Accidental calcium, magnesium, potassium and sodium oxybates (Xywave) overdose: mistiming of a single night's narcolepsy medication leading to respiratory failure requiring mechanical ventilation.

While typically thought of as an illicit substance, oxybate salts or gamma-hydroxybutyrate (GHB) has more recently been prescribed to treat narcolepsy by enhancing night-time sleep resulting in decreased daytime drowsiness. This case involves a college-aged female with prescribed GHB for narcolepsy who took her second nightly dose too early. This resulted in mental depression, respiratory failure, intubation and mechanical ventilation. The patient was successfully extubated in the intensive care unit several hours later with no residual morbidity. We were unable to identify any prior reports of mixed-salt oxybate toxicity following mistimed drug administration. This case should serve as a warning to emergency physicians to be on the lookout for GHB as part of the differential diagnosis for patients with narcolepsy presenting with altered mental status. It should also serve as a warning to patients and prescribers that this medication can have outcomes that require immediate medical intervention.

Pharmacokinetics, bioavailability, and bioequivalence of lower-sodium oxybate in healthy participants in two open-label, randomized, crossover studies.

American Academy of Sleep Medicine practice parameters designate sodium oxybate (SXB) as a standard of care for cataplexy, excessive daytime sleepiness (EDS), and disrupted night-time sleep in narcolepsy. Recently, a lower-sodium oxybate (LXB) with 92% less sodium than SXB was approved in the United States for the treatment of cataplexy or EDS in patients 7 years of age and older with narcolepsy. Two phase I, open-label, randomized, single-dose crossover pharmacokinetic studies in healthy adults were conducted. Single 4.5-g oral doses of LXB and SXB were administered in a fasted or fed state. In the fasted state at equivalent oxybate doses, LXB, compared with SXB, had a lower maximum plasma concentration (Cmax ; study 1 [total aqueous volume, 240 ml]: 101.8 vs. 135.7 µg/ml; study 2 [60 ml]: 94.6 vs. 123.0 µg/ml), delayed time to Cmax (Tmax ; study 1: 0.75 vs. 0.5 h; study 2: 1.0 vs. 0.5 h), but similar area under the curve (AUC; study 1: AUC0-t , 235.4 vs. 263.9 µg∙h/ml; AUC0-∞ , 236.5 vs. 265.2 µg∙h/ml; study 2: AUC0-t , 241.5 vs. 254.7 µg∙h/ml; AUC0-∞ , 243.1 vs. 256.3 µg∙h/ml). Bioequivalence criteria were met for AUC but not Cmax (both studies). Cmax and AUC were lower under fed than fasted conditions (LXB and SXB); differences between fed versus fasted were smaller for LXB than SXB. These pharmacokinetic differences between LXB and SXB are likely due to the lower sodium content in LXB. Pooled analyses demonstrated that a higher Cmax is associated with a higher incidence of nausea and vomiting.

Onset of narcolepsy type 1 in a paraneoplastic encephalitis associated with a thymic seminoma.

Narcolepsy type 1 results from probable autoimmune disruption of hypothalamic hypocretinergic neurons. Secondary narcolepsy can occur as a result of other conditions affecting the central nervous system, including limbic paraneoplastic encephalitis. We report the case of a 19-year-old patient presenting with acute-onset diurnal hypersomnolence, hyperphagia, sexual dysfunction, and psychiatric disturbances. Further investigations revealed a limbic paraneoplastic encephalitis associated with mediastinal thymic seminoma. Tumor removal and immunosuppressive treatment resulted in a partial benefit on psychiatric disturbances but did not improve daytime sleepiness. A comprehensive sleep assessment led to the diagnosis of secondary narcolepsy type 1 with reduced cerebrospinal fluid hypocretin-1 levels and revealed the presence of the HLA DQB1*0602 allele, typically associated with idiopathic narcolepsy, for which we hypothesize a possible immunopathogenic role. Sodium oxybate was successfully administered. Narcolepsy is often overlooked in patients with limbic paraneoplastic encephalitis. A prompt assessment and an adequate symptomatic treatment can improve the disease burden. CITATION: Rossi S, Asioli GM, Rizzo G, et al. Onset of narcolepsy type 1 in a paraneoplastic encephalitis associated with a thymic seminoma. J Clin Sleep Med. 2021;17(12):2557-2560.

Lisdexamfetamine to improve excessive daytime sleepiness and weight management in narcolepsy: a case series

Objective: To report the successful use of lisdexamfetamine in the management of narcolepsy. Methods: Five narcoleptic patients received lisdexamfetamine, at different dosages and for different periods, for management of excessive daytime sleepiness and weight control. Results: All patients experienced improvement of excessive daytime sleepiness and lost weight without side effects. Conclusion: Lisdexamfetamine appears promising for the treatment of two of the most common symptoms of narcolepsy: excessive daytime sleepiness and weight gain.

Pseudotumor cerebri syndrome in a patient with narcolepsy type 1.

Type 1 narcolepsy (NT1) is a chronic primary disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy, sleep paralysis, hypnagogic hallucinations and disrupted nocturnal sleep. NT1 is linked to hypothalamic hypocretin deficiency, strongly associated with Human Leukocyte Antigen (HLA) marker DQB1*06:02 and of probable autoimmune origin. NT1 is usually associated with increased rates of overweight and obesity, and sometimes with increases in overnight blood pressure and increased rates of hypoventilation with raised CO2 levels overnight. Many of these are predisposing factors for pseudotumor cerebri syndrome (PTCS). We present a case of a young girl with both NT1 and PTCS that responded well to treatment with acetazolamide after early identification, with improvement of headache and resolution of hypoventilation.

Risk of amphetamine use disorder and mortality among incident users of prescribed stimulant medications in the Veterans Administration.

BACKGROUND AND AIMS: Non-medical use of prescribed stimulant medications is a growing concern. This study's aims were to ascertain the demographics of stimulant medication users compared with non-users, examine temporal trends of stimulant medication use and estimate risk factors for development of amphetamine use disorder (AUD) and mortality among new users of stimulant medications. DESIGN: Cox proportional hazards regression in a retrospective cohort adjusted by baseline covariates. SETTING: United States, national administrative database of the Veterans Affairs (VA) health-care system. PARTICIPANTS: Adult incident users of stimulant medications (n = 78 829) from fiscal years (FY) 2001 to 2012. MEASUREMENTS: Primary outcomes were time-to-event: (1) occurrence of AUD diagnosis and (2) death. Baseline covariates included demographic information, Food and Drug Administration (FDA)-approved indications for stimulant use, substance use disorders (SUD) and depression. FINDINGS: Stimulant users compared with non-users were younger, more likely to be non-Hispanic white and female. Incident stimulant medication users increased threefold from FY2001-FY2012 and eightfold among adults aged 18-44 years. Nearly one in 10 incident users in FY2012 had a comorbid baseline SUD. Off-label use was common-nearly three of every five incident users in FY2012. Comorbid SUDs among incident stimulant medication users were risk factors for occurrence of AUD during follow-up, with adjusted hazard ratio (AHR) estimates ranging from 1.54 to 2.83 (Ps < 0.05). Increased mortality risk was observed with occurrence of AUD during follow-up [AHR = 1.55, 95% confidence interval (CI) = 1.13-2.14, P = 0.007], while on-label prescribing was protective against death (AHR = 0.686, 95% CI = 0.63-0.75, P < 0.0001). CONCLUSIONS: In a US national cohort of adult incident stimulant medication users in the Veterans Affairs health-care system, measured from fiscal years 2001 to 2012, comorbid substance use disorders were common and were risk factors for development of an amphetamine use disorder (AUD). Increased mortality risk among incident users of stimulant medications was observed among both those who developed an AUD later and those whose use was defined as off-label.

Increased interferon-mediated immunity following in vitro and in vivo Modafinil treatment on peripheral immune cells.

The wake-promoting drug Modafinil has been used for treatment of sleep disorders, such as Narcolepsy, excessive daytime sleepiness and sleep apnea, due to its stimulant action. Despite the known effect of Modafinil on brain neurochemistry, particularly on brain dopamine system, recent evidence support an immunomodulatory role for Modafinil treatment in neuroinflammatory models. Here, we aimed to study the effects of in vitro and in vivo Modafinil treatment on activation, proliferation, cell viability, and cytokine production by immune cells in splenocytes culture from mice. The results show that in vitro treatment with Modafinil increased Interferon (IFN)-γ, Interleukin (IL)-2 and IL-17 production and CD25 expression by T cells. In turn, in vivo Modafinil treatment enhanced splenocyte production of IFN-γ, IL-6 and tumor necrosis factor (TNF), and increased the number of IFN-γ producing cells. Next, we addressed the translational value of the observed effects by testing PBMCs from Narcolepsy type 1 patients that underwent Modafinil treatment. We reported increased number of IFN-γ producing cells in PBMCs from Narcolepsy type 1 patients following continuous Modafinil treatment, corroborating our animal data. Taken together, our results show, for the first time, a pro-inflammatory action of Modafinil, particularly on IFN-mediated immunity, in mice and in patients with Narcolepsy type 1. The study suggests a novel effect of this drug treatment, which should be taken into consideration when given concomitantly with an ongoing inflammatory or autoimmune process.

Consumo de modafinilo en profesionales de la salud mental: reporte de un caso y revisión bibliográfica / Modafinil use in mental health professionals: case report and bibliographic review

INTRODUCCIÓN El presente estudio busca comenzar un abordaje inicial del fenómeno del consumo de Modafinilo en profesionales de la Salud Mental en Chile y los factores precipitantes que promueven el consumo de esta sustancia psicoestimulante. OBJETIVOS: Realizar una revisión bibliográfica respecto del consumo de Psicoestimulantes en Profesionales de la Salud Mental; identificar el psicoestimulante de más fácil acceso; buscar y contactar a profesionales de la salud mental del SSMC que consuman activamente Modafinilo e Identificar los posibles factores precipitantes asociados al consumo de Modafinilo. MATERIAL Y MÉTODOS: Reporte de caso y análisis de discurso de una entrevista en profundidad, identificando las categorías centrales que estructuran la experiencia del profesional respecto de su consumo. RESULTADOS Y DISCUSIÓN: De acuerdo al análisis de la entrevista, podemos destacar cuatro factores que desencadenan el consumo habitual de la sustancia psicoestimulante: la narcolepsia, sobrecarga laboral, sobrecarga emocional y el fácil acceso al Modafinilo. CONCLUSIONES: La bibliografía existente es muy escasa; este estudio se constituye como una primera aproximación al abordaje de este tema a nivel nacional; la sobrecarga emocional cobra gran importancia ya que complementa la dependencia fisiológica; los estados emocionales que generan y mantienen el consumo en el profesional se ven asociados a eventos ambientales, y la dependencia psicológica es una realidad inseparable de la dependencia fisiológica.

BACKGROUND: The present study aims to start an initial approach to the phenomenon of Modafinil use in mental health professionals in Chile, and the precipitating factors that promote the consumption of this psychostimulant substance. OBJETIVES: To carry out a bibliographic review regarding the use of Psychostimulants in Mental Health Professionals; to identify the most easily accessible psychostimulant; to find and contact mental health professionals who actively consume Modafinil and to identify the possible precipitating factors associated with consumption of Modafinil. METHODS: Case report and discourse analysis of an in-depth interview, identifying the central categories that structure the professional's experience regarding their consumption. RESULTS AND DISCUSSION: According to the analysis of the interview, we can highlight four factors that trigger the habitual consumption of the psychostimulant substance: Narcolepsy, work overload, emotional overload and easy access to Modafinil. CONCLUSIONS: The existing literature is very scarce; this study constitutes a first approach of this topic at national level; emotional overload is of great importance since it complements the physiological dependence; the emotional states that generate and maintain consumption in the professional are seen associated with environmental factors, and psychological dependence is an inseparable reality of physiological dependence.

Investigational therapies for the treatment of narcolepsy.

INTRODUCTION: 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. While non-pharmacological treatments are sometimes helpful, more than 90% of narcoleptic patients require a pharmacological treatment. Areas covered: The present review is based on an extensive Internet and PubMed search from 1994 to 2017. It is focused on drugs currently in development for the treatment of narcolepsy. Expert opinion: Currently there is no cure for narcolepsy, with treatment focusing on symptoms control. However, these symptomatic treatments are often unsatisfactory. The research is leading to a better understanding of narcolepsy and its symptoms. New classes of compounds with possible applications in the development of novel stimulant/anticataplectic medications are described. H3 receptor antagonists represent a new therapeutic option for EDS in narcolepsy. JZP-110, with its distinct mechanism of action, would be a new therapeutic option for the treatment of EDS in the coming years. In the future, hypocretin-based therapies and immune-based therapies, could modify the clinical course of the disease. However, more information would be necessary to completely understand the autoimmune process and also how this process can be altered for therapeutic benefits.

Cardiovascular fitness in narcolepsy is inversely related to sleepiness and the number of cataplexy episodes.

OBJECTIVE: Cardiopulmonary fitness depends on daily energy expenditure or the amount of daily exercise. Patients with narcolepsy spent more time being sleepy or asleep than controls; thus we may speculate that they have a lower quantity and quality of physical activity. The aim of the present study was thus to test the hypothesis that exercise tolerance in narcolepsy negatively depends on sleepiness. PATIENTS AND METHODS: The cross-sectional study included 32 patients with narcolepsy with cataplexy, 10 patients with narcolepsy without cataplexy, and 36 age- and gender-matched control subjects, in whom a symptom-limited exercise stress test with expired gas analysis was performed. A linear regression analysis with multivariate models was used with stepwise variable selection. RESULTS: In narcolepsy patients, maximal oxygen uptake (VO2peak) was 30.1 ± 7.5 mL/kg/min, which was lower than 36.0 ± 7.8 mL/kg/min, p = 0.001, in controls and corresponded to 86.4% ± 20.0% of the population norm (VO2peak%) and to a standard deviation (VO2peakSD) of -1.08 ± 1.63 mL/kg/min of the population norm. VO2peak depended primarily on gender (p = 0.007) and on sleepiness (p = 0.046). VO2peak% depended on sleepiness (p = 0.028) and on age (p = 0.039). VO2peakSD depended on the number of cataplexy episodes per month (p = 0.015) and on age (p = 0.030). CONCLUSIONS: Cardiopulmonary fitness in narcolepsy and in narcolepsy without cataplexy is inversely related to the degree of sleepiness and cataplexy episode frequency.

Perioperative risks of narcolepsy in patients undergoing general anesthesia: A case-control study.

STUDY OBJECTIVE: To compare the perioperative outcomes between patients with narcolepsy and matched controls undergoing anesthetic management. DESIGN: Retrospective 2:1 matched study design. SETTING: Large tertiary medical center. PATIENTS: Narcoleptic patients who underwent general anesthesia from January 1, 2011, through September 30, 2015, were matched with controls by age, sex, and type and year of surgery. MEASUREMENTS: Medical records were reviewed for episodes of respiratory depression during phase I recovery and for other meaningful perioperative outcomes. MAIN RESULTS: The perioperative courses of 76 narcoleptic patients and their controls were examined. Compared to controls, narcoleptic patients were more often prescribed central nervous system stimulants (73.7% vs 4.0%, P<0.001) and antidepressants (46.1% vs 27.6%, P=0.007) and more often had obstructive sleep apnea (40.8% vs 19.1%, P<0.001). The intraoperative course was similar. The number of episodes of respiratory depression was not different between patients and controls (5 [6.6%] vs 12 [7.9%], respectively; P=0.80). Narcoleptic patients had a higher frequency of emergency response team activations (5 of 76 [6.6%]; 95% CI, 2.2%-14.7%) compared to controls (2 of 152 [1.3%]; 95% CI, 0.2%-4.7%) (P=0.04). Hemodynamic instability was the indication for all emergency response team activations except 1, which was for a narcoleptic patient who had excessive postoperative sedation and respiratory depression. CONCLUSIONS: Narcoleptic patients had similar intraoperative courses as the matched controls, including phase I anesthetic recovery. However, they had a higher rate of emergency response team activations than the controls, which suggests that patients with narcolepsy may be at increased perioperative risk.

Smoking Prevalence and Its Clinical Correlations in Patients with Narcolepsy-cataplexy.

Narcolepsy-cataplexy (NC) is a chronic neurological disease with suggested autoimmune etiopathogenesis. Nicotine stimulates central nervous system and smoking increases the risk of autoimmune diseases. Assessment of smoking habits and its correlation to clinical parameters among 87 adult NC patients (38 male, 49 female) included night polysomnography and multiple sleep latency test. In our sample, 43.7% NC patients were regular smokers, and 19.5% former smokers compared to 22.2%, and 12.6%, respectively, in the general population. Patients started to smoke in the mean age of 20.0 (SD ±6.0) years. 72.2% of NC smokers started to smoke before the onset of NC and the mean of the delay between smoking onset and NC onset was 9.1 (±5.8) years. We found a direct correlation between smoking duration and the number of awakenings, duration of N1 sleep, REM sleep latency, and apnoea/hypopnoea index (AHI), and, on the contrary, indirect correlation between smoking duration and N3 sleep duration, showing that smoking duration consistently correlates with sleep macrostructure. Smoking is highly prevalent in NC and has relationship with clinical features of NC.

Design and Synthesis of Non-Peptide, Selective Orexin Receptor 2 Agonists.

Orexins are a family of neuropeptides that regulate sleep/wakefulness, acting on two G-protein-coupled receptors, orexin receptors 1 (OX1R) and 2 (OX2R). Genetic and pharmacologic evidence suggests that orexin receptor agonists, especially OX2R agonist, will be useful for mechanistic therapy of the sleep disorder narcolepsy/cataplexy. We herein report the discovery of a potent (EC50 on OX2R is 0.023 µM) and OX2R-selective (OX1R/OX2R EC50 ratio is 70) agonist, 4'-methoxy-N,N-dimethyl-3'-[N-(3-{[2-(3-methylbenzamido)ethyl]amino}phenyl)sulfamoyl]-(1,1'-biphenyl)-3-carboxamide 26.

Orexin neurons suppress narcolepsy via 2 distinct efferent pathways.

The loss of orexin neurons in humans is associated with the sleep disorder narcolepsy, which is characterized by excessive daytime sleepiness and cataplexy. Mice lacking orexin peptides, orexin neurons, or orexin receptors recapitulate human narcolepsy phenotypes, further highlighting a critical role for orexin signaling in the maintenance of wakefulness. Despite the known role of orexin neurons in narcolepsy, the precise neural mechanisms downstream of these neurons remain unknown. We found that targeted restoration of orexin receptor expression in the dorsal raphe (DR) and in the locus coeruleus (LC) of mice lacking orexin receptors inhibited cataplexy-like episodes and pathological fragmentation of wakefulness (i.e., sleepiness), respectively. The suppression of cataplexy-like episodes correlated with the number of serotonergic neurons restored with orexin receptor expression in the DR, while the consolidation of fragmented wakefulness correlated with the number of noradrenergic neurons restored in the LC. Furthermore, pharmacogenetic activation of these neurons using designer receptor exclusively activated by designer drug (DREADD) technology ameliorated narcolepsy in mice lacking orexin neurons. These results suggest that DR serotonergic and LC noradrenergic neurons play differential roles in orexin neuron-dependent regulation of sleep/wakefulness and highlight a pharmacogenetic approach for the amelioration of narcolepsy.

A review of sodium oxybate and baclofen in the treatment of sleep disorders.

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.

Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate.

This study investigates the response of the underlying sleep disorder associated with Chronic Fatigue Syndrome (CFS) and fibromyalgia (FM) to treatment. We retrospectively reviewed 118 cases clinically consistent with CFS or FM, treated in a neurology practice. Abnormal findings on sleep studies and associated human leukocyte antigen markers, and a clinical pattern suggestive of narcolepsy, are present in a high proportion of patients. When considered appropriate based on the clinical picture and test results, treatment with sodium oxybate was offered to these patients. Sixty percent of patients treated with oxybate experienced significant relief of pain, while 75% experienced significant relief of fatigue. We postulate that the response to oxybate in CFS and FM suggests a disturbance of sleep similar to narcolepsy. These findings support this novel approach to intervention and further research. The inability to distinguish CFS and FM by testing and response to treatment suggests that they may represent variations of the same disorder or may be closely related disorders.

Effects of paraxanthine and caffeine on sleep, locomotor activity, and body temperature in orexin/ataxin-3 transgenic narcoleptic mice.

STUDY OBJECTIVE: Caffeine, an adenosine A1 and A2a receptor antagonist, is a widely consumed stimulant and also used for the treatment of hypersomnia; however, the wake-promoting potency of caffeine is often not strong enough, and high doses may induce side effects. Caffeine is metabolized to paraxanthine, theobromine, and theophylline. Paraxanthine is a central nervous stimulant and exhibits higher potency at A1 and A2 receptors, but has lower toxicity and lesser anxiogenic effects than caffeine. DESIGN: We evaluated the wake-promoting efficacy of paraxanthine, caffeine, and a reference wake-promoting compound, modafinil, in a mice model of narcolepsy, a prototypical disease model of hypersomnia. Orexin/ataxin-3 transgenic (TG) and wild-type (WT) mice were subjected to oral administration (at ZT 2 and ZT14) of 3 doses of paraxanthine, caffeine, modafinil, or vehicle. RESULTS: Paraxanthine, caffeine, and modafinil significantly promoted wakefulness in both WT and narcoleptic TG mice and proportionally reduced NREM and REM sleep in both genotypes. The wake-promoting potency of 100 mg/kg p.o. of paraxanthine during the light period administration roughly corresponds to that of 200 mg/kg p.o. of modafinil. The wake-promoting potency of paraxanthine is greater and longer lasting than that of the equimolar concentration of caffeine, when the drugs were administered during the light period. The wake-promotion by paraxanthine, caffeine, and modafinil are associated with an increase in locomotor activity and body temperature. However, the higher doses of caffeine and modafinil, but not paraxanthine, induced hypothermia and reduced locomotor activity, thereby confirming the lower toxicity of paraxanthine. Behavioral evaluations of anxiety levels in WT mice revealed that paraxanthine induced less anxiety than caffeine did. CONCLUSIONS: Because it is also reported to provide neuroprotection, paraxanthine may be a better wake-promoting agent for hypersomnia associated with neurodegenerative diseases.