplexy. Our findings indicate that very few reports provide information regarding treatment of special populations such as children, older adults, and pregnant or breastfeeding women. The available literature provides a modest amount of information about improvement in quality of life in association with treatment, patient preferences among the different medications, or patient compliance.. Several recent studies provide evidence that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy. No studies were identified that report direct comparison of these newer medications with traditional stimulants. Despite significant advances in understanding the pathophysiology of narcolepsy, we do not have an ideal treatment to restore full and sustained alertness. Future investigations should be directed toward development of more effective and better tolerated therapies, and primary prevention.

Topics: Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Disorders of Excessive Somnolence; Evidence-Based Medicine; Fluoxetine; Humans; Modafinil; Narcolepsy; Randomized Controlled Trials as Topic; Sodium Oxybate

Although narcolepsy was first described over 100 years ago, most of what is known about the pathological changes in the CNS that are responsible for this unusual disease has been learned during the past few years. It is now known that narcolepsy is caused by the loss of a relatively few neurons that are responsible for producing the neuropeptide hypocretin in the CNS. The onset of narcolepsy typically occurs in early adulthood and may consist of a variety of symptoms; however, cataplexy (an abrupt, bilateral loss of skeletal muscle tone) is most specific to narcolepsy. TCAs were found to be beneficial for the treatment of cataplexy over 40 years ago and, more recently, the SSRIs have been used to treat the condition. The recent availability of sodium oxybate (the first drug to receive regulatory approval for the treatment of cataplexy) represents a significant advance in the treatment of narcolepsy, as it is highly efficacious for the treatment of cataplexy and shows promise for the treatment of excessive sleepiness and for improving sleep quality in patients with narcolepsy.

Topics: Cataplexy; Humans; Narcolepsy; Neuropeptides; Practice Guidelines as Topic; Selective Serotonin Reuptake Inhibitors; Sodium Oxybate

To review the pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, precautions, dosing recommendations, and patient counseling of sodium oxybate for the treatment of cataplexy in patients with narcolepsy.. OVID and PubMed databases were searched (1966-January 2006) using the key words sodium oxybate, gamma-hydroxybutyrate, narcolepsy, and cataplexy. Only English-language articles were selected.. All information on sodium oxybate related to narcolepsy and cataplexy was considered. Study selection included human trials evaluating safety and efficacy of sodium oxybate for the treatment of cataplexy.. Sodium oxybate is approved by the Food and Drug Administration for the treatment of excessive daytime sleepiness and cataplexy in patients with narcolepsy. In placebo-controlled trials, sodium oxybate demonstrated efficacy in reducing the number of cataplexy attacks. The dosing regimen includes a split dose given at bedtime and 2.5-4 hours later due to its short elimination half-life. The drug is generally well tolerated, with headache, nausea, dizziness, pain, and somnolence being the most common adverse events.. Sodium oxybate is safe and effective for the treatment of cataplexy. Potential disadvantages include a multiple dosing regimen, abuse potential, cost, and a closed distribution system. Potential advantages demonstrated in clinical trials include significant decreases in the number of weekly cataplexy attacks, improvement in daytime sleepiness, and improvement in the Clinical Global Impression of Change score and nighttime awakenings. Overall, sodium oxybate provides a new option for the treatment of cataplexy.

Topics: Cataplexy; Clinical Trials as Topic; Databases, Factual; Humans; Narcolepsy; Sleep; Sodium Oxybate

Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness and cataplexy. The hypocretin/orexin deficiency is likely to be the key to its pathophysiology in most of cases although the cause of human narcolepsy remains elusive. Acting on a specific genetic background, an autoimmune process targeting hypocretin neurons in response to yet unknown environmental factors is the most probable hypothesis in most cases of human narcolepsy with cataplexy. Although narcolepsy presents one of the tightest associations with a specific human leukocyte antigen (HLA) (DQB1*0602), there is strong evidence that non-HLA genes also confer susceptibility. In addition to a point mutation in the prepro-hypocretin gene discovered in an atypical case, a few polymorphisms in monoaminergic and immune-related genes have been reported associated with narcolepsy. The treatment of narcolepsy has evolved significantly over the last few years. Available treatments include stimulants for hypersomnia with the quite recent widespread use of modafinil, antidepressants for cataplexy, and gamma-hydroxybutyrate for both symptoms. Recent pilot open trials with intravenous immunoglobulins appear an effective treatment of cataplexy if applied at early stages of narcolepsy. Finally, the discovery of hypocretin deficiency might open up new treatment perspectives.

Topics: Animals; Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Catechol O-Methyltransferase; Central Nervous System Stimulants; Clomipramine; Genetic Predisposition to Disease; HLA-DQ Antigens; HLA-DQ beta-Chains; Humans; Immunoglobulins, Intravenous; Intracellular Signaling Peptides and Proteins; Membrane Glycoproteins; Modafinil; Molecular Biology; Narcolepsy; Neuropeptides; Orexin Receptors; Orexins; Polymorphism, Genetic; Randomized Controlled Trials as Topic; Receptors, G-Protein-Coupled; Receptors, Neuropeptide; Sodium Oxybate

Sodium oxybate (Xyrem), also known as gamma-hydroxybutyric acid, is the only therapeutic specifically approved in the USA for the treatment of cataplexy in narcolepsy. The US FDA has recently expanded its indication to include excessive daytime sleepiness associated with narcolepsy. In contrast to the antidepressants and stimulants commonly used to treat the disorder, sodium oxybate is the only compound that addresses both sets of symptoms and, when used properly, is less likely to lead to the development of tolerance and other undesirable side effects. In this review, the results of clinical trials and the place of sodium oxybate in narcolepsy treatment are discussed.

Topics: Anesthetics, Intravenous; Cataplexy; Europe; Humans; Incidence; Narcolepsy; Sodium Oxybate; United States

Narcolepsy, a lifelong disease with diverse symptoms, poses a therapeutic challenge to physicians. Psychomotor stimulants are used to provide some relief from excessive sleepiness, whereas a variety of other medications have traditionally been used to treat the other symptoms of this disorder. Cataplexy, consisting of sudden episodes of bilateral skeletal muscle weakness, has long been treated with tricyclic antidepressants or selective serotonin re-uptake inhibitors. Although these drugs have brought relief to some patients, they cause intolerable adverse effects in others, whereas still others become tolerant to their beneficial effects. In July of 2002, sodium oxybate was approved by the US FDA for the treatment of cataplexy, representing a significant advance in the treatment of this unusual disease. The following drug evaluation summarises the role of this novel medication in the practice of sleep medicine.

Topics: Cataplexy; Clinical Trials as Topic; Humans; Narcolepsy; Sleep; Sodium Oxybate

Topics: Animals; Antidepressive Agents; Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Clinical Trials as Topic; Disorders of Excessive Somnolence; Dogs; Humans; Modafinil; Narcolepsy; Sodium Oxybate; Treatment Outcome

Narcolepsy is characterised by excessive daytime sleepiness, usually associated with cataplexy, hypnagogic hallucinations, sleep paralysis and fragmented nocturnal sleep. Although uncommon, it results in significant disability. Most cases occur sporadically, but genetic factors probably form a susceptibility background on which unknown environmental triggers act. The hypocretin system is strongly implicated in the development of narcolepsy. Cerebrospinal fluid levels of hypocretin-1 are significantly reduced in narcoleptic subjects with cataplexy. Despite the advances in our understanding of narcolepsy, current therapy is primarily symptomatic. Stimulants (standard and novel) combat excessive daytime sleepiness. Antidepressants (tricyclics, dual-action or selective serotonin re-uptake inhibitors) and sodium oxybate are anticataplexy agents. Hypnagogic hallucinations and sleep paralysis respond to antidepressants. Sodium oxybate consolidates sleep. Novel and experimental treatments include histamine antagonists, hypocretin agonists, slow-wave sleep enhancers, intravenous gamma-globulin, tramadol and corticosteroids.

Topics: Antidepressive Agents, Tricyclic; Cataplexy; Humans; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Sleep Paralysis; Sleep, REM; Sodium Oxybate; Treatment Outcome

Narcolepsy is a severely debilitating neurologic disease that is not as rare as many believe, affecting an estimated 140,000 Americans. Despite the sometimes debilitating nature of narcolepsy symptoms, the disease may go undiagnosed without an organized method for evaluating patients with sleep complaints. Many of the classic symptoms of narcolepsy, such as excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations, may be mistakenly associated with other disease states and must be differentiated from other sleep disorders. The results of self-administered sleep-disorder questionnaires are useful and may increase the suspicion of narcolepsy; however, referral to an accredited sleep laboratory for a formal sleep study including overnight polysomnography is necessary for a positive narcolepsy diagnosis. A variety of medications may be used to successfully treat excessive daytime sleepiness and cataplexy, the two most debilitating symptoms of the disease. Primary-care physicians who develop the proper diagnostic skills can play a pivotal role in the accurate diagnosis and long-term management of patients suffering from narcolepsy.

Topics: Adjuvants, Anesthesia; Algorithms; Diagnosis, Differential; Humans; Narcolepsy; Sleep Wake Disorders; Sodium Oxybate; Voluntary Health Agencies

Narcolepsy is a primary neurological disorder, which often produces disabling symptoms, including excessive daytime sleepiness and cataplexy. Although the precise aetiology of narcolepsy has not been determined, our understanding of the pathophysiology of this complex disorder has grown dramatically during the past several years, especially as it relates to the newly discovered hypocretin system. While symptomatic treatment of narcolepsy is available, the commonly used pharmacological agents are often not completely effective and may be poorly tolerated. The need for new therapeutic tools is, therefore, apparent. This paper explores some exciting new approaches to the treatment of narcolepsy. It is important to emphasise that, although narcolepsy is not a common disorder, new agents for its treatment will undoubtedly find more extensive use in other conditions.

Topics: Adrenergic Agents; Carrier Proteins; Cataplexy; Humans; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Sodium Oxybate; Wakefulness

Orphan Medical is developing gamma-hydroxybutyrate (Xyrem) for the potential treatment of narcolepsy [183352]. In October 2000, an NDA was filed with the FDA [384422], [405504] and Xyrem received an FDA approvable letter in July 2001. Orphan Medical stated that it believed it could meet the requirements in the letter, including a trial in respiratory-compromised patients, by the end of 2001 [414461]. The FDA also requested follow-up safety data from patients in previous Xyrem trials. At that time, the drug was not expected to be launched until mid-2002 [415301], [416305]. In October 1999, the US House of Representatives passed the HR 2130 bill, allowing the medical use of gamma-hydroxybutyrate, which is classified as a Schedule I controlled substance in the US [343562]; the Senate approved this legislation in November 1999 [348206]. In February 2000, a congressional bill supporting the continued development of medically formulated gamma-hydroxybutyrate was passed, making medically formulated gamma-hydroxybutyrate products Schedule III substances [354108], [356597]. GHB occurs naturally in many human tissues. It has previously been used in the treatment of narcolepsy and is not patentable for that indication.

Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drugs, Investigational; GABA Agonists; GABA-B Receptor Agonists; Humans; Narcolepsy; Sodium Oxybate; Structure-Activity Relationship; Treatment Outcome

Topics: Amphetamines; Humans; Narcolepsy; Oxygen Consumption; Sodium Oxybate; Sympathomimetics

Narcolepsy is a chronic, incurable disorder affecting at least a quarter of a million Americans. It is characterized by a tetrad of symptoms, which include excessive daytime sleepiness, cataplexy, sleep paralysis and hypnogogic hallucinations. Individuals may experience severe negative psychosocial consequences associated with these symptoms. The neuropathology of narcolepsy is largely unknown. Current work implicates decreased production or utilization of norepinephrine, dopamine and serotonin in the brain, and excessively numerous or hypersensitive cholinergic receptors in the brain. Medical management includes the use of separate drug therapies to control sleep attacks and cataplectic episodes. Nursing management requires comprehensive assessment of the interplay between the patient and environment and assistance with long-term coping.

Topics: Amphetamines; Antidepressive Agents, Tricyclic; Humans; Incidence; Narcolepsy; Nursing Assessment; Prevalence; Referral and Consultation; Self-Help Groups; Sodium Oxybate

Narcolepsy is an incurable sleep disorder characterized by attacks of sleepiness and a series of auxiliary symptoms: cataplexy, sleep paralysis and hypnagogic hallucinations. Classic treatment has included stimulants to control sleepiness and tricyclic antidepressants to control the auxiliary symptoms. Polysomnography is necessary to confirm the diagnosis and to detect other sleep disorders. Recent developments in treatment include the use of codeine for sleepiness and gamma-hydroxybutyrate for auxiliary symptoms.

Topics: Amphetamines; Cataplexy; Hallucinations; Humans; Narcolepsy; Paralysis; Propranolol; Sleep Stages; Sodium Oxybate

Clinical guidelines recommend sodium oxybate (SXB; the sodium salt of γ-hydroxybutyrate) for the treatment of disturbed sleep and excessive daytime sleepiness in narcolepsy, yet the underlying mode of action is elusive. In a randomised controlled trial in 20 healthy volunteers, we aimed at establishing neurochemical changes in the anterior cingulate cortex (ACC) following SXB-enhanced sleep. The ACC is a core neural hub regulating vigilance in humans. At 2:30 a.m., we administered in a double-blind cross-over manner an oral dose of 50 mg/kg SXB or placebo, to enhance electroencephalography-defined sleep intensity in the second half of nocturnal sleep (11:00 p.m. to 7:00 a.m.). Upon scheduled awakening, we assessed subjective sleepiness, tiredness and mood and measured two-dimensional, J-resolved, point-resolved magnetic resonance spectroscopy (PRESS) localisation at 3-Tesla field strength. Following brain scanning, we used validated tools to quantify psychomotor vigilance test (PVT) performance and executive functioning. We analysed the data with independent t tests, false discovery rate (FDR) corrected for multiple comparisons. The morning glutamate signal (at 8:30 a.m.) in the ACC was specifically increased after SXB-enhanced sleep in all participants in whom good-quality spectroscopy data were available (n = 16; p

Topics: Disorders of Excessive Somnolence; Glutamic Acid; Gyrus Cinguli; Humans; Magnetic Resonance Spectroscopy; Narcolepsy; Sodium Oxybate

The safety and efficacy of low-sodium oxybate (LXB; Xywav. 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).. 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.. 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.. 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.

Topics: Adult; Cataplexy; Dizziness; Double-Blind Method; Headache; Humans; Narcolepsy; Nasopharyngitis; Sodium Oxybate; Time Factors; Treatment Outcome

Post hoc analyses from the phase 3 REST-ON trial evaluated efficacy of extended-release once-nightly sodium oxybate (ON-SXB; FT218) vs placebo for daytime sleepiness and disrupted nighttime sleep in narcolepsy type 1 (NT1) and 2 (NT2).. Participants were stratified by narcolepsy type and randomized 1:1 to ON-SXB (4.5 g, week 1; 6 g, weeks 2-3; 7.5 g, weeks 4-8; and 9 g, weeks 9-13) or placebo. Assessments included mean sleep latency on Maintenance of Wakefulness Test (MWT) and Clinical Global Impression-Improvement (CGI-I) rating (coprimary endpoints) and sleep stage shifts, nocturnal arousals, and patient-reported sleep quality, refreshing nature of sleep, and Epworth Sleepiness Scale (ESS) score (secondary endpoints) separately in NT1 and NT2 subgroups.. The modified intent-to-treat population comprised 190 participants (NT1, n = 145; NT2, n = 45). Significant improvements were demonstrated with ON-SXB vs placebo in sleep latency for NT1 (all doses, p < .001) and NT2 (6 and 9 g, p < .05) subgroups. Greater proportions of participants in both subgroups had CGI-I ratings of much/very much improved with ON-SXB vs placebo. Sleep stage shifts and sleep quality significantly improved in both subgroups (all doses vs placebo, p < .001). Significant improvements with all ON-SXB doses vs placebo in refreshing nature of sleep (p < .001), nocturnal arousals (p < .05), and ESS scores (p ≤ .001) were reported for NT1 with directional improvements for NT2.. Clinically meaningful improvements of a single ON-SXB bedtime dose were shown for daytime sleepiness and DNS in NT1 and NT2, with less power for the limited NT2 subgroup.

Topics: Disorders of Excessive Somnolence; Humans; Narcolepsy; Sleep; Sodium Oxybate; Treatment Outcome; Wakefulness

Calcium, magnesium, potassium and sodium oxybates (Xywav. Narcolepsy and idiopathic hypersomnia are rare, chronic sleep disorders that can debilitate patients’ cognitive function, social functioning and health-related quality of life. They are primarily characterized by excessive daytime sleepiness (EDS) and often require long-term (even life-long) treatment to reduce symptoms and improve functioning. Sodium oxybate (Xyrem

Topics: Adult; Calcium; Cataplexy; Child; Disorders of Excessive Somnolence; Humans; Idiopathic Hypersomnia; Magnesium; Narcolepsy; Potassium; Quality of Life; Sodium; Sodium Oxybate

Sodium oxybate has been recognized as a gold standard for the treatment of disrupted nighttime sleep due to narcolepsy. Its short half-life and immediate-release formulation require patients to awaken 2.5-4 h after their bedtime dose to take a second dose. A novel extended-release, once-nightly sodium oxybate formulation (ON-SXB; FT218) is under US Food and Drug Administration review for the treatment of adults with narcolepsy.. A phase III trial of ON-SXB in individuals with narcolepsy type 1 (NT1) or 2 (NT2) [the REST-ON trial; NCT02720744] has been conducted and the primary results reported elsewhere. Secondary objectives from REST-ON were to assess the efficacy of ON-SXB on disrupted nighttime sleep; the results of this analysis are reported here.. In the double-blind, phase III REST-ON trial, patients aged ≥ 16 years were randomly assigned 1:1 to ON-SXB (1 week, 4.5 g; 2 weeks, 6 g; 5 weeks, 7.5 g; 5 weeks, 9 g) or placebo. Secondary endpoints included polysomnographic measures of sleep stage shifts and nocturnal arousals and patient-reported assessments of sleep quality and refreshing nature of sleep at 6, 7.5, and 9 g; post hoc analyses included changes in time spent in each sleep stage, delta power, and assessments in stimulant-use subgroups for prespecified endpoints.. In total, 190 participants (n = 97, ON-SXB; n = 93, placebo) were included in the efficacy analyses. All three ON-SXB doses demonstrated a clinically meaningful, statistically significant decrease vs placebo in the number of transitions to wake/N1 from N1, N2, and rapid eye movement (REM) stages (all doses p < 0.001) and the number of nocturnal arousals (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g). Sleep quality and refreshing nature of sleep were significantly improved with all three ON-SXB doses vs placebo (p < 0.001). Post hoc analyses revealed a significant reduction in time spent in N1 (p < 0.05 ON-SXB 6 g; p < 0.001 7.5 and 9 g) and REM (all p < 0.001) and increased time spent in N3 with ON-SXB vs placebo (all p < 0.001), with a significant increase in delta power (p < 0.01 ON-SXB 6 g; p < 0.05 7.5 g; p < 0.001 9 g) and increased REM latency (ON-SXB 7.5 g vs placebo; p < 0.05). Significant improvements in disrupted nighttime sleep were observed regardless of concomitant stimulant use.. The clinically beneficial, single nighttime dose of ON-SXB significantly improved disrupted nighttime sleep in patients with narcolepsy.. ClinicalTrials.gov NCT02720744.

Topics: Adult; Humans; Narcolepsy; Polysomnography; Sleep; Sleep Stages; Sodium Oxybate

Lower-sodium oxybate (LXB) is an oxybate medication with the same active moiety as sodium oxybate (SXB) and a unique composition of cations, resulting in 92% less sodium. LXB was shown to improve cataplexy and excessive daytime sleepiness in people with narcolepsy in a placebo-controlled, double-blind, randomized withdrawal study (NCT03030599). Additional analyses of data from this study were conducted to explore the effects of LXB on cataplexy, including the clinical course and feasibility of transition from other anticataplectics to LXB monotherapy.. The aim of these analyses was to evaluate cataplexy frequency during initiation/optimization of LXB and taper/discontinuation of prior antidepressant/anticataplectic medications.. Eligible participants (adults aged 18-70 years with narcolepsy with cataplexy) entered the study taking SXB only (group A), SXB + other anticataplectics (group B), or anticataplectic medication other than SXB (group C), or were cataplexy-treatment naive (group D). LXB was initiated/optimized during a 12-week, open-label, optimized treatment and titration period (OLOTTP). Other anticataplectics were tapered/discontinued during weeks 3-10 of OLOTTP. A 2-week stable-dose period (SDP; during which participants took a stable dose of open-label LXB) and 2-week double-blind randomized withdrawal period (during which participants were randomized to continue LXB treatment or switch to placebo) followed OLOTTP. Treatment-emergent adverse events (TEAEs) were recorded throughout the duration of the study.. At the beginning of OLOTTP, median weekly cataplexy attacks were lower in participants taking SXB at study entry (SXB only [2.00]; SXB + other anticataplectics [0.58]) versus participants who were taking other anticataplectics (3.50) or were anticataplectic naive (5.83). Median weekly cataplexy attacks decreased during weeks 1-2 of OLOTTP in all groups. Increased cataplexy frequency was observed in participants tapering/discontinuing other anticataplectics during weeks 3-10 and was more prominent in participants taking other anticataplectics alone compared with those taking SXB plus other anticataplectics. Cataplexy frequency decreased throughout initiation/optimization in anticataplectic-naive participants. Median number of cataplexy-free days/week at the end of SDP (study week 14) was similar in all groups (6.0, 6.1, 6.0, and 6.2 in groups A, B, C, and D, respectively). During OLOTTP and SDP, TEAEs of worsening cataplexy were reported in 0%, 47.8%, 16.7%, and 2.2% of participants in groups A, B, C, and D, respectively; most TEAEs of worsening cataplexy were reported during tapering/discontinuation of other anticataplectics.. LXB monotherapy was effective in reducing cataplexy and increasing cataplexy-free days. These results illustrate the feasibility of switching from SXB to LXB while tapering/discontinuing other anticataplectics.. A Study of the Efficacy and Safety of JZP-258 in Subjects With Narcolepsy With Cataplexy; https://clinicaltrials.gov/ct2/show/NCT03030599 ; clinicaltrials.gov identifier: NCT03030599.. People with narcolepsy are often sleepy during the day. They may also have sudden muscle weakness (known as cataplexy). Lower-sodium oxybate (LXB) is a narcolepsy medicine that is similar to sodium oxybate (SXB) but has 92% less sodium. A recent study found that treatment with LXB was better at reducing how often people with narcolepsy had sleepiness and cataplexy than no medicine at all (NCT03030599). This paper is about the first 12 weeks of that study, when all the people taking part in the study first tried LXB to check that they were being given the right amount. In people who only took LXB, cataplexy happened less often over time. Some people were already taking other medicines to treat their cataplexy (such as antidepressants), so they were asked to slowly stop those medicines while taking LXB. In those people, cataplexy happened more often at first as they stopped taking antidepressants and then less often later on. The increase in cataplexy when antidepressants were stopped was smaller in people who switched from SXB to LXB. This study shows that many people getting treatment for narcolepsy can switch to LXB without their cataplexy becoming worse.

Topics: Adult; Cataplexy; Disorders of Excessive Somnolence; Double-Blind Method; Humans; Narcolepsy; Sodium Oxybate

Evaluate long-term efficacy and safety of sodium oxybate (SXB) in children and adolescents (aged 7-16 years) with narcolepsy with cataplexy.. A double-blind randomized withdrawal study was conducted. Prior to randomization, SXB-naive participants were titrated to an efficacious and tolerable dose of SXB; participants taking SXB entered on their established dose. Following a 2-week stable-dose period and 2-week, double-blind, randomized withdrawal period, participants entered an open-label period (OLP; ≤ 47 weeks). Efficacy measures during the OLP included number of weekly cataplexy attacks, cataplexy-free days, and Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Safety outcomes included treatment-emergent adverse events; assessments of depression, anxiety, and suicidality; and polysomnography.. Of 106 enrolled participants, 95 entered and 85 completed the OLP. In SXB-naive participants and participants previously taking SXB, efficacy of SXB established prior to the double-blind, randomized withdrawal period was maintained throughout the OLP for number of weekly cataplexy attacks (median [quartile 1, quartile 3] change from the stable-dose period to end of the OLP: 0.0 [-2.5, 4.9] and 0.0 [-3.4, 2.6], respectively) and ESS-CHAD scores (0.0 [-3.0, 2.5] and 1.0 [-3.0, 3.0], respectively). The median (quartile 1, quartile 3) number of cataplexy-free days per week was 2.3 (0.0, 6.0) in OLP week 1 and 3.8 (0.5, 5.5) in week 48. Treatment-emergent adverse events (≥ 5%) were enuresis, nausea, vomiting, headache, decreased weight, decreased appetite, nasopharyngitis, upper respiratory tract infection, and dizziness.. SXB demonstrated long-term maintenance of efficacy in pediatric narcolepsy with cataplexy, with a safety profile consistent with that observed in adults.. Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem with an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects with Narcolepsy with Cataplexy; URL: https://clinicaltrials.gov/ct2/show/NCT02221869; Identifier: NCT02221869.. Lecendreux M, Plazzi G, Dauvilliers Y, et al. Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients.

Topics: Adolescent; Adult; Cataplexy; Child; Double-Blind Method; Humans; Narcolepsy; Polysomnography; Sodium Oxybate; Treatment Outcome

To assess the efficacy and safety of FT218, a novel once-nightly formulation of sodium oxybate (ON-SXB), in patients with narcolepsy in the phase 3 REST-ON trial.. Narcolepsy patients aged ≥16 years were randomized 1:1 to uptitration of ON-SXB (4.5, 6, 7.5, and 9 g) or placebo. Three coprimary endpoints were change from baseline in mean sleep latency on the Maintenance of Wakefulness Test, Clinical Global Impression-Improvement rating, and weekly cataplexy attacks at 9, 7.5, and 6 g. Secondary endpoints included change from baseline on the Epworth Sleepiness Scale. Safety included adverse drug reactions and clinical laboratory assessments.. In total, 222 patients were randomized; 212 received ≥1 dose of ON-SXB (n = 107) or placebo (n = 105). For the three coprimary endpoints and Epworth Sleepiness Scale, all three doses of ON-SXB demonstrated clinically meaningful, statistically significant improvement versus placebo (all p < 0.001). For ON-SXB 9 g versus placebo, increase in mean sleep latency was 10.8 versus 4.7 min (Least squares mean difference, LSMD [95% CI], 6.13 [3.52 to 8.75]), 72.0% versus 31.6% were rated much/very much improved on Clinical Global Impression-Improvement (OR [95% CI], 5.56 [2.76 to 11.23]), change in mean weekly number of cataplexy attacks was -11.5 versus -4.9 (LSMD [95% CI], -6.65 [-9.32 to -3.98]), and change in Epworth Sleepiness Scale was -6.5 and -2.7 (LSMD [95% CI], -6.52 [-5.47 to -2.26]). Common adverse reactions included nausea, vomiting, headache, dizziness, and enuresis.. ON-SXB significantly improved narcolepsy symptoms; its safety profile was consistent with SXB. ON-SXB conferred efficacy with a clearly beneficial single nighttime dose.. ClinicalTrials.gov: NCT02720744, https://clinicaltrials.gov/ct2/show/NCT02720744.

Topics: Cataplexy; Double-Blind Method; Humans; Narcolepsy; Sleepiness; Sodium Oxybate; Treatment Outcome; Wakefulness

Evaluate efficacy and safety of lower-sodium oxybate (LXB), a novel oxybate medication with 92% less sodium than sodium oxybate (SXB).. Adults aged 18-70 years with narcolepsy with cataplexy were eligible. The study included a ≤30-day screening period; a 12-week, open-label, optimized treatment and titration period to transition to LXB from previous medications for the treatment of cataplexy; a 2-week stable-dose period (SDP); a 2-week, double-blind, randomized withdrawal period (DBRWP); and a 2-week safety follow-up. During DBRWP, participants were randomized 1:1 to placebo or to continue LXB treatment.. Efficacy was assessed in 134 participants who received randomized treatment, and safety was assessed in all enrolled participants (N = 201). Statistically significant worsening of symptoms was observed in participants randomized to placebo, with median (first quartile [Q1], third quartile [Q3]) change in weekly number of cataplexy attacks from SDP to DBRWP (primary efficacy endpoint) in the placebo group of 2.35 (0.00, 11.61) versus 0.00 (-0.49, 1.75) in the LXB group (p < 0.0001; mean [standard deviation, SD] change: 11.46 [24.751] vs 0.12 [5.772]), and median (Q1, Q3) change in Epworth Sleepiness Scale score (key secondary efficacy endpoint) of 2.0 (0.0, 5.0) in the placebo group versus 0.0 (-1.0, 1.0) in the LXB group (p < 0.0001; mean [SD] change: 3.0 [4.68] vs 0.0 [2.90]). The most common treatment-emergent adverse events with LXB were headache (20.4%), nausea (12.9%), and dizziness (10.4%).. Efficacy of LXB for the treatment of cataplexy and excessive daytime sleepiness was demonstrated. The safety profile of LXB was consistent with SXB.. NCT03030599.

Topics: Adolescent; Adult; Aged; Calcium; Cataplexy; Double-Blind Method; Humans; Magnesium; Middle Aged; Narcolepsy; Potassium; Sodium; Sodium Oxybate; Treatment Outcome; Young Adult

Topics: Administration, Oral; Adolescent; Area Under Curve; Body Weight; Cataplexy; Child; Dose-Response Relationship, Drug; Double-Blind Method; Drug Dosage Calculations; Female; Humans; Male; Models, Biological; Narcolepsy; Sodium Oxybate

To determine the time course and duration of common, early-onset treatment-emergent adverse events (TEAEs) associated with sodium oxybate (SXB) use in adults with narcolepsy.. These were post hoc analyses of two 8-week, randomized, double-blind, placebo-controlled trials. In SXB-15, participants (n = 246) received daily placebo (n = 60) or SXB (n = 186) initiated at 4.5 g. Participants assigned to SXB 6 or 9 g were titrated in 1.5-g increments. In SXB-22, participants entering on modafinil (n = 231) received placebo (n = 56), SXB (n = 55), modafinil (n = 63), or SXB and modafinil (n = 57). SXB was initiated at 6 g for weeks 1-4 and increased to 9 g for weeks 5-8. TEAEs reported more frequently in SXB-treated participants than placebo and in ≥5% of any SXB treatment group during week 1 were examined as TEAEs of interest.. Dizziness and nausea met criteria as TEAEs of interest in both studies; headache also met criteria as a TEAE of interest in SXB-15. Incidence of new or worsened TEAEs was highest at week 1 (SXB-15: dizziness, 7.5%; headache, 7.5%; nausea, 5.9%; SXB-22: dizziness, 5.4%; nausea, 7.1%) and decreased over time in both studies. The longest median duration was reported for dizziness: 9.0 and 17.5 days in SXB-15 and SXB-22, respectively. Dizziness caused discontinuation in 2.2% and 3.6% of participants in SXB-15 and SXB-22, respectively; nausea caused discontinuation in 2.7% and 1.8%.. Common early-onset TEAEs associated with SXB treatment were generally of short duration and their incidence decreased over time. These TEAEs accounted for few discontinuations overall.. Registry: ClinicalTrials.gov; Names: Safety and Efficacy of Xyrem Oral Solution (Sodium Oxybate) Compared With Placebo in Narcoleptic Patients; Trial Comparing Effects of Xyrem Taken Orally and Modafinil With Placebo in Treating Daytime Sleepiness in Narcolepsy; URLs: https://clinicaltrials.gov/ct2/show/NCT00049803 and https://clinicaltrials.gov/ct2/show/NCT00066170; Identifiers: NCT00049803 and NCT00066170.

Topics: Adult; Disorders of Excessive Somnolence; Double-Blind Method; Humans; Incidence; Modafinil; Narcolepsy; Sodium Oxybate; Treatment Outcome

Our objective was to define responder criteria using an anchor-based approach for frequency of cataplexy attacks and excessive daytime sleepiness in patients with narcolepsy undergoing sodium oxybate treatment. We used pooled data from two randomized, placebo-controlled, double-blind, multicentre 4- and 8-week trials of sodium oxybate for narcolepsy with cataplexy and analysed using receiver operator characteristics analysis. The percentage change in frequency of weekly cataplexy attacks and the Epworth Sleepiness Scale outcomes were compared with Clinical Global Impression of Change ratings, used as the anchor to define true response. Participants (n = 336) were 39% male, 89% white, with a mean age of 41.5 (15.3) years, reporting a median of 20.5 cataplexy attacks per week and a mean Epworth Sleepiness score of 17.5 at baseline. A majority (51%) were Much Improved or Very Much Improved based on Clinical Global Impression of Change ratings, considered a true response to treatment. Area under the curve values for % reduction in cataplexy attacks (77%) and % change in sleepiness score (78%) supported response definition thresholds of 46% and 12%, respectively. Classification using either response definition agreed with the anchor for approximately 71% of participants. Cataplexy response definition was more sensitive (cataplexy = 0.77, Epworth Sleepiness Scale = 0.69), while sleepiness was more specific (cataplexy = 0.66, Epworth Sleepiness Scale = 0.75). Both responder definitions showed a dose-response relationship with sodium oxybate, demonstrating their validity using an external criterion. Weekly cataplexy attacks and Epworth Sleepiness Scale can be used to help document clinical response to narcolepsy treatment using criteria of 46% and 12% reductions, respectively.

Topics: Adjuvants, Anesthesia; Adult; Cataplexy; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Sleepiness; Sodium Oxybate; Treatment Outcome; Wakefulness

To evaluate adherence to sodium oxybate prescribing information for indication and dosage, patients' compliance with instructions for use, safety/tolerability in routine clinical practice, and abuse potential.. A postauthorization, noninterventional surveillance study (NCT00244465) in patients who were prescribed sodium oxybate according to current practice by sleep disorders specialists. Patients were monitored for ≤18 months.. Overall, 749 patients were enrolled; 730 included in the intent-to-treat population (narcolepsy type 1 n = 670, other indications n = 60). We report on patients with narcolepsy type 1 (female 47.9%, mean age 39.4 years); 495/670 (73.9%) completed the study. Median dose: at start of study 4.5 g per night, 6 g per night throughout study, in two equal doses. According to the treatment compliance checklist, 35.5 per cent of patients consumed alcohol, 19.3 per cent took the medication <2 hr after food, and 27.1 per cent did not adhere to recommended time schedule, with few associated treatment-emergent adverse events (TEAEs). Incidences of higher-than-recommended doses, difficulty in preparing doses, and abuse were low. TEAEs were reported by 67.3 per cent, most frequently headache (11.6%) and nasopharyngitis (6.4%). Discontinuation due to TEAEs: 8.8 per cent. Serious TEAEs: 6.4 per cent. There were no reports of respiratory depression. No particular safety concerns were identified in pediatric or elderly patients, or those with underlying sleep apnea.. In this large postauthorization safety study of sodium oxybate use, indication and dosage prescribing recommendations were generally followed, and most patients complied with instructions, with deviations around alcohol consumption, eating before dosing and timing. The overall safety profile was consistent with previous observations; incidence of abuse was low.. Neurological disorders.. Postauthorization, noninterventional, surveillance, pharmacoepidemiology study to evaluate long-term safety, tolerability, and compliance in administration of Xyrem (sodium oxybate) oral solution in patients who receive treatment with this medication in regular clinical practice. https://clinicaltrials.gov/ct2/show/NCT00244465, ClinicalTrials.gov: NCT00244465.

Topics: Adult; Aged; Anesthetics, Intravenous; Female; Humans; Male; Medication Adherence; Middle Aged; Narcolepsy; Population Surveillance; Sodium Oxybate; Treatment Outcome

Narcolepsy is a lifelong neurological disorder with onset commonly in childhood or adolescence. No drugs are indicated for cataplexy and excessive daytime sleepiness in paediatric patients with narcolepsy. Sodium oxybate is approved for use in adult patients with excessive daytime sleepiness or cataplexy, or both, in narcolepsy. We aimed to examine the safety and efficacy of sodium oxybate oral solution treatment in children and adolescents who have narcolepsy with cataplexy.. This was a prospective, double-blind, placebo-controlled, randomised-withdrawal, multisite study and open-label investigation done at 30 sites in five countries (USA, Finland, France, Italy, and the Netherlands). Eligible participants were aged 7-16 years at screening, had narcolepsy with cataplexy, and were either being treated with sodium oxybate or were sodium oxybate-naive at entry. Sodium oxybate-naive participants were titrated to an optimal dose. Participants were randomly assigned (1:1) with a dynamic randomisation algorithm to receive placebo or to remain on sodium oxybate for 2 weeks; they then entered an open-label sodium oxybate treatment period for a total study duration of up to 1 year. Random assignment to placebo was discontinued if early efficacy was shown in the preplanned interim analysis of the primary efficacy endpoint, which was change in weekly number of cataplexy attacks. Participants entering the study after the interim analysis would then be assigned to receive open-label sodium oxybate for 2 weeks. The primary analysis of efficacy and safety included data collected until the cutoff date of Feb 10, 2017. The efficacy population consisted of all participants randomly assigned to receive an intervention who completed at least 5 days of dosing in the double-blind treatment period, and the safety population consisted of all participants who took the study drug, including open-label sodium oxybate. This study is registered with ClinicalTrials.gov, number NCT02221869.. Between Oct 1, 2014, and Feb 10, 2017, we enrolled 106 participants, and 104 took the study drug (the safety population). 96 (92%) of these participants completed the stable-dose period, of whom 63 participants (the efficacy population) were randomly assigned to receive sodium oxybate (n=31) or placebo (n=32) for 2 weeks. A preplanned interim analysis of the primary endpoint showed efficacy (p=0·0002), resulting in discontinuation of the placebo arm following guidance from the data safety monitoring board; 33 participants then received sodium oxybate on an open-label basis during the double-blind period. Participants who were randomly assigned to receive placebo and who were withdrawn from sodium oxybate (32 [51%] of 63 patients) had increased weekly cataplexy attacks (median increase of 12·7 attacks per week [Q1, Q3=3·4, 19·8]) when compared with those randomly assigned to continue treatment with sodium oxybate (median increase of 0·3 attacks per week [-1·0, 2·5]; p<0·0001). Commonly reported (>5%) adverse events were enuresis (15 [21%] of 72 sodium oxybate-naive participants vs four [13%] of 32 participants taking sodium oxybate at study entry), nausea (16 [22%] vs two [6%]), vomiting (15 [21%] vs two [6%]), headache (13 [18%] vs four [13%]), decreased weight (11 [15%] vs one [3%]), decreased appetite (eight [11%] vs none), nasopharyngitis (seven [10%] vs none), and dizziness (five [7%] vs 1 [3%]). Two serious adverse events (one event of severe acute psychosis and one event of moderate suicidal ideation) were reported, and both were considered to be related to the study drug. There were no reported deaths.. These results support the clinical efficacy of sodium oxybate for the treatment of both excessive daytime sleepiness and cataplexy in narcolepsy in children. The safety profile of sodium oxybate was consistent with that observed in adult patients.. Jazz Pharmaceuticals.

Topics: Adolescent; Child; Double-Blind Method; Female; Humans; Male; Narcolepsy; Prospective Studies; Sodium Oxybate; Treatment Outcome; Withholding Treatment

Gamma-hydroxybutyrate acid (GHB), a GABA. To assess effects of oral GHB (Xyrem®) upon driving as measured by a driving simulator, and to determine plasma concentrations associated with impairment and the time course of recovery.. Randomized, double-blind, two-arm crossover study, during which 16 participants received GHB 50 mg/kg orally or placebo. GHB blood samples were collected prior to and at 1, 3, and 6 h post dosing. Driving simulator sessions occurred immediately after blood sampling.. Plasma GHB was not detectable at baseline or 6 h post dosing. Median GHB concentrations at 1 and 3 h were 83.1 mg/L (range 54-110) and 24.4 mg/L (range 7.2-49.7), respectively. Compared to placebo, at 1 h post GHB dosing, significant differences were seen for the life-threatening outcome collisions (p < 0.001) and off-road accidents (p = 0.018). Although driving was not faster, there was significantly more weaving and erratic driving with GHB as measured by speed deviation (p = 0.002) and lane position deviation (p = 0.004). No significant impairment regarding driving outcomes was found in the GHB group at 3 and 6 h post dose.. GHB in doses used to treat narcolepsy resulted in severe driving impairment at 1 h post dosing. After 3 to 6 h, there was full recovery indicating that safe driving is expected the next morning after bedtime therapeutic GHB use in the absence of other substances.

Topics: Adjuvants, Anesthesia; Administration, Oral; Adult; Automobile Driving; Computer Simulation; Cross-Over Studies; Double-Blind Method; Driving Under the Influence; Female; Humans; Male; Narcolepsy; Sodium Oxybate

To estimate the effect of the compound sodium oxybate (SO) on chin muscle tone in sleep, a re-analysis of the results of the international multicenter study SXB-15 was performed, applying a validated semi-automatic analysis of muscle tone. This analysis distinguishes short (<0.5 s) and long (>0.5 s) muscle activity indices per hour (SMI, LMI) in 116 patients with narcolepsy-cataplexy. While stable stimulant medication was permitted, tricyclics and SSRIs were withdrawn. Polysomnographies were performed at baseline (V5), four weeks after titration of SO to 4.5 g, 6 g, or 9 g or placebo (V6) and after another four weeks on stable SO dose (V7).. SMI and LMI decreased significantly during light sleep. LMI remained stable in all SO groups during slow wave sleep (SWS), but decreased significantly during REM sleep. SMI decreased non-significantly, but consistently during SWS and REM in the 9 g group only. A subgroup analysis of patients who stayed on stimulants showed that they had higher SMIs and LMIs in all groups. Patients who had been treated with anticataplectic medication prior to study inclusion had lower LMIs in the 9 g group during REM sleep in all visits.. SO has a differential effect on muscle tone that is dose and sleep stage dependent. Low dosages increase short muscle activity, possibly enabling the occurrence of parasomnias. High doses are especially efficacious in REM sleep, suggesting that SO could be used to treat REM sleep behavior disorder. Comedication with stimulants and prior medication with anticataplectic medication exerts an influence on muscle tone.

Topics: Adult; Central Nervous System Stimulants; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Movement; Multivariate Analysis; Muscle Tonus; Muscle, Skeletal; Narcolepsy; Polysomnography; Sleep Aids, Pharmaceutical; Sleep Stages; Sodium Oxybate

In evaluating pathologic sleepiness, the Epworth Sleepiness Scale (ESS) assesses subjective sleep propensity; the Maintenance of Wakefulness Test (MWT) is an objective measure of the ability to stay awake. This analysis evaluated the strength of the correlation between ESS and MWT with regard to absolute values in scores.. Data were analyzed separately from the intent-to-treat populations of two eight-week clinical trials of sodium oxybate for the treatment of narcolepsy, SXB-15 and SXB-22. For all treatment groups, correlations between ESS and MWT were evaluated at baseline, week four, and week eight using the Pearson product-moment correlation coefficient.. Overall, correlations across all treatment groups in each study described an inverse relationship, reflecting the scoring of each measure (ie, whereas higher ESS scores indicate greater sleepiness, higher MWT scores indicate a greater ability to remain awake). Significant correlations of low-to-moderate strength were observed at all time points in both studies. In SXB-15, correlation coefficients were -0.272, -0.365, and -0.343 at baseline (n = 221), week four (n = 212), and week eight (n = 205), respectively, with all P < 0.0001. Similarly, in SXB-22, correlation coefficients were -0.302 (n = 216), -0.418 (n = 211), and -0.432 (n = 196) at the three time points, respectively, also with all P < 0.0001.. Although all correlations showed statistical significance, they were of low-to-moderate strength. These results indicate that ESS and MWT measure features of pathologic sleepiness that may be distinct, but partially overlapping. These data corroborate those of other studies, suggesting that physiologic mechanisms that regulate alertness and sleep propensity may function somewhat independently.

Topics: Adolescent; Adult; Aged; Humans; Middle Aged; Narcolepsy; Patient Reported Outcome Measures; Sleep; Sodium Oxybate; Treatment Outcome; Wakefulness; Wakefulness-Promoting Agents; Young Adult

To assess the effects of three narcolepsy treatment modalities on sleep stage shifts associated with disrupted nighttime sleep (DNS) using data from a clinical trial.. Polysomnograms were reviewed from 155 patients (who had these data available at baseline and 8 weeks) of the 278 patients who were randomized to placebo, 9-g sodium oxybate (SXB)/nightly, 200-600 mg/d modafinil, or SXB + modafinil. Major outcomes of these post hoc analyses, analyzed using analysis of covariance, were change from baseline in number of shifts from Stages N2/3/rapid eye movement (REM) to Stage N1/Wake, and from Stage N1/Wake to REM. Sleep quality was evaluated using the sleep-quality question from the Pittsburgh Sleep Quality Index.. SXB alone or in combination with modafinil significantly decreased the number of shifts from Stage N2/3/REM to Stage N1/Wake (p < 0.01); least-squares mean change in number of shifts from baseline was -0.6, -16.5, 1.8, and -13.7 in the placebo, SXB, modafinil and SXB + modafinil groups, respectively. A similar pattern was observed for changes in shifts from REM to Stage N1/Wake and from Stage N1/Wake to REM. Relative to placebo, sleep quality significantly improved with SXB and SXB + modafinil (p ≤ 0.05) but not with modafinil alone.. These results show that SXB with and without modafinil significantly consolidated sleep and improved patient-reported sleep quality relative to placebo. In contrast, no such effects were observed with modafinil alone, suggesting a specific effect of SXB on DNS in addition to its effect on daytime sleepiness. CLINICALTRIALS.. NCT00066170.

Topics: Adult; Benzhydryl Compounds; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Modafinil; Narcolepsy; Polysomnography; Sleep Stages; Sodium Oxybate; Treatment Outcome

γ-Hydroxybutyrate (GHB) is used as a treatment for narcolepsy and alcohol withdrawal and as a recreational substance. Nevertheless, there are limited data on the pharmacokinetics and pharmacokinetic-pharmacodynamic relationships of GHB in humans. We characterized the pharmacokinetic profile and exposure-psychotropic effect relationship of GHB in humans.. Two oral doses of GHB (25 and 35 mg kg(-1) ) were administered to 32 healthy male subjects (16 for each dose) using a randomized, placebo-controlled, cross-over design.. Maximal concentrations of GHB were (geometric mean and 95% CI): 218 (176-270) nmol ml(-1) and 453 (374-549) nmol ml(-1) for the 25 and 35 mg kg(-1) GHB doses, respectively. The elimination half-lives (mean ± SD) were 36 ± 9 and 39 ± 7 min and the AUC∞ values (geometric mean and 95% CI) were 15 747 (12 854-19 290) and 40 113 (33 093-48 622) nmol∙min ml(-1) for the 20 and 35 mg kg(-1) GHB doses, respectively. Thus, plasma GHB exposure (AUC0-∞ ) rose disproportionally (+40%) with the higher dose. γ-Hydroxybutyrate produced mixed stimulant-sedative effects, with a dose-dependent increase in sedation and dizziness. It did not alter heart rate or blood pressure. A close relationship between plasma GHB exposure and its psychotropic effects was found, with higher GHB concentrations associated with higher subjective stimulation, sedation, and dizziness. No clockwise hysteresis was observed in the GHB concentration effect plot over time (i.e., no acute pharmacological tolerance).. Evidence was found of a nonlinear dose-exposure relationship (i.e., no dose proportionality) at moderate doses of GHB. The effects of GHB on consciousness were closely linked to its plasma exposure and exhibited no acute tolerance.

Topics: Administration, Oral; Adult; Blood Pressure; Cross-Over Studies; Dose-Response Relationship, Drug; Drug Tolerance; GABA Agonists; Healthy Volunteers; Heart Rate; Humans; Hypnotics and Sedatives; Male; Narcolepsy; Psychotropic Drugs; Sodium Oxybate; Substance Withdrawal Syndrome; Young Adult

Previous laboratory studies in narcolepsy patients showed altered core body and skin temperatures, which are hypothesised to be related to a disturbed sleep wake regulation. In this ambulatory study we assessed temperature profiles in normal daily life, and whether sleep attacks are heralded by changes in skin temperature. Furthermore, the effects of three months of treatment with sodium oxybate (SXB) were investigated.. Twenty-five narcolepsy patients and 15 healthy controls were included. Core body, proximal and distal skin temperatures, and sleep-wake state were measured simultaneously for 24 hours in ambulatory patients. This procedure was repeated in 16 narcolepsy patients after at least 3 months of stable treatment with SXB.. Increases in distal skin temperature and distal-to-proximal temperature gradient (DPG) strongly predicted daytime sleep attacks (P < 0.001). As compared to controls, patients had a higher proximal and distal skin temperature in the morning, and a lower distal skin temperature during the night (all P < 0.05). Furthermore, they had a higher core body temperature during the first part of the night (P < 0.05), which SXB decreased (F = 4.99, df = 1, P = 0.03) to a level similar to controls. SXB did not affect skin temperature.. This ambulatory study demonstrates that daytime sleep attacks were preceded by clear changes in distal skin temperature and DPG. Furthermore, changes in core body and skin temperature in narcolepsy, previously only studied in laboratory settings, were partially confirmed. Treatment with SXB resulted in a normalisation of the core body temperature profile. Future studies should explore whether predictive temperature changes can be used to signal or even prevent sleep attacks.

Topics: Adolescent; Adult; Aged; Body Temperature; Case-Control Studies; Central Nervous System Agents; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Narcolepsy; Skin Temperature; Sodium Oxybate; Treatment Outcome; Young Adult

Effects of sodium oxybate (SXB) on patients with narcolepsy with cataplexy (NC) or without cataplexy (NWOC) have not been separately evaluated in clinical trials.. Retrospective analysis evaluated data from a phase 3, randomized, placebo-controlled trial of SXB, modafinil, and SXB + modafinil versus placebo in adult NC patients (n = 95) or NWOC patients (n = 127). NC patients were identified based on medical history, concomitant medications, and sleep-onset REM periods on nocturnal polysomnography. The studied outcomes were changes from baseline at eight weeks on the Epworth Sleepiness Scale (ESS), the Maintenance of Wakefulness Test (MWT), and the Clinical Global Impression of Change (CGI-C).. Among NC and NWOC patients, ESS improvement was significantly greater with SXB and SXB + modafinil versus placebo. In NC patients, mean MWT sleep latency was significantly increased with SXB + modafinil versus placebo. In NWOC patients, mean MWT sleep latency significantly increased in all groups versus placebo. Higher percentages of patients in the SXB and SXB + modafinil groups were "very much improved" or "much improved" on the CGI-C versus placebo in both NC and NWOC populations, although the difference did not reach statistical significance in the NWOC populations. Adverse events were consistent with previously-reported profiles for modafinil and SXB. Nausea was more common in the SXB and SXB + modafinil groups. Dizziness and tremor were more common in the SXB + modafinil group only.. SXB alone and in combination with modafinil improved subjective ratings of excessive sleepiness and an objective measure of the ability to stay awake to similar extents in NC patients and NWOC patients.

Topics: Adjuvants, Anesthesia; Adult; Benzhydryl Compounds; Cataplexy; Drug Therapy, Combination; Female; Humans; Male; Modafinil; Narcolepsy; Polysomnography; Retrospective Studies; Sodium Oxybate; Wakefulness; Wakefulness-Promoting Agents

This post hoc analysis evaluated the time to response that can be expected with sodium oxybate (SXB) for treatment of excessive daytime sleepiness (EDS) and cataplexy in patients with narcolepsy.. Data were from a 4-week, double-blind, randomized, placebo-controlled trial (GHB-2; N = 136) of oral SXB 3 g, 6 g, and 9 g nightly, and its 12-month open-label extension (GHB-3). Two response definitions were utilized: ≥ 20% improvement in Epworth Sleepiness Scale (ESS) score (EDS responders), and ≥ 50% reduction in weekly cataplexy attacks (cataplexy responders). These thresholds were previously determined to be clinically relevant based on analysis of the relationship of Clinical Global Impression of Change with ESS and number of cataplexy attacks. Kaplan-Meier curves and median times to first response, based on above criteria, and to maximum response were estimated.. Among 86 patients randomized to SXB in GHB-2 and continued into GHB-3, 77.6% and 90.7% were EDS and cataplexy responders, respectively. The median (95% CI) times to first response were 37 (31-50) days for EDS and 25 (17-29) days for cataplexy, and median times to maximum response were 106 (85-164) days for EDS and 213 (94-279) days for cataplexy. GHB-3 results among 31 patients initially randomized to placebo were consistent with those treated with SXB throughout, but with longer times to maximum response.. Response onset, assessed as clinically meaningful improvements in EDS and cataplexy, was observed in most patients within 2 months; a longer period is needed to achieve maximum response. Clinicians should recognize that time to initial and maximum response may take weeks to months.

Topics: Adult; Disorders of Excessive Somnolence; Double-Blind Method; Female; Humans; Hypnotics and Sedatives; Male; Narcolepsy; Sodium Oxybate; Time Factors; Treatment Outcome

Patients suffering from narcolepsy type 1 show altered skin temperatures, resembling the profile that is related to sleep onset in healthy controls. The aim of the present study is to investigate the effects of sodium oxybate, a widely used drug to treat narcolepsy, on the 24-h profiles of temperature and sleep-wakefulness in patients with narcolepsy and controls. Eight hypocretin-deficient male narcolepsy type 1 patients and eight healthy matched controls underwent temperature measurement of core body and proximal and distal skin twice, and the sleep-wake state for 24 h. After the baseline assessment, 2 × 3 g of sodium oxybate was administered for 5 nights, immediately followed by the second assessment. At baseline, daytime core body temperature and proximal skin temperature were significantly lower in patients with narcolepsy (core: 36.8 ± 0.05 °C versus 37.0 ± 0.05 °C, F = 8.31, P = 0.01; proximal: 33.4 ± 0.26 °C versus 34.3 ± 0.26 °C, F = 5.66, P = 0.03). In patients, sodium oxybate administration increased proximal skin temperature during the day (F = 6.46, P = 0.04) to a level similar as in controls, but did not affect core body temperature, distal temperature or distal-proximal temperature gradient. Sodium oxybate administration normalised the predictive value of distal skin temperature and distal-proximal temperature gradient for the onset of daytime naps (P < 0.01). In conclusion, sodium oxybate administration resulted in a partial normalisation of the skin temperature profile, by increasing daytime proximal skin temperature, and by strengthening the known relationship between skin temperature and daytime sleep propensity. These changes seem to be related to the clinical improvement induced by sodium oxybate treatment. A causal relationship is not proven.

Topics: Adolescent; Adult; Aged; Body Temperature Regulation; Case-Control Studies; Drug Administration Schedule; Humans; Male; Middle Aged; Narcolepsy; Orexins; Skin Temperature; Sleep; Sodium Oxybate; Time Factors; Wakefulness; Young Adult

Hypocretin deficiency causes narcolepsy and may affect neuroendocrine systems, including TSH, ACTH and LH secretion. Symptoms can be treated effectively with sodium oxybate (SXB) in many patients. This study was performed to compare prolactin (PRL) secretion in patients and matched controls and establish the effect of SXB administration on PRL and sleep in both the groups.. Open label intervention. Blood was sampled before and after 5 days of SXB treatment. The study was performed at the Leiden University Medical Centre, Leiden, The Netherlands.. Subjects were admitted to the clinical research centre on both occasions.. Eight male hypocretin-deficient narcolepsy with cataplexy patients and eight controls matched for sex, age, body mass index, waist-to-hip ratio and fat percentage were enrolled.. SXB two times 3 g per night for five consecutive nights.. Patients and controls underwent 24 h blood sampling at 10 min intervals for measurement of PRL concentrations. The PRL concentration time series was analysed with a new deconvolution programme, approximate entropy (ApEn) and Cosinor analysis. Sleep was polygraphically recorded. Basal and pulsatile PRL secretion, as well as pulse regularity and frequency, ApEn and diurnal parameters were similar in patients and controls. SXB treatment caused similar nocturnal increase in PRL secretion, advance of the acrophase and decrease in ApEn in patients and controls. Slow wave sleep was increased to a similar extent in patients and controls.. This detailed study did not demonstrate altered PRL secretion in hypocretin-deficient narcolepsy patients during the basal state or during SXB administration. Therefore, hypocretin signalling is unlikely to be a regulator of the lactotrophic system.

Topics: Adjuvants, Anesthesia; Adult; Animals; Humans; Male; Narcolepsy; Prolactin; Sleep; Sodium Oxybate

Sodium oxybate (SXB) is an approved drug for the treatment of excessive daytime sleepiness (EDS) and cataplexy in narcolepsy. Obstructive sleep apnea syndrome (OSAS) is a condition that frequently co-occurs with narcolepsy. Given the known central nervous system (CNS) depressant effects of SXB, this study aimed to examine its effects on sleep-disordered breathing (SDB) and sleep architecture in patients with OSAS.. Sixty patients with a history of mild to moderate OSAS (apnea-hypopnea index [AHI]>or=10 and or=75%) received one of four treatments of the following: (1) 9g SXB, (2) 9g SXB/modafinil 200mg, (3) zolpidem 10mg, and (4) placebo (PBO) in a randomized, crossover design on four consecutive nights followed by overnight polysomnography.. Forty-two patients (70%) completed the study. The mean change from baseline in AHI and mean SaO(2) was not significantly different among groups following treatment. Central apneas in patients treated with SXB increased, and clinically significant oxygen desaturations were seen in three patients with SXB treatment. The most common treatment related adverse events were headache and nausea.. These results suggest that nighttime administration of 9g SXB in patients with mild to moderate OSAS does not negatively impact SDB, as measured by mean change from baseline in AHI and SaO(2), but might increase central apneas and cause oxygen desaturation in some individuals and should be used with caution.

Topics: Adjuvants, Anesthesia; Adult; Aged; Benzhydryl Compounds; Central Nervous System Stimulants; Comorbidity; Continuous Positive Airway Pressure; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Modafinil; Narcolepsy; Oxygen; Polysomnography; Product Surveillance, Postmarketing; Pyridines; Sleep Apnea, Obstructive; Sleep Stages; Sodium Oxybate; Zolpidem

To further explore the effects of sodium oxybate (SXB) administration on nocturnal sleep in narcolepsy patients during a double-blind, placebo-controlled, parallel group study conducted with 228 adult patients with narcolepsy/cataplexy in the United States, Canada, and Europe.. Patients were withdrawn from antidepressants and sedative/hypnotics, and then randomized to receive 4.5, 6, or 9 g SXB or placebo nightly for 8 weeks. Patients receiving 6 and 9 g/night doses were titrated to their final dose in weekly 1.5 g increments, while patients receiving placebo were randomized to undergo a similar mock dose titration. The use of stimulant therapy continued unchanged. Changes in sleep architecture were measured using centrally scored nocturnal polysomnograms. Daily diaries were used to record changes in narcolepsy symptoms and adverse events.. Following 8 weeks of SXB treatment, study patients demonstrated significant dose-related increases in the duration of stage 3 and 4 sleep, reaching a median increase of 52.5 minutes in patients receiving 9 g nightly. Compared to placebo-treated patients, delta power was significantly increased in all dose groups. Stage 1 sleep and the frequency of nocturnal awakenings were each significantly decreased at the 6 and 9 g/night doses. The changes in nocturnal sleep coincided with significant decreases in the severity and frequency of narcolepsy symptoms.. The nightly administration of SXB to narcolepsy patients significantly impacts measures of slow wave sleep, wake after sleep onset, awakenings, total sleep time, and stage 1 sleep in a dose-related manner. The frequency and severity of narcolepsy symptoms decreased with treatment.

Topics: Adjuvants, Anesthesia; Administration, Oral; Adolescent; Adult; Aged; Analysis of Variance; Cataplexy; Circadian Rhythm; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Middle Aged; Narcolepsy; Polysomnography; Reference Values; Severity of Illness Index; Sodium Oxybate; Time Factors; Treatment Outcome; Young Adult

A double-blind, placebo-controlled sodium oxybate trial provided a unique opportunity to compare changes in cataplexy following gradual withdrawal from antidepressants in narcolepsy patients.. Of 228 enrolled patients, 71 discontinued antidepressant therapy. Data from 57 patients were available for analysis: 37 patients discontinued tricyclic antidepressants (TCAs) and 20 discontinued selective serotonin reuptake inhibitors (SSRIs). The trial included a 21-day withdrawal phase followed by 18-day washout and 14-day single-blind treatment phases. Two additional weeks were permitted for withdrawal from fluoxetine due to its long half-life. Weekly cataplexy attacks were recorded throughout the trial. No historical data on the frequency of cataplexy prior to treatment with antidepressants was available.. Among the patients who were and were not withdrawn from antidepressants treatment, the median frequency of baseline weekly cataplexy was similar (17.5 vs. 14.0, respectively). As expected, significant between-group differences emerged by the end of the washout period (52.04 vs. 15.25, respectively; p<0.05); however, the frequency of cataplexy events became similar again by the end of the trial (16.5 vs. 17.5, respectively).. Patients gradually withdrawn from antidepressants experienced a significant increase in cataplexy, but eventually returned to their baseline frequency, comparable to previously untreated control patients. Compared to SSRIs, discontinuation from TCAs was associated with a greater increase in cataplexy attacks.

Topics: Adult; Antidepressive Agents, Tricyclic; Cataplexy; Cohort Studies; Dose-Response Relationship, Drug; Humans; Narcolepsy; Retrospective Studies; Risk Factors; Selective Serotonin Reuptake Inhibitors; Sodium Oxybate; Substance Withdrawal Syndrome

This study was performed to evaluate the actions of baclofen and sodium oxybate, two medications with gamma-aminobutyric acid type B (GABA(B)) receptor agonist properties, on symptoms of narcolepsy in drug-naïve teenagers. Twenty-six narcoleptic teenagers with recent onset of narcolepsy-cataplexy syndrome who were human leukocyte antigen DQB1 0602 positive were matched for age and sex and received either baclofen or sodium oxybate. If deemed necessary to combat excessive daytime sleepiness, the alerting agent modafinil was also prescribed. Clinical evaluation was performed weekly, and visual analog sleepiness score and cataplexy logs were collected weekly. The Epworth Sleepiness Scale or the Pediatric Daytime Sleepiness Scale, polysomnography, and the Multiple Sleep Latency Test were recorded at baseline and after 3 months of drug intake. The dose of baclofen demonstrating an effect on nocturnal sleep without negative side effects was determined and maintained. Both drugs increased total sleep time and delta waves during sleep, but only sodium oxybate had an effect on daytime sleepiness and cataplexy at 3 months. Improvement of total nocturnal sleep time had no beneficial effect on daytime sleepiness. The mechanism by which sodium oxybate improves cataplexy and sleepiness is inferred to be due to properties beyond direct GABA(B) agonist action.

Topics: Adolescent; Baclofen; Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Female; Follow-Up Studies; GABA Agonists; GABA-B Receptor Agonists; Humans; Male; Modafinil; Narcolepsy; Photoperiod; Polysomnography; Severity of Illness Index; Sleep; Sodium Oxybate; Time Factors

Previous studies indicate that nightly sodium oxybate administration reduces nocturnal sleep disruption in narcolepsy. The present study provided an opportunity to further characterize these sleep-related effects in patients with narcolepsy during treatment with sodium oxybate as monotherapy or in combination with modafinil.. This double-blind, placebo-controlled study enrolled 278 patients with narcolepsy taking modafinil 200-600 mg daily for the treatment of excessive daytime sleepiness (EDS). Following a baseline polysomnogram (PSG) and Maintenance of Wakefulness Test (MWT), patients were randomized to receive treatment with: (1) placebo, (2) sodium oxybate, (3) modafinil, or (4) sodium oxybate+modafinil. PSGs and MWTs were repeated after 4 and 8 weeks. Other efficacy measures included Epworth Sleepiness Scale scores and daily diary recordings.. After 8 weeks, significant changes in sleep architecture among patients receiving sodium oxybate and sodium oxybate/modafinil included a median increase in Stage 3 and 4 sleep (43.5 and 24.25 min, respectively) and delta power and a median decrease in nocturnal awakenings (6.0 and 9.5, respectively). No significant changes in PSG parameters were noted in patients treated with placebo or modafinil alone.. In addition to its established efficacy for the treatment of cataplexy and EDS, nightly sodium oxybate administration significantly reduces measures of sleep disruption and significantly increases slow-wave sleep in patients with narcolepsy.

Topics: Adjuvants, Anesthesia; Adult; Benzhydryl Compounds; Central Nervous System Stimulants; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Modafinil; Narcolepsy; Placebos; Polysomnography; Sleep; Sleep Wake Disorders; Sodium Oxybate; Wakefulness

To assess the effectiveness of sodium oxybate therapy, modafinil therapy and the combination of the two for excessive daytime sleepiness in narcolepsy patients previously taking modafinil.. Double-blind, placebo-controlled, multicenter study.. Forty-four sites in the United States, Canada, the Czech Republic, France, Germany, the Netherlands, Switzerland, and the United Kingdom.. Two hundred seventy- adult patients with narcolepsy taking 200 to 600 mg of modafinil daily for the treatment of excessive daytime sleepiness.. Patients received unchanged doses of modafinil (with sodium-oxybate placebo) during a 2-week baseline phase. Following a baseline polysomnogram and Maintenance of Wakefulness Test, they were randomly assigned to 1 of 4 treatment groups: sodium-oxybate placebo plus modafinil placebo, sodium oxybate plus modafinil placebo, modafinil plus sodium-oxybate placebo, or sodium oxybate plus modafinil. Sodium oxybate was administered as 6 g nightly for 4 weeks and was then increased to 9 g nightly for 4 additional weeks. The primary efficacy measure was the Maintenance of Wakefulness Test; secondary measures included the Epworth Sleepiness Scale, diary recordings, and the Clinical Global Impression-change scale.. Following the switch from modafinil to placebo, the mean average daytime sleep latency on the Maintenance of Wakefulness Test decreased from 9.74 minutes at baseline to 6.87 minutes after 8 weeks (p < .001). In the sodium-oxybate group, there was no decrease in sleep latency, suggesting that this drug was as efficacious in treating the excessive daytime sleepiness as the previously administered modafinil. In contrast, the sodium-oxybate/modafinil group demonstrated an increase in daytime sleep latency from 10.43 minutes to 13.15 minutes (p < .001), suggesting that this combination of drugs produced an additive effect. The sodium-oxybate group also demonstrated a decrease in median average Epworth Sleepiness Scale scores, from 15 to 12.0, whereas the sodium-oxybate/modafinil group decreased from 15.0 to 11.0 (for both, p < .001). The Clinical Global Impression-Change scale demonstrated similar results.. Sodium oxybate and modafinil are both effective for treating excessive daytime sleepiness in narcolepsy, producing additive effects when used together. Sodium oxybate is beneficial as both monotherapy and as adjunctive therapy for the treatment of excessive daytime sleepiness in narcolepsy.

Topics: Adult; Benzhydryl Compounds; Central Nervous System Stimulants; Disorders of Excessive Somnolence; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Modafinil; Narcolepsy; Polysomnography; Severity of Illness Index; Sodium Oxybate; Treatment Outcome; Wakefulness

To evaluate the efficacy of sodium oxybate versus placebo to improve quality of life in patients with narcolepsy.. A multicenter, double-blind, placebo-controlled trial.. Outpatient facility of 42 sleep centers in the United States, Canada, and Europe.. Study participants were 285 patients with narcolepsy, 16 to 75 years of age, with a median Epworth Sleepiness Scale score of 18, a Maintenance of Wakefulness Test sleep latency of 9.56 minutes, and experiencing symptoms of narcolepsy, including cataplexy and excessive daytime sleepiness with recurrent sleep episodes almost daily for at least 3 months at the time of enrollment.. Subjects were gradually withdrawn from narcolepsy medications used for cataplexy, including antidepressants. Subsequently, participants were randomly assigned to receive 4.5, 6.0, or 9.0 g per day of sodium oxybate or placebo taken in two equally divided doses upon retiring to bed and again 2.5 to 4 hours later for 4 weeks during the stable dosing phase.. The change in quality of life following the administration of sodium oxybate was measured with the Functional Outcomes of Sleep Questionnaire. The nightly administration of sodium oxybate produced significant dose-related improvements in the Total Functional Outcomes of Sleep Questionnaire score, as well as in the Activity Level, General Productivity, Vigilance, and Social Outcomes subscales.. The nocturnal administration of sodium oxybate in patients with narcolepsy was associated with statistically significant and clinically relevant improvements in functional status, an important component of quality of life.

Topics: Adjuvants, Anesthesia; Adult; Disorders of Excessive Somnolence; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Narcolepsy; Polysomnography; Quality of Life; Sodium Oxybate; Surveys and Questionnaires; Treatment Outcome

Assess the efficacy of sodium oxybate for the treatment of narcolepsy with an emphasis on excessive daytime sleepiness.. Eight-week, multicenter, double-blind, placebo-controlled trial.. Forty-two sleep clinics in the United States, Canada, and Europe.. Two hundred twenty-eight adults with narcolepsy with cataplexy.. Patients were withdrawn from antidepressant treatment and then randomly assigned to receive 4.5 g, 6 g, or 9 g of sodium oxybate nightly or placebo for 8 weeks. Six-gram and 9-g doses were titrated in weekly 1.5-g increments. Patients who were receiving placebo underwent a mock dose-titration schedule. Stimulant use continued unchanged. Excessive daytime sleepiness was measured using the Epworth Sleepiness Scale and Maintenance of Wakefulness Test. The Clinical Global Impression of Change was used to measure changes in disease severity. Changes in narcolepsy symptoms and adverse events were recorded in daily diaries.. After 8 weeks, patients treated with 9 g of sodium oxybate nightly displayed a significant median increase of > 10 minutes in the Maintenance of Wakefulness Test (p < .001). Patients displayed dose-related decreases in median Epworth Sleepiness Scale scores and frequency of weekly inadvertent naps, which were significant at the 6-g and 9-g doses (for each, p < .001). The improvements in excessive daytime sleepiness were incremental to those achieved by concomitant stimulants alone. Significant improvements in the Clinical Global Impression of Change were noted for each group treated with sodium oxybate (p < or = .001). Adverse events were consistent with the known safety profile of sodium oxybate.. When combined with its previously demonstrated anticataplectic effects, the results of the current study indicate sodium oxybate is the first drug to demonstrate efficacy for the 2 major symptoms of narcolepsy.

Topics: Adolescent; Adult; Aged; Cataplexy; Disorders of Excessive Somnolence; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Narcolepsy; Office Visits; Sodium Oxybate

This trial was conducted to evaluate the pharmacokinetics and safety of a sodium oxybate (gamma-hydroxybutyrate [GHB]) oral solution in narcoleptic patients after acute and chronic treatment. An open-label, two-period, two-treatment study design was used. Trial subjects included 13 patients with polysomnographically confirmed narcolepsy. The patients were administered a bedtime dose of 4.5 g of sodium oxybate while in a sleep research center. They were subsequently treated with sodium oxybate at the nightly dose of 4.5 g for 8 weeks. The patients then returned to the sleep center and were again treated with the 4.5-g sodium oxybate dose at bedtime. Blood samples (5 mL) were collected at 18 time points before and up to 7 hours after both the first dose of sodium oxybate and following 8 weeks of dosing. Plasma samples were analyzed for oxybate content by a validated liquid chromatography/tandem mass spectrometry (LC/MS/MS) method. Noncompartmental methods were applied in the determination of pharmacokinetic parameters from each patient's plasma oxybate concentration versus time curve. No serious adverse events were recorded, and all patients completed the study. Headache, enuresis, and leg cramps were reported as adverse experiences. With both acute and chronic dosing, sodium oxybate was rapidly absorbed and eliminated with an apparent half-life of about 40 minutes. The only changes observed in the kinetics of oxybate after 8 weeks of treatment were a 13% and 16% increase in peak concentration (C(max)) and systemic exposure (AUC), respectively. The pharmacokinetics of sodium oxybate in narcoleptic patients were not changed in any clinically significant manner when the drug was chronically administered. The drug was well tolerated.

Topics: Administration, Oral; Adult; Area Under Curve; Central Nervous System Depressants; Drug Administration Schedule; Female; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Narcolepsy; Pharmaceutical Solutions; Sodium Oxybate; Time Factors

Topics: Cataplexy; Dose-Response Relationship, Drug; Double-Blind Method; Humans; Narcolepsy; Sodium Oxybate

This study was conducted to demonstrate the long-term efficacy of sodium oxybate for the long-term treatment of cataplexy in patients with narcolepsy.. Fifty-five (55) narcoleptic patients with cataplexy who had received continuous treatment with sodium oxybate for 7-44 months (mean 21 months) were enrolled in a double-blind treatment withdrawal paradigm. A 2-week single-blind sodium oxybate treatment phase established a baseline for the weekly occurrence of cataplexy. This was followed by a 2-week double-blind phase in which patients were randomized to receive unchanged drug therapy or placebo. Patients recorded the incidence of cataplexy attacks and adverse events in daily diaries.. During the 2-week double-blind phase, the abrupt cessation of sodium oxybate therapy in the placebo patients resulted in a significant increase in the number of cataplexy attacks (median=21; P<0.001 ) compared to patients who remained on sodium oxybate (median=0). Cataplexy attacks returned gradually with placebo patients reporting a median of 4.2 and 11.7 cataplexy attacks during the first and second weeks, respectively. There were no symptoms of frank withdrawal.. This controlled trial provides evidence supporting the long-term efficacy of sodium oxybate for the treatment of cataplexy. In contrast with antidepressant drug therapy, there is no evidence of rebound cataplexy upon abrupt discontinuation of treatment.

Topics: Anesthetics, Intravenous; Cataplexy; Double-Blind Method; Female; Follow-Up Studies; Humans; Male; Middle Aged; Narcolepsy; Polysomnography; Single-Blind Method; Sodium Oxybate; Time

To measure the effect of nocturnal sodium oxybate administration on sleep architecture in patients with narcolepsy.. Open-label study.. Four accredited sleep clinics.. 25 adult patients with narcolepsy-cataplexy.. Patients were weaned from previously used anticataplectic medications and administered increasing nightly doses of sodium oxybate over a 10-week period: 4.5 g for 4 weeks, 6 g for 2 weeks, 7.5 g for 2 weeks, and 9 g for 2 weeks. The effect of sodium oxybate was measured using nocturnal polysomnograms, the Epworth Sleepiness Scale, the Maintenance of Wakefulness Test, and a narcolepsy symptoms questionnaire.. The nightly administration of sodium oxybate produced dose-related increases in slow-wave sleep and delta power, rapid eye movement sleep increased initially and then decreased in a dose-related manner, nocturnal awakenings decreased, and daytime sleep latency increased. Significant improvements in daytime symptoms were measured by the Maintenance of Wakefulness Test, the Epworth Sleepiness Scale, and the narcolepsy symptom questionnaire.. Nocturnal administration of sodium oxybate in patients with narcolepsy produces significant improvements in sleep architecture, which coincide with significant improvements in daytime functioning.

Topics: Adjuvants, Anesthesia; Administration, Oral; Adult; Central Nervous System Stimulants; Circadian Rhythm; Delta Rhythm; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Narcolepsy; Pilot Projects; Polysomnography; Sleep Stages; Sodium Oxybate; Wakefulness

To evaluate the long-term safety and efficacy of nightly sodium oxybate for the treatment of narcolepsy.. A multicenter, 12-month, open-label trial.. 118 narcolepsy patients previously enrolled in a 4-week double-blind sodium oxybate trial.. Patients were administered 6 g sodium oxybate nightly, taken in equally divided doses at bedtime and 2.5 to 4 hours later. The study protocol permitted the dose to be increased or decreased in 1.5-g increments at 2-week intervals based on efficacy response or adverse experiences but staying within the range of 3 to 9 g nightly.. Narcolepsy symptoms and adverse events were recorded in daily diaries. Safety measures included physical and laboratory examinations repeated at 6 and 12 months. The primary efficacy measure was the change in weekly cataplexy attacks from baseline. Secondary measures included daytime sleepiness using the Epworth Sleepiness Scale (ESS), inadvertent naps/sleep attacks, nighttime awakenings, and the overall change in disease severity as rated by the investigators (Clinical Global Impression of Change; CGI-c).. Sodium oxybate, in doses of 3 to 9 g nightly, produced overall improvements in narcolepsy symptoms, which were significant at 4 weeks and maximal after 8 weeks. Reported improvements included a significant decrease in frequency of cataplexy attacks (p < 0.001); diminished daytime sleepiness (p < 0.001); and patient descriptions of nocturnal sleep quality, level of alertness, and ability to concentrate (for each p < 0.001). Adverse events were generally mild and patients showed no evidence of tolerance.. Sodium oxybate is an effective and well-tolerated treatment for narcolepsy.

Topics: Adjuvants, Anesthesia; Adolescent; Adult; Aged; Double-Blind Method; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Narcolepsy; Prospective Studies; Sodium Oxybate

Sodium oxybate (gamma-hydroxybutyrate; GHB) has demonstrated efficacy for the treatment of narcolepsy. However, there are reports of withdrawal following chronic abuse of illicit GHB which involve escalating both doses and dosing frequency. The present trial afforded an opportunity to test the hypothesis that chronic daily therapeutic dosing of sodium oxybate in narcoleptics does not cause withdrawal following abrupt cessation. Fifty-five narcoleptic patients, taking sodium oxybate (dose range 3-9 gm/night) for 7-44 months (mean 21 months), were randomized into a 2-week double-blind period: 29 patients received placebo and 26 continued to receive sodium oxybate. During this 2-week trial period, the following symptoms were reported in patients receiving placebo (N): anxiety (2), dizziness (1), insomnia (1) and somnolence (1). While these symptoms may represent possible symptoms of mild GHB withdrawal, they are also highly consistent with the returning symptoms of narcolepsy. We conclude there is minimal evidence of withdrawal symptoms following abrupt cessation of chronic sodium oxybate dosing in the therapeutic range.

Topics: Adult; Cataplexy; Double-Blind Method; Female; Humans; Male; Middle Aged; Narcolepsy; Sodium Oxybate; Substance Withdrawal Syndrome

To evaluate and compare the efficacy and safety of three doses of sodium oxybate and placebo for the treatment of narcolepsy symptoms.. A multicenter, double blind, placebo-controlled trial.. N/A.. Study subjects were 136 narcolepsy patients with 3 to 249 (median 21) cataplexy attacks weekly.. Prior to baseline measures, subjects discontinued anticataplectic medications. Stable doses of stimulants were permitted. Subjects were randomized in blinded fashion to receive 3, 6, or 9 g doses of sodium oxybate or placebo taken in equally divided doses upon retiring to bed and 2.5-4 hours later for 4 weeks.. Disease symptoms and adverse events were recorded in daily diaries. The primary measure of efficacy was the change from baseline in weekly cataplexy attacks. Secondary measures included daytime sleepiness using the Epworth Sleepiness Scale (ESS), inadvertent daytime naps/sleep attacks and nighttime awakenings. Investigators assessed changes in disease severity using Clinical Global Impression of Change (CGI-c). Compared to placebo, weekly cataplexy attacks were decreased by sodium oxybate at the 6 g dose (p=0.0529) and significantly at the 9 g dose (p=0.0008). The ESS was reduced at all doses, becoming significant at the 9 g dose (p=0.0001). The CGI-c demonstrated a dose-related improvement, significant at the 9 g dose (p=0.0002). The frequency of inadvertent naps/sleep attacks and the nighttime awakenings showed similar dose-response trends, becoming significant at the 9 g dose (p=0.0122 and p=0.0035, respectively). Sodium oxybate was generally well-tolerated at all three doses. Nausea, headache, dizziness and enuresis were the most commonly reported adverse events.. Sodium oxybate significantly improved symptoms in patients with narcolepsy and was well tolerated.

Topics: Adjuvants, Anesthesia; Adult; Double-Blind Method; Female; Humans; Male; Narcolepsy; Sleep, REM; Sodium Oxybate; Time Factors

Sodium gammahydroxybutyrate (GHB) is an endogenous compound that has been under investigation in the management of narcolepsy for about two decades. The data confirm that GHB treatment decreases daytime sleepiness and episodes of cataplexy, sleep paralysis, and hypnagogic hallucinations. The current study evaluated the pharmacokinetics of GHB, given twice in one night to six narcoleptic patients who had been chronically taking GHB nightly on a similar basis. Results confirmed earlier reports and showed nonlinear pharmacokinetics. Maximum concentrations were reached in 40 +/- 6.2 and 35.7 +/- 7 minutes after the first and second dose respectively. Mean AUCinf was 17731.6 +/- 4867 mg/mL/m. Mean GHB T1/2 was 53 +/- 19 minutes. GHB elimination appears to be capacity-limited in some patients when administered at a fixed dose of 3 g twice nightly at a 4-hour interval.

Topics: Brain; Dose-Response Relationship, Drug; Female; Humans; Hypnotics and Sedatives; Infant, Newborn; Male; Middle Aged; Narcolepsy; Sodium Oxybate; Time Factors

A survey was conducted on 10 polysomnographic studies on the pharmacologic treatment of the sleepiness of narcolepsy. Three studies employed the MSLT and 7 employed the MWT as their polygraphic measure of sleep tendency. Statistically and clinically significant therapeutic changes were apparent for pemoline, modafinil, dextroamphetamine and methylphenidate. Codeine, ritanserin and protriptyline did show statistically significant effects. The common feature among the drugs that did produce clinically significant improvements seems to be facilitatory action on central catecholaminergic transmission. Within this group of drugs, only methylphenidate and dextroamphetamine brought MWT sleep latencies to approximately 70% of normal levels.

Topics: Adult; Arousal; Benzhydryl Compounds; Central Nervous System Stimulants; Codeine; Dextroamphetamine; Female; Humans; Male; Methylphenidate; Modafinil; Narcolepsy; Pemoline; Piperidines; Protriptyline; Reaction Time; Ritanserin; Sleep Stages; Sodium Oxybate; Viloxazine; Wakefulness

The effects of gamma-hydroxybutyrate (GHB: 25 mg/kg h.s. and 3 h later) vs. placebo on objectively evaluated nighttime sleep and daytime sleepiness in narcolepsy were evaluated in a double-blind, counterbalanced crossover design. Twenty narcolepsy patients were given an overnight polysomnogram (PSG), followed by a daytime multiple sleep latency test (MSLT) at baseline and on the 1st and 29th days of GHB and placebo treatment. The overnight PSGs indicated that the narcolepsy patients had the following significant results during GHB versus placebo treatment: decreased stage 1 (p = 0.012), increased stage 3 (p = 0.008), increased delta (stage 3 and 4 combined) sleep (p = 0.049), fewer stage shifts (p = 0.002), and fewer awakenings (p = 0.006). Minutes of wakefulness were significantly increased only for the last 2 h of the 8 h sleep period on GHB versus placebo (p = 0.019), which is beyond the time of GHB's direct influence. The MSLTs indicated that the narcolepsy patients had a marginally increased sleep latency mean during GHB versus placebo treatment (p = 0.074) and significantly increased total stage 0 (wakefulness) on day 29 of GHB versus day 29 of placebo treatment (p = 0.038). Female narcolepsy patients had significantly fewer naps with REM sleep (REM naps) on day 29 of GHB vs. day 29 of placebo treatment (p = 0.020). The therapeutic effect of GHB in narcolepsy patients, i.e., decreases cataplexy, appears to be due to its improving nocturnal sleep quality, since its half-life is only 1.5 to 2 h. It is conjectured that GHB, an endogenous neurochemical, may be a sleep neurotransmitter or neuromodulator, since GHB rapidly induces sleep, and increases sleep continuity and delta sleep without suppressing REM sleep in both normals and narcolepsy patients.

Topics: Adult; Double-Blind Method; Electroencephalography; Electromyography; Electrooculography; Female; Humans; Male; Middle Aged; Narcolepsy; Sleep; Sodium Oxybate; Wakefulness

The efficacy of gamma-hydroxybutyrate (GHB) versus placebo for treating narcolepsy was evaluated in 20 patients with narcolepsy, 10 men and 10 women, using a double-blind counterbalanced crossover design. Each patient completed a daily sleep-wake log and questionnaire during a 14-day baseline, a 29-day placebo period, a 29-day GHB period (50 mg GHB/kg/night given 25 mg/kg h.s. and 25 mg/kg 3 hr later), and a 6-day washout period after each treatment. Cataplexy frequency was significantly lower during GHB treatment than during placebo treatment (p = 0.022). Compared to baseline values, the number of cataplexy attacks per day declined by 52% and 69% during GHB treatment weeks 1 and 4, respectively. The number of subjective arousals from sleep was less with GHB than with placebo (p = 0.035), and the number of sleep attacks was not significantly different during GHB versus placebo treatment. GHB did not have a significant effect on subjective estimates of sleep onset latency, total sleep time, Stanford Sleepiness Scale ratings at morning wake-up, methylphenidate usage, or the number of naps per day. The results indicate that GHB is efficacious for reducing the frequency of cataplexy attacks and subjective nocturnal arousals in patients with narcolepsy within the first 4 weeks of treatment.

Topics: Adolescent; Adult; Arousal; Cataplexy; Circadian Rhythm; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Hydroxybutyrates; Male; Middle Aged; Narcolepsy; Random Allocation; Reaction Time; Sleep, REM; Sodium Oxybate; Wakefulness

Thirty patients with polysomnographically confirmed narcolepsy were treated with GHB (gamma-hydroxybutyrate) for up to 30 weeks. The number of nightly awakenings significantly decreased, while Stages 3 and 4 sleep substantially increased. The clinical symptoms of cataplexy, sleep paralysis, hypnogogic hallucinations, daily naps, and sleep attacks all showed significant improvements. Daytime sleepiness, while not completely eliminated, was controlled with lower doses of stimulant medication than patients were taking before the study. No patient developed tolerance to the drug, and no serious side effects were noted.

Topics: Adult; Aged; Antidepressive Agents, Tricyclic; Cataplexy; Clinical Trials as Topic; Dextroamphetamine; Drug Therapy, Combination; Female; Hallucinations; Humans; Hydroxybutyrates; Male; Methamphetamine; Methylphenidate; Middle Aged; Narcolepsy; Pemoline; Sleep; Sodium Oxybate; Wakefulness

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.. 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.. 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.. 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.. SXB was administered in low-medium doses. Two-nightly doses and sleep fragmentation linked to sleep comorbidities at long-term lead to drug withdrawal.. 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.

Topics: Adult; Apnea; Female; Follow-Up Studies; Humans; Male; Narcolepsy; Sleep; Sodium Oxybate

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.. 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.. 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.

Topics: Adult; Calcium; Cataplexy; Child; Disorders of Excessive Somnolence; Humans; Hypertension; Magnesium; Narcolepsy; Potassium; Sodium; Sodium Oxybate

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 SXB's mechanism of action on narcolepsy.

Topics: Animals; Cataplexy; Dogs; Humans; Locus Coeruleus; Mice; Narcolepsy; Neurons; Opiate Alkaloids; Orexins; Sodium Oxybate

Topics: Humans; Narcolepsy; REM Sleep Behavior Disorder; Sleep; Sodium Oxybate

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.. 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.. 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.. 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 2.5–4 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.

Topics: Humans; Narcolepsy; Quality of Life; Sodium Oxybate; Surveys and Questionnaires; Treatment Outcome

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.. 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.. 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.. 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.

Topics: Child; Cross-Sectional Studies; Female; Follow-Up Studies; Humans; Male; Narcolepsy; Obesity; Orexins; Retrospective Studies; Sodium Oxybate

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.

Topics: Adult; Female; Humans; Male; Narcolepsy; Prospective Studies; Sleep; Sodium Oxybate; Treatment Outcome

Narcolepsy type 1 is a focal degenerative disease of the hypothalamus that selectively affects orexin (hypocretin)-producing neurons. It presents multiple clinical manifestations, both in wakefulness and in sleep. The symptoms are often so disruptive that they cause enormous suffering and impair patients' quality of life. Although a non-pharmacological approach is sometimes sufficient, the vast majority of patients need medication for adequate clinical management.. A male who, at 43 years of age, began to present acutely with excessive daytime sleepiness and episodes of cataplexy. After a thorough examination, he was diagnosed with narcolepsy type 1. Throughout the course of the disease, he was prescribed antidepressants, neurostimulants and sodium oxybate, in monotherapy or in combination. The response to pharmacological treatment was insufficient and accompanied by numerous side effects. Following the introduction of pitolisant, there was a marked improvement in his symptoms and a reduction in the dose of the other drugs and their adverse effects was achieved.. A number of measures are now available to address the cardinal symptoms of the disease, although there are still cases that are resistant to anti-narcoleptic treatment. Drugs with mechanisms of action that act upon receptors in the histaminergic system can be very useful in these cases.. Narcolepsia multirresistente.. Introducción. La narcolepsia de tipo 1 es una enfermedad degenerativa focal del hipotálamo que afecta selectivamente a las neuronas productoras de orexina (hipocretina). Presenta múltiples manifestaciones clínicas, tanto en vigilia como en sueño. Con frecuencia, los síntomas son tan disruptivos que ocasionan enorme sufrimiento y deterioro de la calidad de vida de los pacientes. Aunque en ocasiones es suficiente con un abordaje no farmacológico, la gran mayoría de los enfermos necesita medicación para un adecuado control clínico. Caso clínico. Varón que a los 43 años comenzó a presentar de forma aguda excesiva somnolencia diurna y episodios de cataplejía. Tras un exhaustivo estudio se le diagnosticó narcolepsia de tipo 1. A lo largo de la evolución de la enfermedad se le prescribieron antidepresivos, neuroestimulantes y oxibato sódico, en monoterapia o en combinación. La respuesta al tratamiento farmacológico fue insuficiente y se acompañó de numerosos efectos secundarios. Tras la introducción de pitolisant se objetivó una franca mejoría de los síntomas, y se consiguió reducir la dosis de los otros fármacos y de sus efectos adversos. Conclusión. Son numerosas las medidas disponibles en la actualidad para abordar los síntomas cardinales de la enfermedad, aunque siguen existiendo casos resistentes al tratamiento antinarcoléptico. Los fármacos con mecanismos de acción sobre receptores del sistema histaminérgico pueden resultar de gran utilidad en estos casos.

Topics: Adult; Antidepressive Agents; Cataplexy; Central Nervous System Stimulants; Drug Resistance, Multiple; Humans; Male; Narcolepsy; Quality of Life; Sleepiness; Sodium Oxybate

The goals of this article are to describe the clinical approach to and management of patients with central disorders of hypersomnolence, and to understand and differentiate available diagnostic tools.. Updated clinical practice guidelines for the treatment of central disorders of hypersomnolence and narcolepsy specifically highlight new treatment options. Approval for a lower-sodium oxybate formulation that contains 92% less sodium than the standard sodium oxybate for the treatment of narcolepsy and idiopathic hypersomnia adds to the number of medications available for these disorders, allowing for a more tailored management of symptoms.. Central disorders of hypersomnolence are characterized by excessive daytime sleepiness that impacts daily functions. These disorders can be differentiated by obtaining a detailed clinical sleep history and by a thoughtful interpretation of sleep diagnostic testing. Tailoring treatment approaches to meet the needs of individuals and accounting for medical and psychiatric comorbidities may improve quality of life.

Topics: Disorders of Excessive Somnolence; Humans; Narcolepsy; Quality of Life; Sleep; Sodium Oxybate

To describe the pharmacological treatments (2005-2017) and the healthcare utilization (1997-2016) for patients with narcolepsy in Sweden in order to create a framework for future organizational and economic analyses.. Patients of all ages with a diagnosis of narcolepsy registered in the National Patient Registry in specialist care in Sweden were included and information on treatments for narcolepsy was retrieved from The Swedish Prescribed Drug Register.. We collected 2508 patients with narcolepsy, 43,3% men and 56,7% women and 47,9% were prescribed modafenil, 33,8% metylphenidate and 26,2% amphetamine. In total, 3817 treatments were initiated. Patients treated with amphetamine had a higher mean age. More women than men used modafinil, methylphenidate, amphetamine and antidepressants. The narcolepsy population had more outpatient than inpatient healthcare. Patients treated with sodium oxybate had more outpatient visits than other narcolepsy patients, before and during treatment (p = .00).. This study gives valuable information on pharmaceutical treatments and healthcare utilization for patients with narcolepsy and can be used to estimate the healthcare cost in the future. Patients with sodium oxybate treatment had more outpatient visits than other patients before and during treatment which may be due to the need to monitor potentially severe side-effects or may indicate that patients with sodium oxybate treatment have a severe disease. The number of included patients was less than expected; however, this may depend on patients escaping our collection of data, which does not contain information from primary care.

Topics: Antidepressive Agents; Female; Humans; Male; Modafinil; Narcolepsy; Sodium Oxybate; Sweden

Sodium oxybate (SXB) is a standard of care for cataplexy, excessive daytime sleepiness, and disrupted nighttime sleep in narcolepsy. At recommended dosages in adults (6-9 g/night), SXB increases daily dietary intake of sodium by 1100-1640 mg. Because excess sodium intake is associated with increased blood pressure and cardiovascular risk, an oxybate formulation containing 92% less sodium than SXB (lower-sodium oxybate; LXB) was developed to provide an alternative oxybate treatment option. In 2020, LXB was approved for treatment of cataplexy or excessive daytime sleepiness in patients 7 years of age and older with narcolepsy, and in 2021, for treatment of idiopathic hypersomnia in adults.. Development of LXB from initial concept to regulatory approval is described, including formulation development and preclinical and clinical studies. Pharmacokinetic parameters and bioequivalence evaluations from phase 1 clinical trials are detailed. Efficacy and safety results from phase 3 clinical trials of LXB in patients with narcolepsy or idiopathic hypersomnia are presented and discussed.. Reducing sodium from high sodium‒containing medications is an important step to offset cardiovascular risks associated with high sodium consumption. The development of LXB exemplifies the importance of a collaborative approach to drug development, with patient needs paramount.. Sodium oxybate (Xyrem®) is a medication for people with narcolepsy aged 7 years and older. Xyrem treats symptoms of excessive daytime sleepiness (EDS) or cataplexy (attacks of muscle weakness caused by emotion) in narcolepsy. At the recommended dosages in adults, Xyrem adds a large amount of sodium to daily dietary intake. Too much sodium in the diet is associated with increased blood pressure and risks of damage to the heart and blood vessels. Researchers used calcium, magnesium, and potassium ions in addition to a small amount of sodium to make a new oxybate medication, called Xywav®, that has 92% less sodium than Xyrem. Xywav and Xyrem were similar in laboratory and animal studies. In people, the body absorbs and processes Xywav slightly differently than Xyrem, but Xywav treatment has been shown to work the same to reduce symptoms of cataplexy and EDS in people with narcolepsy and is approved by the US Food and Drug Administration. Another neurological disorder with EDS is called idiopathic hypersomnia. Based on a clinical study, Xywav also reduced EDS and other symptoms in people with idiopathic hypersomnia. Side effects with Xywav are similar to those seen in previous studies with Xyrem.

Topics: Animals; Cataplexy; Child; Disorders of Excessive Somnolence; Humans; Idiopathic Hypersomnia; Narcolepsy; Sodium Oxybate

The Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD) measures daytime sleepiness, but had not previously been validated in children <12 years of age.. Data from a sodium oxybate (SXB) study in pediatric participants with narcolepsy with cataplexy (ClinicalTrials.gov, NCT02221869) were used in this validation study. SXB-naive participants completed an open-label titration period prior to entering a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period.. The analysis population (N = 100) had a mean (SD) age of 11.9 (2.39) years. Internal consistency as assessed by Cronbach's alpha was 0.750 (95% CI, 0.681-0.819). The intraclass correlation coefficient for the test-retest reliability assessment (n = 64 with stable or no stimulant use at study entry) was 0.755 (95% CI, 0.626-0.844). Responsiveness to change, measured as the mean within-person change in 1-week ESS-CHAD score over time in SXB-naive participants (n = 59) from baseline (before taking SXB) to end of the stable-dose period (taking the titrated amount of SXB), was -6.31 (95% CI: -7.61, -5.00; nominal P < 0.0001). For convergent construct validity, the mean (SD) scores for female (n = 40) and male (n = 60) participants were 13.98 (4.440) and 14.65 (4.050), respectively (nominal P = 0.4430). For divergent construct validity, the mean (SD) scores were 16.31 (2.978) in the group who were taking neither SXB nor stimulants at study entry (n = 32) and 13.47 (4.400) in the group taking SXB with or without stimulants at study entry (n = 68; nominal P = 0.0003).. This evidence supports the validity of the 1-week ESS-CHAD in a pediatric population with narcolepsy.

Topics: Adolescent; Cataplexy; Child; Female; Humans; Male; Narcolepsy; Reproducibility of Results; Sleepiness; Sodium Oxybate; Surveys and Questionnaires; Treatment Outcome

Sleep enhances the consolidation of memories. Here, we investigated whether sleep-dependent memory consolidation differs between healthy subjects and narcolepsy type 1 (NT1) patients.. We recruited 18 patients with NT1 and 24 healthy controls. The consolidation of spatial (declarative memory; 2-dimensional object location) and procedural (non-declarative memory; finger sequence tapping) memories was examined across one night of at-home sleep. Sleep was measured by an ambulatory sleep recording device.. The overnight gain in the number of correctly recalled sequences in the finger-tapping test was smaller for NT1 patients than healthy subjects (+8.1% vs. +23.8% from pre-sleep learning to post-sleep recall, p = .035). No significant group differences were found for the overnight consolidation of spatial memory. Compared to healthy subjects, the sleep of NT1 patients was significantly more fragmented and shallow. However, no significant correlations were found between sleep parameters and overnight performance changes on the memory tests in the whole group.. The sleep-dependent consolidation of procedural but not spatial memories may be impaired among patients with NT1. Therefore, future studies are warranted to examine whether sleep improvement, for example, using sodium oxybate, can aid the sleep-dependent formation of procedural memories among NT1 patients.

Topics: Humans; Narcolepsy; Sleep; Sodium Oxybate

Topics: Humans; Narcolepsy; Polysomnography; Sodium Oxybate

Topics: Cataplexy; Humans; Narcolepsy; Sodium Oxybate

Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is approved (in the United States and European Union) to treat excessive daytime sleepiness (EDS) in adults with narcolepsy (75-150 mg/d) or obstructive sleep apnea (OSA) (37.5-150 mg/d). This study characterized real-world titration strategies for patients with narcolepsy (with or without comorbid OSA) initiating solriamfetol therapy.. This virtual, descriptive study included a retrospective medical record review and qualitative survey. US-based physicians prescribing solriamfetol for EDS associated with narcolepsy or OSA participated. Data are reported for patients with narcolepsy with or without comorbid OSA (OSA alone reported separately). On the basis of medical record review, titration strategies were classified de novo (EDS medication naive), transition (switched or switching from existing EDS medication[s] to solriamfetol), or add-on (adding solriamfetol to current EDS medication[s]). The survey included open-ended questions regarding a hypothetical patient-a 32-year-old woman with narcolepsy (Epworth Sleepiness Scale score of 8) treated with 35 mg/d of amphetamine and 6 g per night of sodium oxybate who experiences non-use-limiting adverse events from amphetamine.. Twenty-six physicians participated: 23 provided data from 70 patients with narcolepsy (type 1, n = 24; type 2, n = 46; mean [SD] age, 40 [11] years; 57% female; 6 with comorbid OSA), and 26 responded to the hypothetical patient scenario. From the medical record review, solriamfetol therapy initiation was de novo for 19 of 70 patients (27%), transition for 31 of 70 patients (44%), and add-on for 20 of 70 patients (29%). Efficacy profile of solriamfetol was the primary reason for de novo (12 of 19 [63%]), transition (18 of 31 [58%]), and add-on (19 of 20 [95%]) initiation. Most (86%) initiated use of solriamfetol at 75 mg/d and were stable at 150 mg/d (76%). Most (67%) had 1 dose adjustment, reaching a stable dose over a median (range) of 14 (1-60) days. Physicians most often considered EDS severity (44%) when titrating. Among transitioning patients, 14 of 22 (64%) using wake-promoting agents discontinued their use abruptly, and 5 of 9 (56%) using stimulants were tapered off. At data collection, 90% continued to take solriamfetol. Regarding the hypothetical patient scenario, most physicians (81%) thought solriamfetol was appropriate, highlighting tolerability issues with current treatment and lack of symptom control as drivers for switching; however, 3 physicians (12%) did not think solriamfetol was appropriate, noting current symptoms were not severe enough and/or symptoms could be managed by increasing sodium oxybate dose; 2 (8%) thought it would depend on other factors. Physicians emphasized managing withdrawal symptoms while maintaining EDS symptom control when titrating off a stimulant and starting solriamfetol therapy.. In a real-world study, physicians initiated solriamfetol therapy at 75 mg/d for most patients with narcolepsy, adjusted dosages once, tapered stimulants, and abruptly discontinued therapy with wake-promoting agents.

Topics: Adult; Disorders of Excessive Somnolence; Female; Humans; Male; Narcolepsy; Retrospective Studies; Sleep Apnea, Obstructive; Sodium Oxybate; Wakefulness-Promoting Agents

Sodium oxybate (SO) has been in use for many decades to treat narcolepsy with cataplexy. It functions as a weak GABAB agonist but also as an energy source for the brain as a result of its metabolism to succinate and as a powerful antioxidant because of its capacity to induce the formation of NADPH. Its actions at thalamic GABAB receptors can induce slow-wave activity, while its actions at GABAB receptors on monoaminergic neurons can induce or delay REM sleep. By altering the balance between monoaminergic and cholinergic neuronal activity, SO uniquely can induce and prevent cataplexy. The formation of NADPH may enhance sleep's restorative process by accelerating the removal of the reactive oxygen species (ROS), which accumulate during wakefulness. SO improves alertness in normal subjects and in patients with narcolepsy. SO may allay severe psychological stress - an inflammatory state triggered by increased levels of ROS and characterized by cholinergic supersensitivity and monoaminergic deficiency. SO may be able to eliminate the inflammatory state and correct the cholinergic/ monoaminergic imbalance.

Topics: Cataplexy; Humans; Narcolepsy; Sleep; Sodium Oxybate; Wakefulness

To study the effect of stable treatment with sodium oxybate (SO) on nocturnal REM sleep behavior disorder (RBD) and REM sleep without atonia (RSWA) that severely affected children with type 1 narcolepsy (NT1).. Nineteen children and adolescents with NT1 (9 female, mean age 12.5 ± 2.7 years, mean disease duration 3.4 ± 1.6 years) underwent neurologic investigations and video-polysomnography (v-PSG) at baseline and after 3 months of stable treatment with SO. v-PSG was independently analyzed by 2 sleep experts to rate RBD episodes. RSWA was automatically computed by means of the validated REM sleep atonia index (RAI).. Compared to baseline, RAI significantly improved (. RBD and RSWA improved after treatment with SO, pointing to a direct role of the drug in modulating motor control during REM sleep.. This study offers Class IV evidence of the positive effect of SO on modulation of muscle atonia during REM sleep in children with NT1 because of the absence of a control group.

Topics: Adjuvants, Anesthesia; Adolescent; Child; Cohort Studies; Female; Humans; Male; Narcolepsy; Polysomnography; REM Sleep Behavior Disorder; Sleep, REM; Sodium Oxybate; Treatment Outcome

Narcolepsy type 1 is characterized by excessive daytime sleepiness and cataplexy, as well as hypocretin deficiency. Cataplexy (the loss of voluntary postural muscle tone, often in response to emotional stimuli) is one of the most disabling features and is associated with significant social impairment and risk of injury. Cataplexy is usually alleviated by antidepressants sodium oxybate and pitolisant. In this case report, we describe three patients with severe, drug-resistant cataplexy who experienced a dramatic improvement when treated with tropatepine, an anticholinergic muscarinic antagonist (commonly used to prevent neuroleptic-induced parkinsonism) after the usual treatments had failed. The single side effect was mild mouth dryness. In addition to providing a new therapeutic option for resistant cataplexy, this benefit supports a role of cholinergic muscarinic transmission in rapid eye movement sleep atonia.

Topics: Cataplexy; Cholinergic Antagonists; Dibenzothiepins; Humans; Narcolepsy; Pharmaceutical Preparations; Sodium Oxybate

To describe the most commonly used treatments in pediatric narcolepsy and their perceived effectiveness, as well as to elicit key stakeholder perspectives on the most optimal manner in which care ought to be delivered to youth with narcolepsy.. A cross-sectional survey of youth with narcolepsy, parents, and sleep physicians.. Complete survey results were available for 35 youth with narcolepsy, 116 parents, and 30 sleep physicians. Overall there was general agreement among family and physicians regarding most effective treatments, including both pharmacologic (stimulants, sodium oxybate, and modafinil/armodafinil) and nonpharmacologic (sleep schedule, exercise, diet) approaches. There was a stronger interested in cannabidiol oil (CBD) from families compared to physicians. Both families and physicians also endorsed a need for multispecialty care, ideally delivered in a same day setting and including specialists in mental health, social work, and nutrition. Quality measures were felt to be important but are not currently tracked by most sleep physicians. Qualitative responses highlight the value families place on providers who listen well and remain open-minded.. Our results suggest strong support by key stakeholders for an interdisciplinary approach to care for youth with narcolepsy.

Topics: Adolescent; Central Nervous System Stimulants; Child; Cross-Sectional Studies; Humans; Narcolepsy; Parents; Physicians; Sleep; Sodium Oxybate

Pediatric type 1 narcolepsy (NT1) is often associated with overweight and obesity. Sodium oxybate (SO), approved for the treatment of narcolepsy with cataplexy from the age of 7 years old in the United States, has been associated with weight loss, although longitudinal pediatric studies are lacking. We report a retrospective cohort of 129 consecutive patients with a 4-year follow-up, to analyze the impact of different pharmacological treatments on body mass index (BMI) z-score. At baseline, the prevalence of obesity and overweight was 26.4% (34/129) and 29.5% (38/129), respectively. Patients were divided into three groups: children treated with SO alone (group 1), with SO-combined therapy (group 2), and without SO (group 3). At the end of the first year of follow-up, group 1 and group 2 showed a significant BMI z-score reduction compared to baseline: from 1.2 ± 1.1 to 0.4 ± 1.4 for group 1 (p < 0.001), and from 1.4 ± 1.1 to 1 ± 1.3 for group 2 (p = 0.002), independently from baseline clinical features. In the second year, only group 2 experienced a further and significant BMI z-score decrease (from 1.0 ± 1.2 to 0.6 ± 1.2, p = 0.037). No further significant BMI z-score changes were observed in SO-treated patients in the following years. Instead, children treated without SO developed a significant weight increase between the second and third year of therapy (BMI z-score from 0.3 ± 0.9 to 0.5 ± 0.9). In conclusion, SO treatment in pediatric NT1 is associated with a favorable weight reduction in the first year of treatment.

Topics: Body Mass Index; Child; Humans; Narcolepsy; Overweight; Retrospective Studies; Sodium Oxybate

During upward titration of a dose of sodium oxybate therapy for narcolepsy with cataplexy, a 25-year-old woman was observed by her husband to have new onset of knuckle-cracking and moaning behaviors during sleep ≥1 nights each week. The patient did previously occasionally crack her knuckles during the day (but never at night). These behaviors had not been evaluated by polysomnography. After transition of care, polysomnography with video monitoring was ordered and revealed 2 knuckle-cracking episodes that developed out of stage N2 sleep and were likely a non-rapid eye movement sleep parasomnia associated with sodium oxybate treatment.

Topics: Adult; Cataplexy; Female; Humans; Narcolepsy; Polysomnography; Sleep Stages; Sodium Oxybate

FT218 is an investigational, once-nightly, modified-release formulation of sodium oxybate (SO). SO effectively treats excessive daytime sleepiness and cataplexy in patients with narcolepsy. Current approved SO formulations, at effective doses of 6, 7.5, and 9 g, require twice-nightly divided dosing, with the first dose taken at bedtime and the second 2.5-4 h later. The purpose of the following studies was to evaluate the pharmacokinetic properties, safety profile, and tolerability of FT218 in healthy adults.. Four crossover, single-dose studies were conducted. The first was a pilot study (n = 16) that compared 3 prototype formulations of FT218 4.5 g to twice-nightly SO 4.5 g (2 divided doses of 2.25 g); the second, a dose-proportionality study (n = 20) that evaluated FT218 4.5, 7.5, and 9 g; the third, a relative bioavailability study (n = 28) that compared FT218 6 g with twice-nightly SO 6 g (2 divided doses of 3 g); and the fourth, a food-effect study (n = 16) of FT218 6 g.. In the pilot study, FT218 prototype 2 had a lower C. Once-nightly FT218 at 4.5 and 6 g had lower overall C

Topics: Adult; Biological Availability; Cross-Over Studies; Humans; Narcolepsy; Pilot Projects; Sodium Oxybate

Topics: Australia; Dextroamphetamine; Drug Costs; Health Expenditures; Health Services Accessibility; Humans; Methylphenidate; Modafinil; Narcolepsy; Polysomnography; Practice Guidelines as Topic; Prevalence; Randomized Controlled Trials as Topic; Sodium Oxybate; Treatment Outcome; Wakefulness-Promoting Agents

Gamma hydroxybutyrate (GHB) is a central nervous system depressant that is an approved drug for the treatment of narcolepsy with cataplexy and other syndromes. Due to its dose dependent stimulating, relaxing or sedative effects, illicit abuses include recreational use by young people and cases of drug-facilitated crime (DFC). Since GHB is also produced endogenously, for forensic questions, it is important to be able to differentiate between endogenous GHB and elevated levels due to additional intake. In this study, we measured GHB concentrations in hair of patients with narcolepsy receiving daily GHB treatment. The results were compared to endogenous concentrations and concentrations after chronic intake presented in several former studies. The aim of this study was to investigate whether a regular intake of a known dosage of GHB leads to elevated levels of GHB concentration in hair. We collected hair samples of 19 patients (14 female, 5 male) with narcolepsy under regular GHB treatment and examined the hair samples segmentally by digestion of the hair followed by liquid-liquid extraction and analysis using a Shimadzu LC20 UFLC system coupled with an AB Sciex API 4000 Qtrap tandem mass spectrometer. All volunteers received daily treatment with different doses of sodium oxybate (sodium salt of GHB) ranging between 3 and 9g per night. The observed mean value of GHB concentration in hair was 2.69ng GHB per mg hair for the 5 male participants, 1.56ng/mg for the 14 female participants giving an overall mean value of 1.86ng/mg for all participants. Our results showed no correlation between the daily dose or the duration intake of GHB and the measured concentration of GHB in hair. Although we did find a significant (p<0.01) difference between published endogenous levels of GHB in hair and GHB levels in hair of patients with regular daily GHB intake, the forensic relevance however is disputable. We hypothesise this narrow margin or even overlap to be the reason why analytical results from hair analysis in some cases fail to provide a reliable prove of a single exposition.

Topics: Adolescent; Adult; Central Nervous System Depressants; Chromatography, Liquid; Female; Hair; Humans; Male; Narcolepsy; Sodium Oxybate; Tandem Mass Spectrometry; Young Adult

The aim of this study was to evaluate the impact of different therapy regimens, including sodium oxybate (SXB)-containing regimens, on patient-reported outcomes (PROs) in people with narcolepsy.. Online surveys were used to collect information from persons with narcolepsy in the Nexus Narcolepsy Registry. Surveys contained questionnaires assessing self-reported sleep quality (SQ; via single question), daytime sleepiness and function (Epworth Sleepiness Scale and Functional Outcomes of Sleep Questionnaire), health-related quality of life (HRQoL; 36-Item Short Form Health Survey [SF-36]), work productivity and impairment (Work Productivity and Activity Impairment: Specific Health Problem), and history of injuries or motor vehicle accidents. Treatment with SXB (including monotherapy or combination therapy; SXB group) was compared with non-SXB therapy (No SXB group). The P values presented are nominal, as there are no adjustments for multiplicity.. From June 2015 through December 2017, 983 participants completed 1760 surveys. SQ and daytime functioning scores were better in the SXB group compared with the No SXB group (all P < 0.001). HRQoL scores were better for the SXB group compared with the No SXB group for the SF-36 Physical Component (P = 0.016), Mental Component (P < 0.001), and all 8 subscales. Additionally, PROs were better for the SXB group for presenteeism, overall work and activity impairment, and risk of motor vehicle accidents (all P ≤ 0.001).. Based on participants' self-assessments, treatment regimens with SXB were associated with better outcomes than regimens not containing SXB across many PROs, including SQ, HRQoL, work and activities, and risk of traffic accidents. CLINICALTRIALS.. NCT02769780.

Topics: Humans; Narcolepsy; Quality of Life; Registries; Sodium Oxybate; Treatment Outcome

We aimed to evaluate the association between patient-reported outcomes (PROs) and treatment regimen/standardized dose (STD), a measure of drug burden, in patients with narcolepsy type 1 (NT1)/type 2 (NT2) and idiopathic hypersomnia (IH).. Patients age 18 years or older with NT1/NT2 and IH with baseline and ≥ 6-month follow-up during 2008-2010 were included. Changes in PROs (Epworth Sleepiness Scale [ESS], Fatigue Severity Scale [FSS], Patient Health Questionnaire 9 [PHQ-9], total sleep time [TST]) by diagnosis, treatment regimen (monotherapy versus polytherapy, sodium oxybate [SO] use), and STD were assessed by t tests and univariable/multivariable linear regressions, adjusting for patient characteristics.. A total of 92 patients (26 [28.3%] NT1, 27 [29.3%] NT2, 39 [42.4%] IH) were included (age 43.8 ± 14.8 years; 66 [71.7%] female). Baseline PROs suggested excessive daytime sleepiness (ESS 14.2 ± 5.2 [74% patients > 10]), significant fatigue (FSS 47.5 ± 12.9), and mild depression (PHQ-9 9.0 [4.0, 14.0] [49.4% ≥ 10]). At follow-up, ESS and PHQ-9 improved significantly overall and within diagnostic, monotherapy/polytherapy, and SO use groups (all P < .01). FSS improved significantly overall (P = .016), but improvements were not significant for IH, monotherapy, polytherapy, and non-SO using groups. In multivariable models, PRO changes were not significantly different between groups, but baseline STD was associated with worsening PHQ-9 across PHQ-9 change models, and ESS worsened with increasing STD at follow-up (P = .056).. Significant improvements in sleep-related PROs were seen with pharmacotherapy use, regardless of diagnosis or treatment type, highlighting the importance of individualized prescribing decisions for this population.

Topics: Adult; Central Nervous System Stimulants; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Hypnotics and Sedatives; Idiopathic Hypersomnia; Male; Middle Aged; Narcolepsy; Patient Reported Outcome Measures; Polysomnography; Retrospective Studies; Sodium Oxybate; Treatment Outcome

Narcolepsy is a disabling sleep-wake disorder characterized by the pentad symptoms of excessive daytime sleepiness, sleep paralysis, sleep fragmentation, sleep-related hallucinations, and cataplexy. There is no curative therapy for narcolepsy. Treatment is therefore symptom directed. Symptom management is generally directed at improving excessive daytime sleepiness, sleep fragmentation, and cataplexy. First-line treatment for excessive daytime sleepiness is typically daily use of wake-promoting agents, such as modafinil or armodafinil, or stimulant therapy, such as methylphenidate or amphetamines. Alternatively, sodium oxybate can be used nightly for improved cataplexy, sleep consolidation, and following day wakefulness. These therapies can be limited in some patients because of inadequate efficacy, poor tolerability, or side effects.. We describe five narcolepsy patients with severe excessive daytime sleepiness who had an inadequate response or experienced side effects with the initial therapies but had a positive response to treatment with baclofen.. These patients reported subjective improvement in sleep maintenance without fragmentation and daytime sleepiness. Average Epworth Sleepiness Scale assessment before treatment was 15.8 with post-treatment assessment being 10.4 (P < 0.05).. Baclofen may be an effective treatment for excessive daytime sleepiness and sleep fragmentation in narcolepsy and warrants further study.

Topics: Adolescent; Baclofen; Central Nervous System Depressants; Female; GABA-B Receptor Agonists; Humans; Male; Narcolepsy; Sodium Oxybate; Treatment Outcome

The most common sleep disorders that can result in injurious or violent behaviors include REM sleep behavioral disorder, sleepwalking, comorbid parasomnias, sleep-related dissociative disorder, and obstructive sleep apnea. Video polysomnography is usually indicated to evaluate recurring sleep-related injury in adults. Only one-third of patients with complex paroxysmal nocturnal events will have one of their habitual events on a single night of in-laboratory video polysomnography, most often those who have prominent, high-frequency motor features. We report evidence of sleep walking induced by sodium oxybate identified by steps recorded on a consumer wearable device coinciding with clinical history and evidence of injury.

Topics: Adult; Disorders of Excessive Somnolence; Equipment Design; Female; Humans; Narcolepsy; Parasomnias; Polysomnography; Sodium Oxybate; Somnambulism; Video Recording

A 12-year-old girl with normal neurodevelopment and narcolepsy type 1 presented with unexpected central apneas in response to sodium oxybate (SO). The patient underwent overnight polysomnography on SO (2.75 + 2.5 grams) which showed an apnea-hypopnea index of 4.3 events/h, and all the events were central apneas. A majority of central apneas clustered at about 1.5 hours after the first dose of SO. Remarkably, after a second dose of SO that was 0.25 grams smaller, she did not exhibit clusters of central sleep apneas. However, she did experience similar but milder breathing abnormalities that did not meet criteria to be scored as central apneas or hypopneas. Based on this observation, there may be an association between SO treatment and the development of central apnea. Further polysomnographic research on pediatric patients taking SO would help determine if there is a significant association between SO treatment and the development of central apnea in the pediatric population.

Topics: Child; Female; Humans; Narcolepsy; Polysomnography; Sleep Apnea, Central; Sodium Oxybate

Although there are reports of narcolepsy type 1 caused by lesions of the central nervous system, there are far fewer reports of narcolepsy type 2 (NT2) caused by discrete brain lesions. We report a case of a patient in whom NT2 was diagnosed after a viral illness, and inflammatory lesions in the right thalamus and amygdala were found. In addition, symptoms of autonomic impairment developed and postural tachycardia syndrome was subsequently diagnosed in this patient. To our knowledge this is the first reported case of NT2 resulting from central nervous system lesions in these discrete locations, as well as the first reported case of postural tachycardia syndrome associated with narcolepsy.

Topics: Adolescent; Adrenergic beta-Antagonists; Amphetamine; Amygdala; Central Nervous System Stimulants; Dextroamphetamine; Female; Humans; Magnetic Resonance Imaging; Narcolepsy; Postural Orthostatic Tachycardia Syndrome; Propranolol; Sodium Oxybate; Thalamus

Sodium oxybate (SXB) is a GABAergic agent widely used as off-label treatment in pediatric type 1 narcolepsy (NT1). Here, we aimed at analyzing by wrist actigraphy the sleep/wake profile of NT1 children and adolescents in drug-naïve condition and after 1 year of SXB treatment. As secondary aim, we investigated changes on sleepiness, cataplexy, and children's anthropometric profile after 1 year of SXB treatment.. Twenty-four drug-naïve NT1 children underwent 7 days of actigraphy during the school week. Information on sleepiness, narcolepsy symptoms, and anthropometric features were collected during the same week with questionnaires and semistructured clinical interview. Children started SXB treatment and underwent a second evaluation encompassing actigraphy, clinical interview, questionnaires, and anthropometric assessment after 1 year of stable treatment.. Actigraphy effectively documented an improvement of nocturnal sleep quality and duration coupled with a reduction of diurnal total sleep time, nap frequency, and duration at 1 year follow-up. Reduction of sleepiness, cataplexy frequency and severity, and weight loss, mainly in obese and overweight NT1 children, were also observed at the 1 year follow-up.. Actigraphy objectively documented changes in nocturnal sleep quality and diurnal napping behavior after 1 year of SXB treatment, thus representing a valid approach to ecologically assess SXB treatment effect on NT1 children's sleep/wake profile. NT1 symptoms severity and children's anthropometric features also changed as expected. Actigraphy offers the possibility to longitudinally follow up children and has potential to become a key tool to tailor treatment in pediatric patients.

Topics: Actigraphy; Adolescent; Child; Female; Follow-Up Studies; Humans; Male; Narcolepsy; Obesity; Sleep; Sodium Oxybate; Treatment Outcome; Wakefulness; Weight Loss

Currently, cardiovascular measurements in children affected with type 1 narcolepsy (NT1) have never been investigated, and neither have their modulation by the administration of sodium oxybate (SO).. Twelve drug-naïve NT1 children (four males, eight females) with a mean age of 11 ± 3.16 years underwent a nocturnal polysomnography, at baseline and during the first night of SO administration. Data were contrasted with those recorded in 23 age-matched healthy controls. Heart rate variability (HRV) analysis was performed by analyzing the electrocardiogram signal for automatic detection of R waves with a computer program calculating a series of standard time-domain measures and obtaining spectral parameters, by means of a Fast-Fourier Transform.. In sleep stages N2 and N3, NT1 children showed increased power in the low-frequency (LF) and very-LF (VLF) ranges, when compared to controls. In addition, HRV (as measured by time domain parameters) during all sleep stages tended to be slightly higher in patients when compared to controls. Treatment with SO did not change significantly any parameter, but an overall trend to mildly decreased HRV that reached a significant value only during R sleep.. HRV during all sleep stages tended to be slightly higher in young patients when compared to controls, confirming the presence of a slight sympathovagal system imbalance even in NT1 children. SO tends to decrease these values especially during REM sleep and in that regard, further studies supporting these preliminary findings and considering the long-term effects of SO on heart rate parameters are warranted.

Topics: Adjuvants, Anesthesia; Child; Electrocardiography; Female; Heart Rate; Humans; Male; Narcolepsy; Polysomnography; Sleep Stages; Sodium Oxybate

Cross-sectional studies show a lower health-related quality of life (HRQoL) in individuals with narcolepsy. We aimed to describe changes in HRQoL after two years of multidisciplinary follow-up in a cohort of mainly post-H1N1 vaccination narcolepsy type-1 (NT1) patients in Norway.. Prospective-cohort study. Narcolepsy diagnosis was based on the International Classification of Sleep Disorders (third edition). Psychiatric comorbidity was assessed using the Achenbach System of Empirically Based Assessment (ASEBA). HRQoL was evaluated with the Pediatric Quality of Life Inventory (PedsQL™ Generic Core Scales 4.0) at baseline and follow-up. Mean follow-up time was 20.7 (2.7) months.. Thirty one patients (18 females) with NT1, mean age 14.6 (SD = 4.8) years answered questionnaires at baseline and follow-up. On a group level, the PedsQL Total Health Summary score significantly improved by a mean of 5.9 (95%CI = 0.4, 11.9), p = 0.038; this was mainly driven by improvements in the Physical Health Summary score by 9.8 (3.0, 16.5) points, p = 0.006 and the School Functioning Scale score by 7.5 (1.0, 13.9) points p = 0.025. The Total ASEBA score was correlated with PedsQL Total Health Summary score at baseline, but not with changes in HRQoL. Sodium oxybate (Xyrem®) treatment at follow up was positively associated with changes in PedsQL Total Health Summary score, after adjusting for age and gender, p = 0.027.. HRQoL in NT1 patients improved after two years of follow-up. The use of sodium oxybate (Xyrem®) at follow-up was associated with increases in HRQoL. Psychiatric comorbidity was correlated with HRQoL at baseline but did not predict changes in HRQoL at follow-up.

Topics: Adjuvants, Anesthesia; Adolescent; Child; Comorbidity; Cross-Sectional Studies; Female; Humans; Immunization Programs; Influenza A Virus, H1N1 Subtype; Influenza, Human; Male; Narcolepsy; Norway; Prospective Studies; Quality of Life; Severity of Illness Index; Sodium Oxybate; Vaccination; Young Adult

Topics: Child; Double-Blind Method; Drug Administration Schedule; Humans; Narcolepsy; Sodium Oxybate

The rare constellation of multiple episodes of cataplexy that are refractory to therapy is called

Topics: Adolescent; Cataplexy; Clomipramine; Electroencephalography; Female; Humans; Narcolepsy; Polysomnography; Psychotherapy; Selective Serotonin Reuptake Inhibitors; Sodium Oxybate; Somatoform Disorders

Topics: Adult; Female; Humans; Locus Coeruleus; Narcolepsy; Neurologic Examination; Predictive Value of Tests; Reflex, Pupillary; Sodium Oxybate; Treatment Outcome; Wakefulness-Promoting Agents

Topics: Alcoholism; Animals; Central Nervous System Agents; Humans; Illicit Drugs; Narcolepsy; Sodium Oxybate; Toxicology

Sodium oxybate is licensed in Europe for the treatment of narcolepsy with cataplexy in adults. The aim of this study was to assess the efficacy and safety of sodium oxybate in clinical practice in patients with narcolepsy and cataplexy refractory to other treatments.. This was a retrospective single centre study including patients with severe narcolepsy with cataplexy refractory to other treatments, who were initiated on sodium oxybate between 2009 and 2015. Patients were allowed to be on other stimulants or/and anti-cataplectic agents. Epworth sleepiness scale (ESS) and weekly cataplexy events were recorded. Side effects (SEs) were recorded at every follow-up visit.. 90 patients were prescribed sodium oxybate, with a total of 3116 patient-months of drug exposure. ESS and weekly cataplexy events were significantly reduced by sodium oxybate for all patients (ΔESS = 4.3 ± 4.4 and Δcataplexy = 21.8 ± 18.5 events/week; p < 0.0001, respectively). The required maintenance dose could not be predicted based upon gender, body mass index, or clinical factors. 60% of patients were able to reduce or come off other medications. Half of the patients experienced at least one SE, and 26.6% had to stop treatment due to limiting SEs. Nausea, mood swings and enuresis were the most commonly reported SEs. SEs that led to drug discontinuation, particularly psychosis, were associated with increasing age and were observed early after the initiation of the drug.. Sodium oxybate provides a good clinical efficacy and acceptable safety profile in routine clinical practice for the treatment of patients suffering from narcolepsy with cataplexy. A quarter of patients experience SEs requiring withdrawal of the drug with older patients being more vulnerable to the more serious SEs.

Topics: Adult; Female; Humans; Male; Narcolepsy; Retrospective Studies; Sodium Oxybate; Time Factors; Treatment Outcome; Wakefulness-Promoting Agents

To determine GHB levels in breast milk of women taking sodium oxybate (Xyrem) for treatment of narcolepsy and cataplexy.. Two women with narcolepsy and cataplexy treated with sodium oxybate before pregnancy collected breast milk for analysis of GHB concentration after resuming sodium oxybate postpartum. One woman collected samples across two consecutive nights (doses: 3.0 gm and 4.5 gm twice per night) five months after delivering her first child; the other collected samples on three separate days (doses: 2.25 gm and 3.0 gm twice per night) nine months after the births of her first two children. GHB concentration was determined by gas chromatography/mass spectrometry.. Milk GHB levels before sodium oxybate ranged from 5.81 to 7.60 μM. Levels were 2-4 times higher four hours after the first sodium oxybate dose (10.44-23.58 μM) and 3-5 times higher four hours after the second dose (ie, eight hours after first dose; 14.60-34.01 μM). GHB levels returned to endogenous levels 6-10 h following the second dose, however variability was observed between patients and pregnancies. Higher breast milk GHB levels were observed with higher doses for both patients.. Sodium oxybate is transmitted to breast milk. Despite its short half-life, GHB concentrations remained two-to-five times higher than endogenous levels four hours after both nighttime doses. To avoid excess GHB exposure, breastfeeding mothers who take sodium oxybate should consider expressing and discarding their morning milk. Future work should examine milk GHB levels after chronic sodium oxybate and determine whether levels change as milk composition changes across the postpartum period.

Topics: Adult; Female; Gas Chromatography-Mass Spectrometry; Humans; Milk, Human; Narcolepsy; Sodium Oxybate; Time Factors; Wakefulness-Promoting Agents

To report a challenging patient a girl who developed narcolepsyy with cataplexy (NT1) and a psychosis during adolescence. To discuss diagnostic and therapeutic challenges of the comorbid cases.. A 14-year-old girl was referred to Sleep and Epilepsy Unit for excessive daytime sleepiness, impaired nocturnal sleep, binge eating and weight gain, over the last year. After being diagnosed with a NT1 the patient was treated with modafinil and sodium oxybate. She was hospitalized for psychotic symptoms after starting NT1 treatment. Withdrawal of the narcolepsy treatment and initiation of haloperidol 1 mg/day (the only antipsychotic treatment she could tolerate) improved the delusions, hallucinations and dysphoria but worsened the narcolepsy symptoms. Polysomnography showed fragmented nocturnal sleep and five sleep REM onset periods in MSLT. Positive HLA-QB1*06:02 and undetectable level of hypocretine in the cerebrospinal fluid were found. MRI and CT-scan were normal. Diagnostic Interview for Genetic Studies Adapted for Narcolepsy (DIGSAN) questionnaire confirmed that patient presented a dual diagnostic NT1 and psychotic symptoms. The last sleep follow-up while on psychopharmacological treatment, showed an increased sleep efficiency index. She currently has severe somnolence, obesity, and partial cataplectic attacks along with normal mood, academic failure and social isolation.. The coexistence of narcolepsy with psychoses is a rare clinical entity, more frequent in adolescents than in adults. The comorbidity of the two illnesses worsens clinical and therapeutic prognosis and also suggests interesting pathophysiological hypotheses.. Narcolepsia-cataplejia y psicosis: estudio de un caso.. Objetivo. Describir una paciente que en la adolescencia desarrollo narcolepsia con cataplejia (NT1) y psicosis. Caso clinico. Niña de 14 años remitida a la unidad de sueño por presentar somnolencia diurna, sueño nocturno fragmentado, hambre compulsiva y aumento de peso durante el ultimo año. Tratada inicialmente con modafinilo y oxibato sodico, tuvo que ser hospitalizada por presentar sintomas psicoticos. Se suprimio el tratamiento antinarcoleptico y se administraron antipsicoticos. El unico que tolero fue el haloperidol 1 mg/dia, con mejoria del delirio, las alucinaciones y los sintomas disforicos, pero con empeoramiento de los sintomas narcolepticos. La polisomnografia mostro un sueño nocturno muy fragmentado, y en la prueba de latencias multiples del sueño, la latencia de sueño fue de un minuto, y tuvo cinco adormecimientos directos en la fase del sueño REM. Presentaba HLA-DQB1*06:02 positivo y nivel de hipocretina-1 en el liquido cefalorraquideo indetectable. La entrevista diagnostica para estudios geneticos adaptada para narcolepsia (DIGSAN) ayudo a confirmar que presentaba una doble patologia de NT1 y sintomas psicoticos. La ultima revision de su sueño con tratamiento psicofarmacologico muestra un aumento del indice de eficacia del sueño. Clinicamente presenta somnolencia diurna excesiva, ataques parciales de cataplejia y una obesidad muy importante. No muestra alteraciones del humor, pero tiene fracaso escolar y aislamiento social. Conclusion. La coexistencia de narcolepsia con psicosis es una entidad clinica rara, mas frecuente en adolescentes que en adultos. La comorbilidad de ambas enfermedades tiene un mal pronostico clinico y terapeutico, y sugiere hipotesis fisiopatologicas interesantes.

Topics: Adolescent; Antipsychotic Agents; Attention Deficit Disorder with Hyperactivity; Benzhydryl Compounds; Female; Food Addiction; Hallucinations; Haloperidol; HLA-DQ beta-Chains; Humans; Learning Disabilities; Methylphenidate; Modafinil; Narcolepsy; Orexins; Pediatric Obesity; Polysomnography; Psychotic Disorders; Risperidone; Sleep Deprivation; Sleep Latency; Social Isolation; Sodium Oxybate; Suicidal Ideation

Based on class-I studies, sodium oxybate is regarded as a first-line treatment for both EDS and cataplexy. The cost-effectiveness of sodium oxybate is largely unknown, though. In this study, we estimate the cost-effectiveness of sodium oxybate as treatment for patients with narcolepsy as compared to standard treatment, by calculating incremental cost-effectiveness ratios (cost per quality-adjusted life year, QALY) for patients in a Swedish setting.. Calculations were performed using a Markov model with a 10-year time horizon. The study population consisted of adult patients treated for narcolepsy with cataplexy. Healthcare utilization and quality-adjusted life years (QALYs) for each treatment alternative were calculated assuming no treatment effect on survival. Sensitivity analyses were performed for treatment effectiveness and healthcare cost parameters.. The cost per additional quality-adjusted life year was estimated at SEK 563,481. The cost-effectiveness measure was demonstrated to be particularly sensitive to the duration of the relative quality-of-life improvements accruing to patients treated with sodium oxybate.. The estimated cost per additional QALY for the sodium oxybate treatment alternative compared with standard treatment was estimated above the informal Swedish willingness-to-pay threshold (SEK 500,000). The estimated cost per additional QALY obtained here is likely to overestimate the true cost-effectiveness ratio as potentially beneficial effects on productivity of treatment with sodium oxybate were not included (due to lack of data).

Topics: Adult; Anesthetics, Intravenous; Cost-Benefit Analysis; Female; Humans; Narcolepsy; Sodium Oxybate; Sweden

Topics: Breast Feeding; Female; Humans; Mothers; Narcolepsy; Pregnancy; Pregnancy Complications; Sodium Oxybate

Topics: Adolescent; Adult; Central Nervous System Agents; Chromatography, High Pressure Liquid; Female; Glucuronides; Hair; Humans; Male; Middle Aged; Narcolepsy; Sodium Oxybate; Tandem Mass Spectrometry

Topics: Cataplexy; Female; Humans; Milk, Human; Narcolepsy; Sodium Oxybate

Topics: Female; Humans; Milk, Human; Narcolepsy; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Adult; Feeding and Eating Disorders; Female; Humans; Narcolepsy; Parasomnias; Sodium Oxybate

Current treatment recommendations for narcolepsy suggest that modafinil should be used as a first-line treatment ahead of conventional stimulants or sodium oxybate. In this study, performed in a tertiary sleep disorders centre, treatment responses were examined following these recommendations, and the ability of sleep-stage sequencing of sleep-onset rapid eye movement periods in the multiple sleep latency test to predict treatment response. Over a 3.5-year period, 255 patients were retrospectively identified in the authors' database as patients diagnosed with narcolepsy, type 1 (with cataplexy) or type 2 (without) using clinical and polysomnographic criteria. Eligible patients were examined in detail, sleep study data were abstracted and sleep-stage sequencing of sleep-onset rapid eye movement periods were analysed. Response to treatment was graded utilizing an internally developed scale. Seventy-five patients were included (39% males). Forty (53%) were diagnosed with type 1 narcolepsy with a mean follow-up of 2.37 ± 1.35 years. Ninety-seven percent of the patients were initially started on modafinil, and overall 59% reported complete response on the last follow-up. Twenty-nine patients (39%) had the sequence of sleep stage 1 or wake to rapid eye movement in all of their sleep-onset rapid eye movement periods, with most of these diagnosed as narcolepsy type 1 (72%). The presence of this specific sleep-stage sequence in all sleep-onset rapid eye movement periods was associated with worse treatment response (P = 0.0023). Sleep-stage sequence analysis of sleep-onset rapid eye movement periods in the multiple sleep latency test may aid the prediction of treatment response in narcoleptics and provide a useful prognostic tool in clinical practice, above and beyond their classification as narcolepsy type 1 or 2.

Topics: Adult; Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Female; Humans; Male; Modafinil; Narcolepsy; Polysomnography; Prognosis; Retrospective Studies; Sleep, REM; Sodium Oxybate

Few stimulants have been evaluated for the treatment of idiopathic hypersomnia (IH). Sodium oxybate (indicated in narcolepsy type 1, NT1) has not been tested in IH patients.. The aim of this study is to retrospectively evaluate the benefit/risk ratio of sodium oxybate in IH versus NT1 using a chart review.. We reviewed the files of 46 patients with IH (35.7 ± 12.6 years old, 78% women) and 47 patients with NT1 (44.1 ± 18 years old, 47% women) and evaluated the benefits of sodium oxybate using the Epworth sleepiness scale (ESS) and a four-point scale assessing the global benefit, sleep inertia, sleepiness, sleep duration, and sleep onset latency. The spontaneously reported side effects were collected.. Sodium oxybate was prescribed at a lower dose in IH than in NT1 (4.3 ± 2.2 vs. 6.6 ± 2.8 g/night, p <0.0001) patients after having tried more (3.2 ± 1.4 vs. 2.2 ± 1, p <0.0001) stimulants, but it produced a similar ESS change (-3.5 ± 4.5 vs. -3.2 ± 4.2 points) in the IH and NT1 groups. Severe morning inertia was improved in 24/34 (71%) patients with IH. During the follow-up period (15.8 months in IH vs. 35 months in NT1 groups), 53% IH and 68% NT1 patients dropped out. The side effects were as frequent in the IH group as in the NT1 group (67% vs. 52%), but nausea (40% vs. 13%) and dizziness (34.3% vs. 4.3%) were more frequent in the IH group.. The benefit/risk ratio of sodium oxybate in IH- was similar to NT1-associated sleepiness, with additional benefits on severe morning inertia, despite using smaller doses in more refractory patients.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Female; Humans; Idiopathic Hypersomnia; Male; Middle Aged; Narcolepsy; Off-Label Use; Retrospective Studies; Risk Assessment; Sodium Oxybate; Young Adult

This two-centre observational study of vigilance measurements assessed the feasibility of vigilance measurements on multiple days using the Sustained Attention to Response Task and the Psychomotor Vigilance Test with portable task equipment, and subsequently assessed the effect of sodium oxybate treatment on vigilance in patients with narcolepsy. Twenty-six patients with narcolepsy and 15 healthy controls were included. The study comprised two in-laboratory days for the Maintenance of Wakefulness Test and the Oxford Sleep Resistance test, followed by 7-day portable vigilance battery measurements. This procedure was repeated for patients with narcolepsy after at least 3 months of stable treatment with sodium oxybate. Patients with narcolepsy had a higher Sustained Attention to Response Task error count, lower Psychomotor Vigilance Test reciprocal reaction time, higher Oxford Sleep Resistance test omission error count adjusted for test duration (Oxford Sleep Resistance testOMIS / MIN ), and lower Oxford Sleep Resistance test and Maintenance of Wakefulness Test sleep latency compared with controls (all P < 0.01). Treatment with sodium oxybate was associated with a longer Maintenance of Wakefulness Test sleep latency (P < 0.01), lower Oxford Sleep Resistance testOMIS / MIN (P = 0.01) and a lower Sustained Attention to Response Task error count (P = 0.01) in patients with narcolepsy, but not with absolute changes in Oxford Sleep Resistance test sleep latency or Psychomotor Vigilance Test reciprocal reaction time. It was concluded that portable measurements of sustained attention as well as in-laboratory Oxford Sleep Resistance test and Maintenance of Wakefulness Test measurements revealed worse performance for narcoleptic patients compared with controls, and that sodium oxybate was associated with an improvement of sustained attention and a better resistance to sleep.

Topics: Adult; Attention; Case-Control Studies; Data Collection; Feasibility Studies; Female; Humans; Laboratories; Male; Narcolepsy; Polysomnography; Reaction Time; Sleep; Sodium Oxybate; Time Factors; Wakefulness

Sodium oxybate is used in the treatment of narcolepsy. Currently no published literature supports its safety during breastfeeding, although it has a favorable pharmacokinetic profile for minimizing exposure.. We report a case of a 27-year-old primigravida with narcolepsy who was taking sodium oxybate for symptom control and contacted our Lactation Study Center for advice. Based on our current pharmacokinetic knowledge, she was advised to avoid breastfeeding 4 hours after a dose.. Follow-up phone interviews were done and the patient reported that the feeding schedule was manageable, and she was able to exclusively breastfeed for 6 months of her infant's life. Based on pediatric records, her infant's growth and development were excellent. There were no noted side effects of the medication for the infant.. This is the first report to our knowledge of breastfeeding during maternal therapy with sodium oxybate, which appears to be compatible with safe, exclusive breastfeeding when managed appropriately.

Topics: Adjuvants, Anesthesia; Adult; Breast Feeding; Feeding Behavior; Female; Guidelines as Topic; Humans; Infant; Infant, Newborn; Lactation; Mothers; Narcolepsy; Patient Education as Topic; Sodium Oxybate; Treatment Outcome

Topics: Adjuvants, Anesthesia; Humans; Narcolepsy; Prescriptions; Sodium Oxybate; United Kingdom

Topics: Adjuvants, Anesthesia; England; Health Care Rationing; Humans; Narcolepsy; Sodium Oxybate; State Medicine

Topics: Adolescent; Drug Costs; England; Female; Humans; Legislation, Drug; Narcolepsy; Rare Diseases; Sodium Oxybate; State Medicine

Topics: Humans; Hypnotics and Sedatives; Male; Middle Aged; Narcolepsy; REM Sleep Behavior Disorder; Sodium Oxybate

The aim of this study is to describe the possible co-occurrence of narcolepsy type 1 and generalized epilepsy, focusing on diagnostic challenge and safety of dual treatments.. Four patients with comorbidity for narcolepsy type 1 and idiopathic generalized epilepsy are reported: in three cases the onset of epilepsy preceded narcolepsy type 1 appearance, whereas in one case epileptic spells onset was subsequent. Patients presented with absences, myoclonic and tonic-clonic seizure type: in the patient with tonic-clonic seizures the dual pathology was easily recognized, in the other cases the first diagnosis caused the comorbid disease to be overlooked, independent of the time-course sequence. All four patients underwent neurological examination, video-electroencephalogram during which ictal and interictal epileptic discharges were recorded, and sleep polysomnographic studies. Repeated sleep onset rapid eye movement periods (SOREMPs) were documented with the multiple sleep latency test (MLST) in all the four cases. All patients had unremarkable brain magnetic resonance imaging studies and cerebrospinal hypocretin-1 was assessed in two patients, revealing undetectable levels. The association of antiepileptic drugs and substances currently used to treat narcolepsy type 1, including sodium oxybate, was effective in improving seizures, sleep disturbance, and cataplexy.. Narcolepsy type 1 may occur in association with idiopathic generalized epilepsy, leading to remarkable diagnostic and therapeutic challenges. Electrophysiological studies as well as a comprehensive somnologic interview can help confirm the diagnosis in patients with ambiguous neurological history. Sodium oxybate in combination with antiepileptic drugs is safe and effective in treating cataplexy and excessive daytime sleepiness.

Topics: Adult; Anticonvulsants; Electroencephalography; Epilepsy, Generalized; Humans; Male; Narcolepsy; Polysomnography; Sodium Oxybate; Treatment Outcome; Young Adult

The usual age at onset of narcolepsy with cataplexy is in the second or third decade. In cases with late onset narcolepsy with cataplexy, symptoms are usually mild with relatively less severe daytime sleepiness and less frequent cataplexy. Here we present a case of narcolepsy with cataplexy with onset of symptoms around sixty years of age. This case is unique, with severe daytime sleepiness both by subjective report as well as on objective Multiple Sleep Latency Test and having multiple cataplexy episodes in a day.

Topics: Amphetamine; Cataplexy; Central Nervous System Stimulants; Dextroamphetamine; Diagnosis, Differential; Hallucinations; Humans; Male; Middle Aged; Narcolepsy; Polysomnography; Sodium Oxybate

γ-Hydroxybutyrate (GHB) is an approved therapeutic for the excessive sleepiness and sudden loss of muscle tone (cataplexy) characteristic of narcolepsy. The mechanism of action for these therapeutic effects is hypothesized to be GABAB receptor dependent. We evaluated the effects of chronic administration of GHB and the GABAB agonist R-baclofen (R-BAC) on arousal state and cataplexy in two models of narcolepsy: orexin/ataxin-3 (Atax) and orexin/tTA; TetO diphtheria toxin mice (DTA). Mice were implanted for EEG/EMG monitoring and dosed with GHB (150 mg/kg), R-BAC (2.8 mg/kg), or vehicle (VEH) bid for 15 d-a treatment paradigm designed to model the twice nightly GHB dosing regimen used by human narcoleptics. In both models, R-BAC increased NREM sleep time, intensity, and consolidation during the light period; wake bout duration increased and cataplexy decreased during the subsequent dark period. GHB did not increase NREM sleep consolidation or duration, although NREM delta power increased in the first hour after dosing. Cataplexy decreased from baseline in 57 and 86% of mice after GHB and R-BAC, respectively, whereas cataplexy increased in 79% of the mice after VEH. At the doses tested, R-BAC suppressed cataplexy to a greater extent than GHB. These results suggest utility of R-BAC-based therapeutics for narcolepsy.

Topics: Animals; Arousal; Ataxin-3; Cataplexy; Data Interpretation, Statistical; Diphtheria Toxin; Dose-Response Relationship, Drug; Electroencephalography; Electromyography; GABA Agonists; Humans; Intracellular Signaling Peptides and Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Narcolepsy; Nerve Tissue Proteins; Neuropeptides; Nuclear Proteins; Orexins; Receptors, GABA-B; Repressor Proteins; Sleep; Sleep, REM; Sodium Oxybate

Narcolepsy is associated with obesity though it is uncertain whether this is caused by changes in glucose and fat metabolism. Therefore, we performed a detailed analysis of systemic energy homeostasis in narcolepsy patients, and additionally, investigated whether it was affected by three months of sodium oxybate (SXB) treatment.. Nine hypocretin deficient patients with narcolepsy-cataplexy, and nine healthy sex, age, and BMI matched controls were enrolled. A hyperinsulinemic-euglycemic clamp combined with stable isotopes ([6,6-(2)H2]-glucose and [(2)H5]- glycerol) was performed at baseline. In seven patients a second study was performed after three months of SXB treatment.. Glucose disposal rate (GDR) per unit serum insulin was significantly higher in narcolepsy patients compared to matched controls (1.6 ± 0.2 vs. 1.1 ± 0.3 μmol/kgFFM/min/mU×L; P = 0.024), whereas β-cell function was similar (P = 0.50). Basal steady state glycerol appearance rate tended to be lower in narcolepsy patients (5.2 ± 0.4 vs. 7.5 ± 1.3 μmol/kgFM/min; P = 0.058), suggesting a lower rate of lipolysis. SXB treatment induced a trend in reduction of the GDR (1.4 ± 0.1 vs. 1.1 ± 0.2 μmol/kgFFM/min/mU×L; P = 0.063) and a reduction in endogenous glucose production (0.24 ± 0.03 vs. 0.16 ± 0.03 μmol/kgFFM/min/mU×L: P = 0.028) per unit serum insulin. After SXB treatment lipolysis increased (4.9 ± 0.4 vs. 6.5 ± 0.6 μmol/kgFM/min; P = 0.018), and body weight decreased in narcolepsy patients (99.2 ± 6.0 vs. 94.0 ± 5.4 kg; P = 0.044).. We show that narcolepsy patients are more insulin sensitive and may have a lower rate of lipolysis than matched controls. SXB stimulated lipolysis in narcolepsy patients, possibly accounting for the weight loss after treatment. While sodium oxybate tended to decrease systemic insulin sensitivity, it increased hepatic insulin sensitivity, suggesting tissue-specific effects.

Topics: Adult; Body Composition; Body Weight; Case-Control Studies; Female; Glucose; Glucose Clamp Technique; Humans; Insulin Resistance; Intracellular Signaling Peptides and Proteins; Lipid Metabolism; Lipolysis; Male; Narcolepsy; Neuropeptides; Orexins; Sodium Oxybate

To analyze the acute effects of sodium oxybate (SO) on polysomnographic night-time recordings (PSG) and multiple sleep latency test (MSLT) on patients with narcolepsy with cataplexy (NC).. Sixteen NC adult patients were recruited, together with 16 normal controls. Two consecutive PSG followed by two MSLT sessions were carried out, before and during the first night of SO assumption, respectively.. The administration of SO was followed by a significant decrease in number of stage shifts and awakenings, wakefulness after sleep onset, and percentage of sleep stage 1. Sleep efficiency and slow wave sleep percentage increased. REM latency decreased significantly from 73 to 12 min. Cyclic alternating pattern (CAP) rate remained unchanged but the percentage of CAP A3 subtypes decreased. The number of CAP A3 subtypes per hour of NREM sleep decreased significantly, whereas that of A1 remained unchanged. The duration of A1 and A3 subtypes was slightly increased. Chin muscle tone was not modified by SO as well as periodic leg movements during sleep, but their periodicity index decreased, becoming similar to that of controls. MSLT sleep latency also significantly improved after SO intake.. The administration of SO in NC patients is followed by immediate important and complex effects on PSG parameters and MSLT, including an evident (over)increase in slow wave sleep, which does not display a physiological microstructure, a moderate decrease in periodic and isolated LMs, possibly mediated by a disinhibited dopaminergic neuronal activity, and an improvement on daytime mean sleep latency at the MSLT.

Topics: Adult; Cataplexy; Electromyography; Female; Humans; Male; Middle Aged; Narcolepsy; Polysomnography; Sleep; Sleep Stages; Sodium Oxybate

The purpose of this report is to describe a 57-year-old man who was admitted to a nursing facility for physical therapy. His home medication list included sodium oxybate. This article will provide the pharmacist with a therapeutic overview of sodium oxybate as well as review the unique processes involved with drug acquisition, dosing, patient education, and monitoring.. Community pharmacy, nursing facility pharmacy, consultant pharmacy practice.. Sodium oxybate is the only medication in the United States that has approval for both treatment of cataplexy in narcolepsy and treatment of excessive daytime sleepiness in narcolepsy. Sodium oxybate has many unique properties that cause it to differ from past therapies for cataplexy and excessive daytime sleepiness associated with narcolepsy.. It is important for pharmacists to understand the therapeutic uses of sodium oxybate and to review the processes for acquisition, dosing, and administration to better assist physicians and patients and improve therapeutic outcomes.

Topics: Humans; Male; Middle Aged; Narcolepsy; Pharmacists; Sodium Oxybate

Gamma-hydroxybutyric acid (GHB), well known as a party drug, especially in Europe, is also legally used (sodium oxybate, Xyrem(®)) to treat a rare sleep disorder, narcolepsy with cataplexy. This exploratory study was set up to measure GHB concentrations in dried blood spots (DBS) collected by narcoleptic patients treated with sodium oxybate. Intra- and inter-individual variation in clinical effects following sodium oxybate administration has been reported. The use of DBS as a sampling technique, which is stated to be easy and convenient, may provide a better insight into GHB concentrations following sodium oxybate intake in a real-life setting.. The aim was twofold: evaluation of the applicability of a recently developed DBS-based gas chromatography-mass spectrometry (GC-MS) method, and of the feasibility of the sampling technique in an ambulant setting.. Seven narcoleptic patients being treated with sodium oxybate at the Department for Respiratory Diseases of Ghent University Hospital were asked to collect DBS approximately 20 min after the first sodium oxybate (Xyrem(®); UCB Pharma Ltd, Brussels, Belgium) intake on a maximum of 7 consecutive days. Using an automatic lancet, patients pricked their fingertip and, after wiping off the first drop of blood, subsequent drops were collected on a DBS card. The DBS cards were sent to the laboratory by regular mail and, before analysis, were visually inspected to record DBS quality (large enough, symmetrically spread on the filter paper with even colouration on both sides of the filter paper).. Of the seven patients, three patients succeeded to collect five series of DBS, one patient decided to cease participation because of nausea, one was lost during follow-up and two patients started falling asleep almost immediately after the intake of sodium oxybate. Analysing the DBS in duplicate resulted in acceptable within-DBS card precision. DBS with acceptable quality were obtained by patients without supervision.. Our results demonstrate the acceptable precision of the complete procedure, from sampling at home to quantitative analysis in the laboratory. Given the intra- and inter-individual variability in clinical effects seen with sodium oxybate, the easy adaptation of DBS sampling opens the possibility of following up GHB concentrations in patients in real-life settings in future studies.

Topics: Belgium; Dried Blood Spot Testing; Feasibility Studies; Follow-Up Studies; Gas Chromatography-Mass Spectrometry; Humans; Narcolepsy; Sodium Oxybate; Specimen Handling

Topics: Adolescent; Female; Humans; Narcolepsy; Psychoses, Substance-Induced; Sodium Oxybate; Suicide, Attempted

Topics: Adjuvants, Anesthesia; Adult; Cataplexy; Diagnosis, Differential; Epilepsy; Humans; Male; Narcolepsy; Polysomnography; REM Sleep Parasomnias; Sodium Oxybate

Sodium oxybate (γ-hydroxybutyric acid, GHB) is a neurotransmitter in the human brain which exerts sedative effects and is used therapeutically in the treatment of narcolepsy. Current safety recommendations have been formulated for the use of GHB in patients with preexisting breathing disorders. We report the case of a 39-year-old female with narcolepsy and cataplexy revealing the de novo emergence of central sleep apneas in a Cheyne-Stokes pattern under constant treatment with GHB. After discontinuation of GHB, polysomnographic re-evaluation demonstrated the disappearance of central sleep apneas. To our knowledge, this is the first report of de novo central sleep apneas induced by GHB in a patient without pre-existing sleep-disordered breathing, suggesting that there is a need for further investigation and potentially an extension of the safety guidelines to patients without a pre-existing breathing disorder.

Topics: Adjuvants, Anesthesia; Adult; Cheyne-Stokes Respiration; Female; Humans; Narcolepsy; Respiration; Sleep Apnea, Central; Sodium Oxybate

Narcolepsy is caused by a selective loss of hypocretin neurons and is associated with obesity. Ghrelin and leptin interact with hypocretin neurons to influence energy homeostasis. Here, we evaluated whether human hypocretin deficiency, or the narcolepsy therapeutic agent sodium oxybate, alter the levels of these hormones.. Eight male, medication free, hypocretin deficient, narcolepsy with cataplexy patients, and 8 healthy controls matched for age, sex, body mass index (BMI), waisttohip ratio, and body fat percentage were assessed. Blood samples of total ghrelin and leptin were collected over 24 hours at 60 and 20-min intervals, respectively, during 2 study occasions: baseline, and during the last night of 5 consecutive nights of sodium oxybate administration (2 × 3.0 g/night).. At baseline, mean 24-h total ghrelin (936 ± 142 vs. 949 ± 175 pg/mL, p = 0.873) and leptin (115 ± 5.0 vs. 79.0 ± 32 mg/L, p = 0.18) levels were not different between hypocretin deficient narcolepsy patients and controls. Furthermore, sodium oxybate did not significantly affect the plasma concentration of either one of these hormones.. The increased BMI of narcolepsy patients is unlikely to be mediated by hypocretin deficiency-mediated alterations in total ghrelin or leptin levels. Thus, the effects of these hormones on hypocretin neurons may be mainly unidirectional. Although sodium oxybate may influence body weight, the underlying mechanism is unlikely to involve changes in total ghrelin or leptin secretion.

Topics: Adjuvants, Anesthesia; Adult; Body Composition; Body Mass Index; Ghrelin; Humans; Leptin; Male; Narcolepsy; Obesity; Sodium Oxybate

γ-Hydroxybutyric acid (GHB) is an endogenous compound and a drug used clinically to treat the symptoms of narcolepsy. GHB is known to be an agonist of GABAB receptors with millimolar affinity, but also binds with much higher affinity to another site, known as the GHB receptor. While a body of evidence has shown that GHB does not bind to GABAA receptors widely, recent evidence has suggested that the GHB receptor is in fact on extrasynaptic α4β1δ GABAA receptors, where GHB acts as an agonist with an EC50 of 140 nM. We investigated three neuronal cell types that express a tonic GABAA receptor current mediated by extrasynaptic receptors: ventrobasal (VB) thalamic neurons, dentate gyrus granule cells and striatal medium spiny neurons. Using whole-cell voltage clamp in brain slices, we found no evidence that GHB (10 µM) induced any GABAA receptor mediated current in these cell types, nor that it modulated inhibitory synaptic currents. Furthermore, a high concentration of GHB (3 mM) was able to produce a GABAB receptor mediated current, but did not induce any other currents. These results suggest either that GHB is not a high affinity agonist at native α4β1δ receptors, or that these receptors do not exist in classical areas associated with extrasynaptic currents.

Topics: Adjuvants, Anesthesia; Animals; Brain; Female; Male; Narcolepsy; Neurons; Rats; Rats, Wistar; Receptors, GABA-A; Sodium Oxybate

Our case describes clinical features of two families defined by joint phenotypes: sodium oxybate intolerance and elevated serum acylcarnitines. Oxybate intolerance variably presents as either cervical dystonia or sleep-related eating disorder. Our objective is to identify biological markers which predict a poor response to sodium oxybate as a treatment for disturbed sleep. Familial inheritance pattern, genotype analysis, multiorgan system involvement, and response to treatment suggest the presence of a secondary cause of fatty oxidation defect, i.e., mitochondrial disorder. Our case report supports the possible conclusion that variance in human mitochondrial metabolism may affect sodium oxybate tolerability.

Topics: Acyl-CoA Dehydrogenase; Carnitine; Child; Female; Humans; Hypnotics and Sedatives; Male; Middle Aged; Narcolepsy; Polymorphism, Single Nucleotide; Sleep Initiation and Maintenance Disorders; Sodium Oxybate

This study aims to report on catathrenia occurring in narcolepsy with cataplexy (NC) patients under sodium oxybate (SO) treatment. Catathrenia is a parasomnia characterized by groaning and an abnormal respiratory pattern during sleep.. Fifty-one patients with NC and starting SO therapy underwent a baseline overnight polysomnography (PSG) to detect any sleep-related breathing disorders (SRBD). To avoid risks due to a possible central respiratory control depression by SO, all patients with concomitant obstructive sleep apnea (OSA) were treated with a nasal continuous positive airway pressure (nCPAP) device. After 2 months of treatment with SO, all patients underwent a follow-up overnight PSG to investigate possible newly occurring SRBD. They also underwent a semi-structured clinical interview to monitor other potential SO side effects.. At baseline, four out of 51 patients showed simple snoring, and eight, mild to severe OSA. After a titration PSG night, patients with OSA received a nCPAP device. After 2 months of SO treatment, 28 patients (54.9%) showed SO-related side effects, including SRBD in 11 (21.6%). The follow-up PSG showed a respiratory pattern characteristic of catathrenia in seven patients (13.7%) as a newly observed and possibly benign SO side effect, and ruled out a worsening of OSA.. Catathrenia should be considered a possible side effect in NC patients under SO treatment and should be accurately identified to prevent unnecessary SO withdrawal.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Cataplexy; Central Nervous System Depressants; Child; Combined Modality Therapy; Comorbidity; Continuous Positive Airway Pressure; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Narcolepsy; Parasomnias; Patient Compliance; Polysomnography; Sleep Apnea, Obstructive; Sodium Oxybate; Young Adult

Hypocretin deficiency causes narcolepsy. It is unknown whether melatonin secretion is affected in this sleep disorder. Therefore, in both narcolepsy patients and matched controls, the authors measured plasma melatonin levels hourly for 24 h before and after 5 days of sodium oxybate (SXB) administration. Although mean melatonin concentrations were similar between patients and controls, in narcoleptics the percentage of 24-h melatonin secreted during the daytime was significantly higher, and melatonin secretion exhibited a weaker coupling to sleep. SXB did not affect melatonin secretion. These findings suggest that hypocretin deficiency might disturb both the circadian control of melatonin release and its temporal association with sleep.

Topics: Adult; Case-Control Studies; Circadian Rhythm; Humans; Intracellular Signaling Peptides and Proteins; Male; Melatonin; Narcolepsy; Neuropeptides; Orexins; Sleep; Sleep Disorders, Circadian Rhythm; Sodium Oxybate

To evaluate the efficacy and side effect profile of sodium oxybate in the treatment for narcolepsy-cataplexy in the pediatric age group.. A retrospective study was conducted on 15 children and adolescents with narcolepsy-cataplexy who had been treated with sodium oxybate. The mean age at diagnosis of narcolepsy was 11 years (range 3-17 years). Subjects were followed for 3-90 months (mean 33) after starting sodium oxybate. During this period of time they were also maintained on other medications for sleepiness (n=14) and cataplexy (n=6). The charts were reviewed for documentation of improvement in sleepiness or cataplexy, side effects, and functioning in daily life.. Subsequent to the addition of sodium oxybate, sleepiness improved in 13/15 patients. In patients who had Epworth Sleepiness Scale (ESS) assessments, the score fell from a baseline median of 18 to 12 (n=10, p=0.01). The number of cataplexy episodes estimated by parents decreased from a median of 38/week pre-treatment to <1/week post treatment (n=14, p<0.001). Cataplexy severity, measured on an arbitrary scale, fell from a median of 3 (severe) to 1 (mild) in all 15 subjects (p<0.001). Two of the 15 patients (13%) discontinued sodium oxybate, one for insurance reasons and the other due to constipation and dissociative feelings. A third patient stopped the medication temporarily due to body aches and dizziness, but then resumed treatment without recurrence of symptoms. Side effects in four others included tremor, blurring of vision, nocturnal awakenings, and increased nightmares. Overall, side effects occurred in 6/15 (40%) individuals. Improvement in social/academic spheres was noted in 11/15 (73%) subjects after starting sodium oxybate. The median BMI before and after treatment remained unchanged at 23 (n=14, p=0.99). Median values of height and weight before and after treatment also did not change significantly. The mean dose of sodium oxybate was 5 ± 2 g. Dose escalation owing to development of tolerance was not encountered.. Sodium oxybate is effective in alleviating sleepiness and cataplexy in childhood onset narcolepsy-cataplexy. The therapeutic response was sustained over time, and without development of tolerance. Forty percent of the subjects experienced adverse effects.

Topics: Adjuvants, Anesthesia; Adolescent; Child; Child, Preschool; Drug Tolerance; Female; Humans; Male; Narcolepsy; Off-Label Use; Retrospective Studies; Sleep Stages; Sleep, REM; Sodium Oxybate; Treatment Outcome; Wakefulness

Narcolepsy with cataplexy is a sleep disorder characterized by excessive daytime sleepiness, irresistible sleep episodes, and sudden loss of muscle tone (cataplexy) mostly triggered by emotions. Narcolepsy with cataplexy is a disabling lifelong disorder frequently arising during childhood. Pediatric narcolepsy often results in severe learning and social impairment. Improving awareness about this condition increases early diagnosis and may allow patients to rapidly access adequate treatments, including pharmacotherapy and/or non-medication-based approaches. Even though children currently undergo pharmacotherapy, data about safety and efficacy in the pediatric population are scarce. Lacking international guidelines as well as drugs registered for childhood narcolepsy with cataplexy, physicians have no other alternative but to prescribe in an off-label manner medications identical to those recommended for adults. We retrospectively evaluated 27 children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy, who had been treated with off-label sodium oxybate and had been followed in a clinical setting. Throughout a semi-structured interview, we documented the good efficacy and tolerability of sodium oxybate in the majority of the patients. This study constitutes a preliminary step towards a further randomized controlled trial in childhood narcolepsy with cataplexy.

Topics: Adolescent; Child; Drug Tolerance; Female; Humans; Hypnotics and Sedatives; Male; Narcolepsy; Retrospective Studies; Sodium Oxybate; Treatment Outcome

Narcolepsy is characterized by recurrent brief attacks of irresistible sleepiness. Signs can begin during childhood. However, diagnoses are frequently delayed by 10-15 years because of unfamiliarity with pediatric narcolepsy and variable presentations of its associated features (cataplexy, hypnagogic/hypnopompic hallucinations, and sleep paralysis). Therefore, patients may remain untreated during their formative years. Three children with narcolepsy who were initially misdiagnosed are described. Each child's signs were initially related to depression, hypothyroidism, jaw dysfunction, or conversion disorder. However, after a multiple sleep latency test, the diagnosis of narcolepsy was established. All three patients were treated appropriately with stimulant medications, selective serotonin reuptake inhibitors, or sodium oxybate, and demonstrated positive responses. Although no definitive cure exists for narcolepsy, early recognition and appropriate symptomatic treatment with medications can allow affected children to improve quality of life and achieve normality, both academically and socially.

Topics: Child; Diagnostic Errors; Female; Humans; Male; Narcolepsy; Polysomnography; Selective Serotonin Reuptake Inhibitors; Sodium Oxybate

Topics: Drug Industry; Human Rights; Humans; Marketing; Narcolepsy; New York; Off-Label Use; Prescription Drugs; Sodium Oxybate; Supreme Court Decisions; United States; United States Food and Drug Administration

Sodium oxybate (SO; Xyrem®) has been approved in most countries for treatment of narcolepsy and cataplexy. In this study, we present a single-center experience of a series of 18 patients with narcolepsy with cataplexy (18/18 DQB1*0602 positive, 17/17 with low/absent cerebrospinal fluid hypocretin) in whom SO was prescribed. After 26 ± 13 months, 13/18 patients were still on SO at a mean dosage of 6.1 ± 1.2 g (in 8 of them in combination with stimulants). The following significant effects were observed: improved subjective sleepiness (12/13), cataplexy (13/13; median number of attacks from 20 to 1/month), hallucinations (8/10) and sleep paralysis (8/8); increase in mean sleep latency on the Maintenance of Wakefulness Test (from 5.5 to 17.4 min) and sleep/rest efficiency on actigraphy (from 61 to 76%); decrease in Epworth Sleepiness Scale score (from 18 to 14), sleep onset REM periods on the Multiple Sleep Latency Test (from 3.6 to 2.4) and errors in the Steer-Clear Test (from 11 to 2%). Five patients discontinued SO because of insufficient compliance (n = 2), lack of efficiency (n = 1) and side effects (n = 1). These data confirm and expand previous reports on the good effects and tolerability of SO as a treatment for narcolepsy with cataplexy.

Topics: Actigraphy; Adolescent; Adult; Aged; Cataplexy; Female; Humans; Male; Middle Aged; Narcolepsy; Polysomnography; Sodium Oxybate; Treatment Outcome

Hypocretin deficiency causes narcolepsy and may affect neuroendocrine systems and body composition. Additionally, growth hormone (GH) alterations my influence weight in narcolepsy. Symptoms can be treated effectively with sodium oxybate (SXB; γ-hydroxybutyrate) in many patients. This study compared growth hormone secretion in patients and matched controls and established the effect of SXB administration on GH and sleep in both groups. Eight male hypocretin-deficient patients with narcolepsy and cataplexy and eight controls matched for sex, age, BMI, waist-to-hip ratio, and fat percentage were enrolled. Blood was sampled before and on the 5th day of SXB administration. SXB was taken two times 3 g/night for 5 consecutive nights. Both groups underwent 24-h blood sampling at 10-min intervals for measurement of GH concentrations. The GH concentration time series were analyzed with AutoDecon and approximate entropy (ApEn). Basal and pulsatile GH secretion, pulse regularity, and frequency, as well as ApEn values, were similar in patients and controls. Administration of SXB caused a significant increase in total 24-h GH secretion rate in narcolepsy patients, but not in controls. After SXB, slow-wave sleep (SWS) and, importantly, the cross-correlation between GH levels and SWS more than doubled in both groups. In conclusion, SXB leads to a consistent increase in nocturnal GH secretion and strengthens the temporal relation between GH secretion and SWS. These data suggest that SXB may alter somatotropic tone in addition to its consolidating effect on nighttime sleep in narcolepsy. This could explain the suggested nonsleep effects of SXB, including body weight reduction.

Topics: Adult; Body Composition; Body Mass Index; Cataplexy; Data Interpretation, Statistical; Entropy; Human Growth Hormone; Humans; Intracellular Signaling Peptides and Proteins; Male; Narcolepsy; Neuropeptides; Orexins; Polysomnography; Sleep; Sleep Stages; Sleep, REM; Sodium Oxybate; Waist-Hip Ratio; Weight Loss

Hypnosedative-induced complex behaviors have gained increased attention in recent years as a potential complication of benzodiazepines and benzodiazepine-receptor agonist use. Sodium oxybate (SO), the sodium salt of γ-hydroxybutyrate, an inhibitory neurotransmitter, has been associated with dose-dependent rates of somnambulism; however, there is limited information about complex motor behaviors with SO. We describe a patient with narcolepsy-cataplexy who experienced one episode of sleep-driving and at least two sleep-related eating episodes with therapeutic doses of SO.

Topics: Adjuvants, Anesthesia; Adult; Automobile Driving; Feeding and Eating Disorders; Humans; Male; Narcolepsy; Parasomnias; Sleep Wake Disorders; Sodium Oxybate

Topics: Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Catalepsy; Central Nervous System Stimulants; Dextroamphetamine; Humans; Hypnotics and Sedatives; Idiopathic Hypersomnia; Life Style; Methylphenidate; Modafinil; Narcolepsy; Polysomnography; Selective Serotonin Reuptake Inhibitors; Sodium Oxybate; Treatment Outcome

Sodium oxybate (brand name Xyrem) is a sodium salt of gamma-hydroxybutyric acid (GHB), an endogenous CNS depressant, which is an effective treatment of narcolepsy. As a drug of abuse, GHB produces severe psychiatric side effects and withdrawal. However, there are no reports of these effects when using clinically recommended doses. This paper presents a case of a patient who developed altered mental status while taking the recommended dose of sodium oxybate and subsequently became psychotic upon abrupt discontinuation of the medication. It is important for prescribers of sodium oxybate to be aware of the possibility of significant psychiatric side effects of this medication, as well as withdrawal symptoms, even at clinical doses.

Topics: Adult; Central Nervous System Depressants; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Narcolepsy; Psychotic Disorders; Risk Assessment; Severity of Illness Index; Sodium Oxybate; Substance Withdrawal Syndrome

Sodium oxybate (GHB, Xyrem, Jazz Pharmaceuticals) is used to treat cataplexy in patients with narcolepsy. We report the case of a middle aged, normo-ponderal narcoleptic woman without risk factors who developed reversible sleep apnea and objective sleepiness when treated by sodium oxybate, with an apnea-hypopnea index (AHI) of 19.7 on sodium oxybate and AHI 4.8 without treatment. Despite a subjective improvement in vigilance, mean sleep latency on MWT decreased from 21 minutes to 8 minutes on sodium oxybate.

Topics: Adult; Cataplexy; Central Nervous System Depressants; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Narcolepsy; Nocturnal Myoclonus Syndrome; Polysomnography; Risk Assessment; Severity of Illness Index; Sleep Apnea Syndromes; Sodium Oxybate; Treatment Outcome

Topics: Adjuvants, Anesthesia; Animals; Dose-Response Relationship, Drug; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Narcolepsy; Randomized Controlled Trials as Topic; Rats; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Cataplexy; Continuous Positive Airway Pressure; Dose-Response Relationship, Drug; Drug Chronotherapy; Humans; Male; Middle Aged; Narcolepsy; Polysomnography; Sleep Apnea, Obstructive; Sleep Stages; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Combined Modality Therapy; Continuous Positive Airway Pressure; Diagnosis, Dual (Psychiatry); Dose-Response Relationship, Drug; Humans; Narcolepsy; Polysomnography; Sleep Apnea, Obstructive; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Adult; Benzhydryl Compounds; Central Nervous System Stimulants; Depression; Drug Interactions; Humans; Male; Modafinil; Narcolepsy; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Adverse Drug Reaction Reporting Systems; Drug Industry; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Narcolepsy; Pharmacies; Product Surveillance, Postmarketing; Sodium Oxybate; United States; United States Food and Drug Administration

Narcolepsy is characterised by excessive daytime sleepiness and cataplexy and has a prevalence of 25 per 100,000. We suspect this is higher than presently seen in the Republic of Ireland. We aimed to calculate the Irish prevalence of Narcolepsy and to examine current management practices. We conducted an online survey of respiratory physicians, neurologists, paediatric neurologists, and psychiatrists with an interest in sleep disorders (73% response rate). Of this group, a total of 16 physicians managed 180 patients prior to January 2009. A clinical diagnosis alone was reached in 67 (41%) patients, the remainder by polysomnography or multiple sleep latency testing. No patients were diagnosed by cerebro-spinal fluid analysis of hypocretin levels. While 70 (42%) patients received modafanil, only 7 (4%) were treated with sodium oxybate. Even allowing for missing data it is apparent that Narcolepsy is hugely under-diagnosed in Ireland, however, current practises adhere with new international guidelines.

Topics: Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Health Surveys; Humans; Intracellular Signaling Peptides and Proteins; Ireland; Modafinil; Narcolepsy; Neuropeptides; Orexins; Polysomnography; Prevalence; Sodium Oxybate

to report on symptoms and therapies used in childhood narcolepsy-cataplexy.. retrospective series of 51 children who completed the Stanford Sleep Inventory. HLA-DQB1*0602 typing (all tested, and 100% positive), polysomnography or Multiple Sleep Latency Test (76%), and cerebrospinal fluid hypocretin-1 measurements (26%, all with low levels) were also conducted. Prospective data on medication response was collected in 78% using a specially designed questionnaire.. patients were separated into children with onset of narcolepsy prior to (53%), around (29%), and after (18%) puberty. None of the children had secondary narcolepsy. Clinical features were similar across puberty groups, except for sleep paralysis, which increased in frequency with age. Common features included excessive weight gain (84% ≥ 4 kg within 6 months of onset of narcolepsy) and earlier puberty (when compared with family members), notably in subjects who gained the most weight. Streptococcus-positive throat infections were reported in 20% of cases within 6 months of onset of narcolepsy. Polysomnographic features were similar across groups, but 3 prepubertal children did not meet Multiple Sleep Latency Test diagnostic criteria. Regarding treatment, the most used and continued medications were modafinil (84% continued), sodium oxybate (79%), and venlafaxine (68%). Drugs such as methylphenidate, tricyclic antidepressants, or selective serotonin reuptake inhibitors were often tried but rarely continued. Modafinil was reported to be effective for treating sleepiness, venlafaxine for cataplexy, and sodium oxybate for all symptoms, across all puberty groups. At the conclusion of the study, half of children with prepubertal onset of narcolepsy were treated "off label" with sodium oxybate alone or with the addition of one other compound. In older children, however, most patients needed more than 2 drugs.. this study reports on the clinical features of childhood narcolepsy and documents the safe use of treatments commonly used in adults in young children.

Topics: Adjuvants, Anesthesia; Adolescent; Age Distribution; Age of Onset; Antidepressive Agents, Second-Generation; Benzhydryl Compounds; Central Nervous System Stimulants; Child; Cyclohexanols; Drosophila Proteins; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Modafinil; Narcolepsy; Nerve Tissue Proteins; Nuclear Proteins; Overweight; Polysomnography; Puberty; Retrospective Studies; Sodium Oxybate; Streptococcal Infections; Surveys and Questionnaires; Transcription Factors; United States; Venlafaxine Hydrochloride; Weight Gain

Narcolepsy is often associated with increased body weight. Sodium oxybate has efficacy in many narcolepsy symptoms. The purpose of this study was to evaluate the effects of sodium oxybate on weight in patients with narcolepsy.. Charts from three centers of all patients with narcolepsy who had been using sodium oxybate for at least 3 months were reviewed. Patients in whom anti-cataplexy medications were added or withdrawn or wake-promoting medications added after the start of sodium oxybate were excluded from further analysis. In the remainder, pre-sodium oxybate and, most recently, on-sodium oxybate weights were compared using Student's t-tests. Sodium oxybate dose and duration of therapy were also noted.. A total of 54 patients meeting inclusion criteria were identified. Of these 54, 33 (61%) were women; the mean age was 48.3 years. The mean dose of sodium oxybate was 6.9g/night and the duration of therapy was 25 months. The mean pre-sodium oxybate weight was 78.3 (+/-15.7)kg. The most recent on-sodium oxybate weight was 74.9 (+/-15.1, p=0.003). The average weight loss was 3.4kg, whereas the maximum was 30.9kg.. This study suggests that treatment of patients with narcolepsy with sodium oxybate can result in weight loss.

Topics: Adolescent; Adult; Aged; Cataplexy; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Narcolepsy; Retrospective Studies; Sodium Oxybate; Weight Loss; Young Adult

Topics: Anesthesia, General; Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Narcolepsy; Neuropeptides; Orexins; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) is best known as a recreational depressant drug, whose use has also been implicated in drug facilitated sexual assault cases. It is also available as a therapeutic agent (Xyrem) used for the treatment of daytime sleepiness or cataplexy associated with narcolepsy. This is a report of a case of a 53-year-old woman undergoing treatment with Xyrem for narcolepsy. The decedent was also prescribed tramadol, gabapentin, cetirizine, modafinil, carisoprodol, and Xyrem. Toxicological analysis of the blood revealed GHB 165.6 mg/L, and 90.7 mg/L in the urine. Blood GHB concentrations in the range 156-260 mg/L have been reported to induce moderately sound sleep. The combined use of central nervous system depressant drugs, together with her problematic sleep apnea, and snoring (both contraindications for GHB use) were determined to have caused this subject's death. The manner of death was determined to be accidental.

Topics: Amines; Benzhydryl Compounds; Carisoprodol; Central Nervous System Depressants; Cetirizine; Cyclohexanecarboxylic Acids; Drug Interactions; Drug Therapy, Combination; Female; Forensic Toxicology; Gabapentin; gamma-Aminobutyric Acid; Gastrointestinal Contents; Humans; Middle Aged; Modafinil; Narcolepsy; Sleep Apnea Syndromes; Snoring; Sodium Oxybate; Tramadol; Vitreous Body

Fatalities resulting from popular use of gamma hydroxybutyrate (GHB) have previously been reported. We report three deaths associated with use of Xyrem (sodium oxybate), a pharmaceutical preparation of GHB initially approved for treatment of narcolepsy with cataplexy. One death appears associated with Xyrem abuse, with extremely high postmortem blood GHB levels documented. Although postmortem blood GHB levels in two other deaths are consistent with therapeutic levels, cause and effect cannot be established. We discuss these cases and factors which may have exerted contributory respiratory depressant effects, singly or in combination, including concurrent use of sedative hypnotics, obstructive sleep apnea, and obesity.

Topics: Adult; Central Nervous System Agents; Fatal Outcome; Female; Humans; Male; Middle Aged; Narcolepsy; Respiration; Risk Factors; Sodium Oxybate

Topics: Humans; Narcolepsy; Respiration; Sodium Oxybate

Narcolepsy is a neurological disorder affecting the regulation of sleep and wakefulness. It is characterized by excessive daytime sleepiness, cataplexy, and other rapid eye movement (REM) sleep-associated manifestations (eg, hypnagogic hallucinations and sleep paralysis). The recognition of this disorder is usually delayed by 10 to 15 years, largely because of its protean manifestations, insidious nature, and lack of physician awareness. Delayed diagnosis is associated with poor quality of life, depression, and increased likelihood of accidents. Health care providers should include narcolepsy in the differential diagnosis of patients with excessive sleepiness, chronic fatigue, sleep-disordered breathing, depression, and attention-deficit/hyperactivity disorder. Narcolepsy is a lifelong disorder that often requires pharmacological treatments, which may include wake-promoting stimulants for excessive sleepiness and gamma-hydroxybutyrate (sodium oxybate) and antidepressants for REM sleep-associated manifestations. This article presents a case of a 47-year-old man with long-standing sleepiness and cataplexy who was eventually diagnosed with narcolepsy 30 years after the first onset of symptoms. The presenting manifestations of narcolepsy, diagnostic criteria, and its management are also discussed.

Topics: Adjuvants, Anesthesia; Attention Deficit and Disruptive Behavior Disorders; Benzhydryl Compounds; Catalepsy; Central Nervous System Stimulants; Diagnosis, Differential; Drug Therapy, Combination; Evidence-Based Medicine; Follow-Up Studies; Humans; Male; Middle Aged; Modafinil; Narcolepsy; Polysomnography; Sleep, REM; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Female; Humans; Male; Middle Aged; Narcolepsy; Severity of Illness Index; Sleep Apnea, Obstructive; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) has re-emerged as a major treatment for narcolepsy. As dopaminergic transmission is clearly involved in the pathophysiology of restless legs syndrome (RLS), and GHB reduces dopamine release, one may hypothesize that RLS may occur in narcolepsy in the presence of GHB. We report a case of narcolepsy with a severe occurrence of typical RLS with GHB, symptoms never previously experienced by the subject and reversible after withdrawal.

Topics: Diagnosis, Differential; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Male; Middle Aged; Narcolepsy; Restless Legs Syndrome; Sodium Oxybate

Gamma-hydroxybutyrate (GHB) is used to treat narcolepsy but is also abused. GHB has many actions in common with the GABA(B) receptor agonist baclofen.. To further study the role of GABA(B) receptors in the effects of GHB.. The experiments examined the ability of the GABA(B) receptor antagonist CGP35348 to attenuate GHB-induced catalepsy in comparison with its ability to attenuate the cataleptic effects of GABA(B) receptor agonists.. In C57BL/6J mice, GHB, the GHB precursor gamma-butyrolactone (GBL), and the GABA(B) receptor agonists baclofen and SKF97541 all produced catalepsy but differed in potency (i.e., SKF97541>baclofen>GBL>GHB) and in onset of action. The cataleptic effects of drug combinations were assessed at the time of peak effect of each compound, i.e., 60 min after CGP35348 and 60, 30, 30, and 15 min after baclofen, SKF97541, GHB, and GBL, respectively. At 100 mg/kg, CGP35348 shifted the dose-response curves of baclofen and SKF97541 to the right but not those of GHB and GBL; at 320 mg/kg, CGP35348 shifted the curves of all four compounds to the right.. The finding that CGP35348 was about threefold less potent to antagonize GHB and GBL than baclofen and SKF97541 is further evidence that the mechanisms mediating the effects of GHB and GABA(B) agonists are not identical. Differential involvement of GABA(B) receptor subtypes, or differential interactions with GABA(B) receptors, may possibly explain why GHB is effective for treating narcolepsy and is abused whereas baclofen is not.

Topics: 4-Butyrolactone; Animals; Baclofen; Catalepsy; Dose-Response Relationship, Drug; GABA Agonists; GABA Antagonists; GABA-B Receptor Agonists; Male; Mice; Mice, Inbred C57BL; Narcolepsy; Organophosphorus Compounds; Receptors, GABA-B; Sodium Oxybate; Substance-Related Disorders

(1) Narcolepsy is characterised by sudden, overwhelming daytime drowsiness, sometimes associated with cataplexy (more or less complete loss of muscle tone during an emotional reaction). (2) Modafinil moderately reduces daytime drowsiness but has no effect on cataplexy. Methylphenidate, an amphetamine psychostimulant, seems to act on both drowsiness and cataplexy, although its clinical evaluation is limited to observational series. (3) Oxybic acid, long used in general anaesthesia, but also misused for recreational and criminal purposes (chemical or drug-induced submission), has been approved to treat adults with both narcolepsy and cataplexy, in the form of an oral solution of sodium oxybate. (4) The rationale behind the use of sodium oxybate is to re-establish a near-normal pattern of the different phases of sleep. Because of its short-lasting action, sodium oxybate has to be taken once at bedtime and then again 2.5 to 4 hours later. (5) Clinical evaluation mainly consists of 4 double-blind placebo-controlled trials of sodium oxybate. Three short-term trials, involving 136 patients treated for 4 weeks and 228 and 270 patients treated for 8 weeks, showed that sodium oxybate at a dose of 4.5 g to 9 g a day reduced the number of cataplexy attacks but that a dose of at least 6 g was needed to reduce daytime drowsiness. A trial involving 56 patients who had been taking sodium oxybate for nearly 2 years, assessed the effects of stopping versus continuing treatment. The results suggest that sodium oxybate is effective in the long term. (6) During clinical trials, 61% of patients had adverse effects attributed to sodium oxybate. These included gastrointestinal disorders (nausea (18%)), neurological disorders (dizziness (15%), headache (6%)), confusion (3%), and enuresis (7%). (7) Altered consciousness and respiratory depression occurred after a single intake of a dose two or three times higher than the recommended dose. (8) Misuse, especially to obtain chemical or drug-induced submission (i.e. as a 'date rape' drug), is facilitated by the odourless and colourless nature of the oral solution. (9) In practice, for some patients who are seriously affected by persistent episodes of cataplexy or drowsiness, despite treatment of narcolepsy, sodium oxybate is preferable to methylphenidate, which has been less thoroughly evaluated. However, the risks of misuse and overdose mean that this drug should only be proposed to patients in whom the benefits are likely to outweig

Topics: Adjuvants, Anesthesia; Adult; Cataplexy; Clinical Trials as Topic; Double-Blind Method; Drug Administration Schedule; Drug Approval; France; Humans; Narcolepsy; Randomized Controlled Trials as Topic; Sleep; Sodium Oxybate; Substance-Related Disorders; Treatment Outcome; Wakefulness

Pharmacologic management of patients with narcolepsy is usually based on treating the separate symptoms of cataplexy and excessive daytime sleepiness (EDS). For treating cataplexy, the most widely used medications include the antidepressants venlafaxine, imipramine, and protriptyline, usually at lower doses than prescribed with depression, and sodium oxybate. Monoamine oxidase inhibitors are also sometimes used, but much less frequently. The U.S. Food and Drug Administration has approved 4 medications for EDS: dextroamphetamine, methylphenidate, modafinil, and sodium oxybate. Sodium oxybate is the only drug approved for treating both cataplexy and EDS. Modafinil and sodium oxybate have similar, long-term efficacies in treating EDS at prescribed doses.

Topics: Antidepressive Agents; Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Circadian Rhythm; Combined Modality Therapy; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Drug Approval; Health Education; Humans; Long-Term Care; Modafinil; Monoamine Oxidase Inhibitors; Narcolepsy; Psychotropic Drugs; Sodium Oxybate

Topics: Central Nervous System Depressants; Clinical Trials as Topic; Humans; Narcolepsy; Sodium Oxybate

To evaluate the efficacy and side-effect profile of off-label sodium oxybate (gamma hydroxy butyrate) therapy in severe childhood narcolepsy-cataplexy.. Retrospective; chart review.. A multidisciplinary tertiary sleep center.. A group of eight children with severe narcolepsy-cataplexy diagnosed on the basis of clinical history, nocturnal polysomnography and the multiple sleep latency test were studied. A modified Epworth Sleepiness Scale and an arbitrary cataplexy severity scale (1 = minimal weakness, 2 = voluntarily preventable falls, 3 = falls to the ground) were utilized.. Sodium oxybate therapy; concurrent medications were maintained.. Before sodium oxybate therapy, all subjects had suboptimally controlled sleepiness and cataplexy. Following treatment with sodium oxybate, 7/8 subjects (88%) improved. Cataplexy frequency decreased from a median of 38.5 to 4.5/ week (p = 0.0078). Cataplexy severity decreased from 2.75 to 1.75 (p = 0.06). The Epworth Sleepiness Scores improved from a median of 19 to 12.5 (p = 0.02). Suicidal ideation, dissociative episodes, tremor and constipation occurred in one subject each and terminal insomnia in two. Three of the 8 (38%) discontinued therapy. Two stopped the drug owing to side effects and one due to problems with postal delivery of the medication.. This is the first report on sodium oxybate therapy in childhood narcolepsy-cataplexy. Our finding of improvement in cataplexy and sleepiness suggests that this medication is effective in treating severe childhood narcolepsy-cataplexy.

Topics: Adolescent; Body Mass Index; Child; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Male; Narcolepsy; Polysomnography; Quality of Life; Retrospective Studies; Sleep, REM; Sodium Oxybate; Treatment Outcome; Wakefulness

Management of narcolepsy with or without cataplexy relies on several classes of drugs, namely stimulants for excessive daytime sleepiness and irresistible episodes of sleep, antidepressants for cataplexy and hypnosedative drugs for disturbed nocturnal sleep. In addition, behavioral measures can be of notable value. Guidelines on the management of narcolepsy have already been published. However contemporary guidelines are necessary given the growing use of modafinil to treat excessive daytime sleepiness in Europe within the last 5-10 years, and the decreasing need for amphetamines and amphetamine-like stimulants; the extensive use of new antidepressants in the treatment of cataplexy, apart from consistent randomized placebo-controlled clinical trials; and the present re-emergence of gamma-hydroxybutyrate under the name sodium oxybate, as a treatment of all major symptoms of narcolepsy. A task force composed of the leading specialists of narcolepsy in Europe has been appointed. This task force conducted an extensive review of pharmacological and behavioral trials available in the literature. All trials were analyzed according to their class evidence. Recommendations concerning the treatment of each single symptom of narcolepsy as well as general recommendations were made. Modafinil is the first-line pharmacological treatment of excessive daytime sleepiness and irresistible episodes of sleep in association with behavioral measures. However, based on several large randomized controlled trials showing the activity of sodium oxybate, not only on cataplexy but also on excessive daytime sleepiness and irresistible episodes of sleep, there is a growing practice in the USA to use it for the later indications. Given the availability of modafinil and methylphenidate, and the forseen registration of sodium oxybate for narcolepsy (including excessive daytime sleepiness, cataplexy, disturbed nocturnal sleep) in Europe, the place of other compounds will become fairly limited. Since its recent registration cataplexy sodium oxybate has now become the first-line treatment of cataplexy. Second-line treatments are antidepressants, either tricyclics or newer antidepressants, the later being increasingly used these past years despite few or no randomized placebo-controlled clinical trials. As for disturbed nocturnal sleep the best option is still hypnotics until sodium oxybate is registered for narcolepsy. The treatments used for narcolepsy, either pharmacological or behavioral

Topics: Advisory Committees; Antidepressive Agents; Benzhydryl Compounds; Catalepsy; Central Nervous System Stimulants; Disease Management; Europe; Humans; Modafinil; Narcolepsy; Sodium Oxybate

Topics: Adult; Cataplexy; Comorbidity; Cyclohexanols; Hallucinations; Humans; Male; Morpholines; Narcolepsy; Patient Education as Topic; Reboxetine; Selective Serotonin Reuptake Inhibitors; Sodium Oxybate; Venlafaxine Hydrochloride

Topics: Adjuvants, Anesthesia; Cataplexy; Circadian Rhythm; Humans; Narcolepsy; Pilot Projects; Sodium Oxybate; Treatment Outcome; Wakefulness

Patients with sleep disorders present with a variety of complaints including excessive daytime sleepiness, daytime spells, inability to sleep, uncomfortable sensation in the extremities, and unusual night time behaviors. This article provides eight vignettes on patients with sleep disorders including narcolepsy, idiopathic hypersomnia, obstructive sleep apnea, restless legs syndrome, and rapid eye movement behavior disorder. The discussion provides data regarding the epidemiology, pathophysiology, and diagnostic approach for these conditions. The various treatment options for these sleep disorders are also identified.

Topics: Adjuvants, Anesthesia; Adolescent; Adult; Aged; Aged, 80 and over; Cataplexy; Disorders of Excessive Somnolence; Electroencephalography; Female; HLA Antigens; Humans; Male; Middle Aged; Narcolepsy; Polysomnography; REM Sleep Behavior Disorder; Restless Legs Syndrome; Sleep Apnea, Obstructive; Sleep Stages; Sleep Wake Disorders; Sodium Oxybate

Topics: Controlled Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Interactions; Economics, Pharmaceutical; Half-Life; Humans; Hypnotics and Sedatives; Narcolepsy; Sodium Oxybate

Topics: Anesthetics, Intravenous; Cataplexy; History, 20th Century; Humans; Narcolepsy; Sodium Oxybate

Topics: Adjuvants, Anesthesia; Ethanol; Humans; Narcolepsy; Sodium Oxybate; Substance Withdrawal Syndrome

There is growing public concern about the use of gamma-hydroxybutyrate (GHB) as a party drug. This justified concern about misuse, however, should not lead to prohibition of the drug as it is efficacious in narcolepsy.

Topics: Central Nervous System Stimulants; Drug and Narcotic Control; Humans; Illicit Drugs; Narcolepsy; Netherlands; Sodium Oxybate; Substance-Related Disorders

The polygraphically recorded sleep-wake continuum of 21 Prader-Willi syndrome (PWS) patients was compared with that of 19 normal people. In the Prader-Willi group, excessive daytime sleepiness (EDS) is found in 95% of subjects, and rapid eye movement (REM) sleep disorders occur in 52%. These two features were significantly different from the normal group of subjects. No indications were found for the presence of the apnoea syndrome. The REM sleep disorders are: sleep onset rapid eye movements (SOREM), REM sleep in naps, many arousals during REM sleep, and a significant decrease in total REM sleep. These disturbances in the Prader-Willi group, combined with the presence of EDS and sometimes of cataplexy, are likely to be expressions of a narcoleptic syndrome although this was not sustained by the HLA-DR2 expression above normal. The quality of life of PWS subjects can be improved in some cases by treating them as narcoleptic patients.

Topics: Adolescent; Adult; Catalepsy; Clomipramine; Female; Humans; Hypoventilation; Imipramine; Male; Middle Aged; Narcolepsy; Polysomnography; Prader-Willi Syndrome; Sleep Apnea Syndromes; Sleep, REM; Sodium Oxybate

By means of a wrist accelerometer, motor activity of 14 narcoleptic patients was continuously monitored. The accelerometer registered accelerations exceeding a threshold value of 0.1 gr and stored activity integrated over 3 minutes. After a registration period of 20 days, the data were read out, graphically displayed and compared to the patient's diary. Interruptions of night sleep and some sleep attacks during day correlated closely with the patient's diary. However, sleep attacks of less than about 5 minutes duration were not identified, because they could not be differentiated from normal rest. Except for that, activity monitoring with this accelerometer is a useful and simple method for ambulatory activity recording in narcoleptics.

Topics: Circadian Rhythm; Double-Blind Method; Humans; Microcomputers; Monitoring, Physiologic; Motor Activity; Narcolepsy; Pilot Projects; Sleep Stages; Sodium Oxybate; Wakefulness

Topics: Base Sequence; HLA-D Antigens; Humans; Molecular Sequence Data; Narcolepsy; Sodium Oxybate

Periodic leg movements during sleep (PMS) is a disorder frequently encountered in narcolepsy. In the present study, 12 narcoleptic patients (six with PMS and six without) were recorded in a sleep laboratory for 2 consecutive nights before and after treatment with gamma-hydroxybutyrate (GHB) taken at bedtime for 1 month. Treatment resulted in decreased rapid eye movement (REM) sleep latency and increased REM efficiency without change in the total duration of REM sleep. GHB was associated with the appearance of pathological levels of PMS in patients who were unaffected before treatment. These results are discussed in relation to the role of dopamine in the physiopathology of narcolepsy and PMS.

Topics: Adult; Humans; Hydroxybutyrates; Leg; Middle Aged; Movement; Movement Disorders; Narcolepsy; Sleep, REM; Sodium Oxybate

Topics: Arousal; Cataplexy; Humans; Hydroxybutyrates; Narcolepsy; Sleep Stages; Sodium Oxybate

Five narcoleptic patients presenting periodic movements in sleep were investigated during treatment with L-dopa administered together with a decarboxylase inhibitor. One of these patients was also treated with gamma-hydroxybutyrate and zimelidine, and recorded at the sleep laboratory under each condition. L-dopa was effective in controlling periodic movements in sleep in all patients, but gamma-hydroxybutyrate or zimelidine were not. These results are discussed in view of a dopaminergic implication in the pathogenesis of periodic movements in sleep.

Topics: Adult; Female; Humans; Levodopa; Male; Movement; Narcolepsy; Periodicity; Sleep; Sodium Oxybate; Zimeldine

Topics: Animals; Dogs; Histocompatibility Antigens Class II; HLA-DR2 Antigen; Humans; Narcolepsy; Research; Sodium Oxybate; Viloxazine

Narcoleptic patients were compared to idiopathic hypersomniac patients and REM hypersomnia patients with regard to nocturnal sleep disruption. Results showed specificity of the narcoleptic sleep pattern and a possible correlation between REM fragmentation and cataplexy. Patients with and without periodic movements in sleep (PMS) were compared and no difference was found in their nocturnal sleep pattern, suggesting that PMS is not the major determinant of sleep disruption previously described in narcoleptic patients. Finally, nocturnal sleep disruption was treated with gamma-hydroxybutyrate (GHB) and results further indicate a possible link between REM fragmentation and cataplexy.

Topics: Cataplexy; Humans; Movement; Narcolepsy; Periodicity; Sleep; Sleep Stages; Sodium Oxybate

Previous studies on the effects of gamma-hydroxybutyrate (GHB) on the sleep and clinical response of patients with narcolepsy are reviewed. New information on 48 patients treated with GHB for as long as 9 years is presented. These studies indicate that 2.25 to 3.00 g of GHB, taken in conjunction with a low dose of a stimulant during the day, rapidly alleviate the symptoms of narcolepsy in most patients. Tolerance does not develop to this treatment regimen; neither have any patients discontinued the treatment because of side effects. In poor responders, daytime drowsiness and not cataplexy has been the most common residual symptom. Sleep studies reveal that GHB induces REM followed by slow wave sleep. Although total sleep time at night may be unchanged, sleep is less fragmented. GHB appears to be effective because it can induce the symptoms of narcolepsy and contain them at night. It is noteworthy, therefore, that the central biochemical changes induced by GHB also appear comparable to those found naturally in narcolepsy.

Topics: Female; Humans; Hydroxybutyrates; Male; Narcolepsy; Sleep, REM; Sodium Oxybate; Time Factors

The action of sodium hydroxybutyrate, a GABA derivative, was examined in 11 patients with narcolepsy. A two-week course of therapy was evaluated using clinical and electrophysiological research methods including polygraphic examination of night sleep. The use of the drug was associated with improvement in the patients' nocturnal sleep attended by an increase in the IV stage of the slow sleep phase, synchronizing shifts on the EEG in the period of diurnal wakefulness and a decrease in the initial emotional tension. To correct night sleep disturbances, it is advisable to include sodium hydroxybutyrate into a multimodality treatment of narcolepsy.

Topics: Autonomic Nervous System; Female; Humans; Hydroxybutyrates; Male; Narcolepsy; Personality; Sodium Oxybate

Sleep attacks, cataplexy, sleep paralysis and hypnagogic hallucinations are the cardinal signs of narcolepsy. However most patients present only with sleep attacks at disease onset. Animal and human studies on the psychopharmacology and neurochemistry of narcolepsy, suggest abnormalities on rapid eye movement (REM) sleep. Thus, most drugs used on its treatment, such as tricyclic antidepressants and psychostimulant agents, are aimed to reduce REM sleep. However, there is growing evidence that some drugs that can alleviate fragmentation of sleep rather than suppress REM sleep can also be clinically effective for this condition. The authors review the subject and comment on their experience with clonidine, an imidazoline derivative marketed as an antihypertensive agent, and suggest that REM suppression is not always necessary for narcoleptics to improve.

Topics: Animals; Clonidine; Dogs; Humans; Hydroxybutyrates; Indoles; Mazindol; Narcolepsy; Sleep, REM; Sodium Oxybate

Gammahydroxybutyrate was administered to a patient who experienced narcolepsy associated with central sleep apnea. The treatment relieved the major symptoms of narcolepsy, and significantly decreased the number of apneic periods. Gammahydroxybutyrate did not cause the prolonged and potentially fatal apneic periods associated with the use of other hypnotic agents.

Topics: Humans; Hydroxybutyrates; Male; Middle Aged; Narcolepsy; Sleep Apnea Syndromes; Sleep Stages; Sodium Oxybate

Topics: Administration, Oral; Humans; Hydroxybutyrates; Injections, Intravenous; Movement Disorders; Narcolepsy; Sodium Oxybate

Sixteen patients with narcolepsy and cataplexy were treated with gamma-hydroxybutyrate (GHB) given at night and tailored to achieve as continuous a night's sleep as possible. The dosage usually consisted of 1.5-2.25 gm orally at bedtime and then one or two further 1.0-1.5 gm doses with awakenings during the night, and totaled about 50 mg/kg. Apart from one patient who took only the bedtime dose, the subjective quality of night sleep improved in all patients and the number of irresistible daytime attacks of sleep and cataplexy substantially diminished. Some residual daytime drowsiness remained and this usually responded well to low doses of methylphenidate. Improvement has been maintained for up to 20 months without the development of tolerance. Two patients experienced adverse side effects necessitating withdrawal of GHB treatment, but no serious toxic effects have occurred.

Topics: Adult; Cataplexy; Female; Humans; Hydroxybutyrates; Male; Middle Aged; Narcolepsy; Sodium Oxybate