The use of modafinil for the treatment of fatigue in multiple sclerosis: A systematic review and meta-analysis of controlled clinical trials.

INTRODUCTION: Multiple sclerosis (MS) is a debilitating neurological condition affecting nearly one million people across the United States. Among the most prominent symptoms of the condition are excessive fatigue and daytime sleepiness. Numerous clinical trials have investigated the efficacy of modafinil in addressing fatigue among these patients. OBJECTIVE: The objective of the present study is to assess the safety and efficacy of modafinil for the treatment of fatigue in MS. METHODOLOGY: An electronic search of PUBMED, ScienceDirect, and Cochrane Central was conducted for articles published from inception to December 2023 using search terms such as "modafinil," "fatigue," and "MS." RESULTS: Seven studies were included in our analysis. Modafinil leads to a meaningful reduction in fatigue when compared with placebo, as measured by Modified Fatigue Impact Scale [mean difference (MD) = -4.42 [-8.01, -.84]; I2 = 45%; p = .02] and Epworth Sleepiness Scale [MD = -.87 [-1.64, -.10]; I2 = 0%; p = .03]. Modafinil also demonstrated a greater risk of precipitating adverse events (e.g., insomnia, gastrointestinal symptoms) when compared with placebo [RR = 1.30 [1.03, 1.66]; I2 = 0%; p = .03]. In quality-of-life assessments, modafinil was associated with overall improvement in well-being [standardized mean difference = .18 [.01, .35]; I2 = 56%; p = .04]. CONCLUSION: The data indicates that modafinil confers a therapeutic benefit when treating fatigue in patients with MS and improves overall quality of life; however, there is a risk of precipitating adverse events. Ultimately, higher quality of evidence may be required to better inform clinical management.

Tackling obstructive sleep apnea with pharmacotherapeutics: expert guidance.

INTRODUCTION: The efficacy of non-pharmacotherapeutic treatment of obstructive sleep apnea, a highly prevalent condition with serious cardiometabolic and neurocognitive health consequences, is well established. Supplementing traditional treatment strategies with medications can improve symptoms and reduce side effects. Efforts to identify medications that target the causes of sleep apnea have met with mixed success. However, this remains a worthwhile objective for researchers to pursue, given the potential benefit pharmacotherapy could bring to those patients who reject or struggle to adhere to existing treatments. AREAS COVERED: This article presents the case for obstructive sleep apnea pharmacotherapy including drugs that reduce the occurrence of apnea events, such as weight loss agents, ventilation activators and muscle and nervous system stimulants, drugs that alleviate symptoms, such as wake-promoting agents for excessive daytime sleepiness, and drugs that improve adherence to existing treatments, such as hypnotics. Literature was accessed from PubMed between 1 March 2024 and 18 April 2024. EXPERT OPINION: Exciting recent advances in both our understanding of obstructive sleep apnea pathology and in the techniques used to identify therapeutic agents and their targets combine to embolden a positive outlook for the expanded use of drugs in tackling this consequential disease.

Modafinil Subjectively Does Not Impair Sleep in Aviators After a Period of Extended Wakefulness.

INTRODUCTION: Modafinil is used as a countermeasure to limit the effects of fatigue in military aviation. However, literature is conflicting about its negative effects on subsequent sleep.METHODS: This randomized placebo-controlled trial conducted by the Center of Man in Aviation of the Royal Netherlands Airforce is part of a larger study. It included 32 subjects (mean age 35 yr old, 84% male) who followed a normal daily routine and stayed awake the subsequent night. At midnight, all subjects received either 300 mg caffeine, 200 mg modafinil, or placebo. At the end of the test night, subjects were awake for a median period of 26 h. Afterwards, sleep questionnaires containing qualitative (Groningen Sleep Quality Scale) and quantitative parameters of sleep for the subsequent day (recovery sleep) and consecutive night (post-test sleep) were completed and statistically analyzed using Friedman and Wilcoxon signed rank tests.RESULTS: A statistically significant difference in the reported recovery sleep was observed. The modafinil group slept 30% shorter than placebo, but sleep efficiency was not statistically different. Quantitatively post-test sleep did not vary statistically significantly between the three groups. However, Groningen Sleep Quality Scale scores were lower post-test than pre-test in the modafinil group, while this was not the case in the caffeine and placebo group.DISCUSSION:This study found that modafinil subjectively does not negatively impact recovery sleep or subsequent nighttime sleep after an extended period of wakefulness and suggests it may decrease the need for recovery sleep compared to placebo or caffeine.Wingelaar-Jagt YQ, Wingelaar TT, Riedel WJ, Ramaekers JG. Modafinil subjectively does not impair sleep in aviators after a period of extended wakefulness. Aerosp Med Hum Perform. 2024; 95(6):290-296.

[Wakefulness-promoting agents for severe fatigue: to use or not to use?] / Medicatie tegen ernstige aanhoudende vermoeidheid.

About 20% of adults experience excessive daytime sleepiness or severe fatigue. Causes include somatic conditions, psychiatric disorders, and medication or drug use. Treatment depends on the underlying cause. If sleepiness persists despite optimal treatment of the underlying condition, exclusion of other causes, and behavioral interventions, wakefulness-promoting agents may be considered. However, no established pharmacological strategy exists for symptomatic treatment. Modafinil and stimulants like methylphenidate may offer some benefit based on experiences with narcolepsy or idiopathic hypersomnia. Studies in specific patient groups (e.g., multiple sclerosis, Parkinson's disease, traumatic brain injury, cancer-related fatigue) show variable results. The use of wakefulness-promoting agents is discouraged for addressing unexplained fatigue, as seen in the context of chronic fatigue syndrome.

Effects of modafinil on nocturnal sleep patterns in patients with narcolepsy: A cohort study.

BACKGROUND: Patients with narcolepsy often experience disturbed nighttime sleep. Modafinil is commonly prescribed for hypersomnolence, but its impacts on nocturnal sleep remain unclear. This study uses actigraphy to examine the effect of modafinil on both hypersomnolence and nocturnal sleep patterns in patients with narcolepsy. METHODS: Prior to treatment, 87 patients with narcolepsy wore an actigraphy for 7-14 days to assess their nighttime sleep. After evaluation, they received a daily dose of 200-400 mg of modafinil in the morning and wore an actigraphy again six months after initiating treatment. Questionnaires, including the Epworth-Sleepiness-Scale (ESS), the Visual-Analogue-for-Hypersomnolence (VAS), and the Short-Form-36-Health-Survey (SF-36), were used to evaluate hypersomnolence and quality of life both before and after treatment. Paired t-tests and independent samples t-tests were used for pre- and post-treatment comparisons and subgroup analysis. We used the Pearson's correlation test to measure the correlations between the sleep parameters of the actigraphy and data of the questionnaires. RESULTS: Improvements in hypersomnolence were noted following modafinil treatment, and we observed no significant deterioration in nocturnal sleep parameters by the actigraphy. The total number of awakenings by actigraphy significantly decreased (p = 0.005), especially in females (p = 0.008), while sleep onset latency significantly increased in children/adolescents (p = 0.014). Correlations were found between the sleep parameters of the actigraphy and ESS, VAS, and SF-36 scores. CONCLUSION: Modafinil treatment may not worsen nighttime sleep in patients with narcolepsy. However, it should be administered with care in children and adolescents.

Modafinil Therapy and Mental Status Following Aneurysmal Subarachnoid Hemorrhage: Comprehensive Stroke Center Analysis.

BACKGROUND: Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating fatigue in stroke survivors, but data pertaining to its use in the acute setting are scarce. This study sought to assess the effects of modafinil use on mental status after aSAH. METHODS: Modafinil timing and dosage, neurological examination, intubation status, and physical and occupational therapy participation were documented. Repeated-measures paired tests were used for a before-after analysis of modafinil recipients. Propensity score matching (1:1 nearest neighbor) for modafinil and no-modafinil cohorts was used to compare outcomes. RESULTS: Modafinil (100-200 mg/day) was administered to 21% (88/422) of aSAH patients for a median (IQR) duration of 10.5 (4-16) days and initiated 14 (7-17) days after aSAH. Improvement in mentation (alertness, orientation, or Glasgow Coma Scale score) was documented in 87.5% (77/88) of modafinil recipients within 72 hours and 86.4% (76/88) at discharge. Of 37 intubated patients, 10 (27%) were extubated within 72 hours after modafinil initiation. Physical and occupational therapy teams noted increased alertness or participation in 47 of 56 modafinil patients (83.9%). After propensity score matching for baseline covariates, the modafinil cohort had a greater mean (SD) change in Glasgow Coma Scale score than the no-modafinil cohort at discharge (2.2 [4.0] vs. -0.2 [6.32], P = 0.003). CONCLUSIONS: A temporal relationship with improvement in mental status was noted for most patients administered modafinil after aSAH. These findings, a favorable adverse-effect profile, and implications for goals-of-care decisions favor a low threshold for modafinil initiation in aSAH patients in the acute-care setting.

Narcolepsy Severity Scale-2 and Idiopathic Hypersomnia Severity Scale to better quantify symptoms severity and consequences in Narcolepsy type 2.

STUDY OBJECTIVES: Narcolepsy type 2 (NT2) is an understudied central disorder of hypersomnolence sharing some similarities with narcolepsy type 1 and idiopathic hypersomnia (IH). We aimed: (1) to assess systematically the symptoms in patients with NT2, with self-reported questionnaires: Epworth Sleepiness Scale (ESS), Narcolepsy Severity Scale (NSS), IH Severity Scale (IHSS), and (2) to evaluate the responsiveness of these scales to treatment. METHODS: One hundred and nine patients with NT2 (31.4 ±â€…12.2 years old, 47 untreated) diagnosed according to ICSD-3 were selected in a Reference Center for Narcolepsy. They all completed the ESS, subgroups completed the modified NSS (NSS-2, without cataplexy items) (n = 95) and IHSS (n = 76). Some patients completed the scales twice (before/during treatment): 42 ESS, 26 NSS-2, and 30 IHSS. RESULTS: Based on NSS-2, all untreated patients had sleepiness, 58% disrupted nocturnal sleep, 40% hallucinations, and 28% sleep paralysis. On IHSS, 76% reported a prolonged nocturnal sleep, and 83% sleep inertia. In the independent sample, ESS and NSS-2 scores were lower in treated patients, with same trend for IHSS scores. After treatment, ESS, NSS-2, and IHSS total scores were lower, with a mean difference of 3.7 ±â€…4.1, 5.3 ±â€…6.7, and 4.1 ±â€…6.2, respectively. The minimum clinically important difference between untreated and treated patients were 2.1 for ESS, 3.3 for NSS-2, and 3.1 for IHSS. After treatment, 61.9% of patients decreased their ESS > 2 points, 61.5% their NSS-2 > 3 points, and 53.3% their IHSS > 3 points. CONCLUSIONS: NSS-2 and IHSS correctly quantified symptoms' severity and consequences in NT2, with good performances to objectify response to medications. These tools are useful for monitoring and optimizing NT2 management, and for use in clinical trials.

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

OBJECTIVE: The Transition Experience of persons with Narcolepsy taking Oxybate in the Real-world (TENOR) study assessed the real-world experience of people with narcolepsy switching from sodium oxybate (SXB) to low-sodium oxybate (LXB; 92 % less sodium than SXB). METHODS: TENOR is a patient-centric, prospective, observational, virtual-format study. Eligible participants included US adults with narcolepsy transitioning from SXB to LXB (±7 days from LXB initiation). Longitudinal data were collected from baseline (taking SXB) through 21 weeks post-transition. RESULTS: TENOR included 85 participants with narcolepsy (type 1, n = 45; type 2, n = 40). Mean (SD) age was 40.3 (13.0) years; the majority (73 %) were female and White (87 %). At study completion, wake-promoting agents were the most common concomitant medications (47 %). Mean (SD) SXB treatment duration was 57.8 (52.1) months; 96 % took SXB twice nightly. After transitioning, 97 % continued on twice-nightly regimens. Mean (SD) dose of both total nightly SXB (n = 85) and baseline LXB (n = 84) was 7.7 (1.5) g; SXB-LXB dose conversions at baseline were gram-for-gram in 87 % of participants. The mean final total nightly dose of LXB was 7.9 g. The most common participant-reported reasons for transitioning included lower sodium content for improved long-term health (93 %), physician recommendation (47 %), to avoid cardiovascular issues (39 %), to avoid side effects (31 %), and to improve control of narcolepsy symptoms (18 %). CONCLUSION: Most participants transitioned from SXB to LXB using a gram-for-gram strategy. The most commonly cited reason for transition was long-term health benefits due to lower sodium.

Recovery Mimicking “Ideal” CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents

Introduction: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. Methods: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic “ideal” continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. Results: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. Conclusion: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition. (AU)

Recovery Mimicking "Ideal" CPAP Adherence Does Not Improve Wakefulness or Cognition in Chronic Murine Models of OSA: Effect of Wake-Promoting Agents.

INTRODUCTION: Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS. METHODS: Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic "ideal" continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments. RESULTS: IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL. CONCLUSION: Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition.

Comparative Efficacy and Safety of Wakefulness-Promoting Agents for Excessive Daytime Sleepiness in Patients With Obstructive Sleep Apnea : A Systematic Review and Network Meta-analysis.

BACKGROUND: Excessive daytime sleepiness (EDS) is common among patients with obstructive sleep apnea (OSA). The comparative effectiveness of pharmacologic agents is unknown. PURPOSE: To compare the effectiveness of drugs for EDS in OSA using network meta-analysis. DATA SOURCES: MEDLINE, CENTRAL, EMBASE, and ClinicalTrials.gov to 7 November 2022. STUDY SELECTION: Reviewers identified randomized trials that enrolled patients with EDS-associated OSA on or eligible for conventional therapy assigned to any pharmacologic intervention. DATA EXTRACTION: Paired reviewers independently extracted data addressing effects of drugs on the Epworth Sleepiness Scale (ESS), Maintenance of Wakefulness Test (MWT), and adverse events at the longest reported follow-up. The certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. DATA SYNTHESIS: Fourteen trials (3085 patients) were eligible. At 4 weeks, compared with placebo, solriamfetol improves ESS scores (mean difference [MD], -3.85 [95% CI, -5.24 to -2.50]; high certainty), and armodafinil-modafinil (MD, -2.25 [CI, -2.85 to -1.64]; moderate certainty) and pitolisant-H3-autoreceptor blockers (MD, -2.78 [CI, -4.03 to -1.51]; moderate certainty) probably improve ESS scores. At 4 weeks, compared with placebo, solriamfetol (standardized mean difference [SMD], 0.9 [CI, 0.64 to 1.17]) and armodafinil-modafinil (SMD, 0.41 [CI, 0.27 to 0.55]) improve MWT (both high certainty), whereas pitolisant-H3-autoreceptor blockers probably do not (moderate certainty). At 4 weeks, armodafinil-modafinil probably increases the risk for discontinuation due to adverse events (relative risk [RR], 2.01 [CI, 1.14 to 3.51]; moderate certainty); solriamfetol may increase the risk for discontinuation due to adverse events (RR, 2.07 [CI, 0.67 to 6.25]; low certainty). Low certainty evidence suggests these interventions may not increase the risk for serious adverse events. LIMITATIONS: There is limited evidence on long term or effectiveness among patients nonadherent or with mixed adherence to conventional OSA therapies. CONCLUSION: Solriamfetol, armodafinil-modafinil, and pitolisant reduce daytime sleepiness for patients with OSA already on conventional therapy, with solriamfetol likely superior. Adverse events probably increase the risk for discontinuation of armodafinil-modafinil and may increase the risk for discontinuation with solriamfetol. PRIMARY FUNDING SOURCE: None.

Solriamfetol Titration & AdministRaTion (START) in Patients With Narcolepsy.

PURPOSE: 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. METHODS: 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. FINDINGS: 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. IMPLICATIONS: 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.

Paediatric narcolepsy: a review of diagnosis and management.

Narcolepsy is a chronic disabling neurological sleep disorder that requires lifelong treatment. We have outlined the clinical features of narcolepsy, the assessment and diagnosis process and have summarised the existing treatment options for children and adolescents with narcolepsy. In the future, the approach to management of paediatric narcolepsy should ideally be in a multidisciplinary setting, involving specialists in sleep medicine, sleep physiology, neurologists and psychologists/psychiatrists. A multidisciplinary approach will help to manage the potential impact of narcolepsy on children and adolescents who are in a stage of their life that is critical to their physical, emotional and social development and their academic attainment.

Application of armodafinil-loaded microneedle patches against the negative influence induced by sleep deprivation.

Cognition maintenance is essential for healthy and safe life if sleep deprivation happens. Armodafinil is a wake-promoting agent against sleep deprivation related disorders. However, only the tablet formulation is available, which may limit its potential in some circumstances. Here, we report the synthesis of a new formulation of armodafinil, microneedle patches, which can be conveniently used by any individual and removed in time if not wanted. To produce the needles of higher mechanical strength and higher drug loading, polyvinylpyrrolidone (PVP) K90 was used to fabricate armodafinil-loaded microneedles by applying the mold casting method after dissolving in methanol and drying. The higher mechanical strength was validated by COMSOL Multiphysics® software stimulation and universal mechanical testing machines. The obtained armodafinil microneedles can withstand a force of 70 N and penetrate the skin to a depth of 230 µm, and quickly released the drug within 1.5 h in vitro. The pharmacokinetic analysis showed that microneedle administration can maintain a more lasting and stable blood concentration as compared to oral administration. After the treatment of sleep deprived mice with microneedles, the in vivo pharmacodynamics study clearly demonstrated that armodafinil microneedles could eliminate the effects of sleep deprivation and improve the cognitive functions of sleep-deprived mice. A self-administered, high drug-loaded microneedle patch were prepared successfully, which appeared to be highly promising in preserving cognition by transdermal administration.

Pitolisant, a wake-promoting agent devoid of psychostimulant properties: Preclinical comparison with amphetamine, modafinil, and solriamfetol.

Several therapeutic options are currently available to treat excessive daytime sleepiness (EDS) in patients suffering from narcolepsy or obstructive sleep apnea. However, there are no comparisons between the various wake-promoting agents in terms of mechanism of action, efficacy, or safety. The goal of this study was to compare amphetamine, modafinil, solriamfetol, and pitolisant at their known primary pharmacological targets, histamine H3 receptors (H3R), dopamine, norepinephrine, and serotonin transporters, and in various in vivo preclinical models in relation to neurochemistry, locomotion, behavioral sensitization, and food intake. Results confirmed that the primary pharmacological effect of amphetamine, modafinil, and solriamfetol was to increase central dopamine neurotransmission, in part by inhibiting its transporter. Furthermore, solriamfetol increased levels of extracellular dopamine in the nucleus accumbens, and decreased the 3,4-dihydroxyphenyl acetic acid (DOPAC)/DA ratio in the striatum, as reported for modafinil and amphetamine. All these compounds produced hyperlocomotion, behavioral sensitization, and hypophagia, which are common features of psychostimulants and of compounds with abuse potential. In contrast, pitolisant, a selective and potent H3R antagonist/inverse agonist that promotes wakefulness, had no effect on striatal dopamine, locomotion, or food intake. In addition, pitolisant, devoid of behavioral sensitization by itself, attenuated the hyperlocomotion induced by either modafinil or solriamfetol. Therefore, pitolisant presents biochemical, neurochemical, and behavioral profiles different from those of amphetamine and other psychostimulants such as modafinil or solriamfetol. In conclusion, pitolisant is a differentiated therapeutic option, when compared with psychostimulants, for the treatment of EDS, as this agent does not show any amphetamine-like properties within in vivo preclinical models.

Residual excessive daytime sleepiness in patients treated for obstructive sleep apnea: guidance for assessment, diagnosis, and management.

Excessive daytime sleepiness (EDS) affects approximately half of patients with obstructive sleep apnea (OSA) and can persist in some despite normalization of breathing, oxygenation, and sleep quality with primary OSA therapy, such as continuous positive airway pressure (CPAP). EDS is often overlooked and under discussed in the primary care setting and in the follow-up of CPAP-treated patients due to difficult assessment of such a multi-dimensional symptom. This review aims to provide suggestions for procedures that can be implemented into routine clinical practice to identify, evaluate, and manage EDS in patients treated for OSA, including how to appropriately use various self-report and objective assessments along the clinical pathway and options for pharmacotherapy. In addition, examples of when it is appropriate to refer a patient to a sleep specialist for evaluation are discussed.

Medications for daytime sleepiness in individuals with idiopathic hypersomnia.

BACKGROUND: Idiopathic hypersomnia is a disorder of excessive daytime sleepiness, often accompanied by long sleep times or pronounced difficulty in awakening, in the absence of a known cause. The optimal treatment strategy for idiopathic hypersomnia is currently unknown. OBJECTIVES: To assess the effects of medications for daytime sleepiness and related symptoms in individuals with idiopathic hypersomnia and, in particular, whether medications may: 1. reduce subjective measures of sleepiness; 2. reduce objective measures of sleepiness; 3. reduce symptoms of cognitive dysfunction; 4. improve quality of life; and 5. be associated with adverse events. SEARCH METHODS: We searched the following databases on 4 February 2021: Cochrane Register of Studies (CRS Web), MEDLINE (Ovid, 1946 to 1 February 2021), and reference lists of articles. CRS Web includes randomized or quasi-randomized controlled trials from PubMed, Embase, ClinicalTrials.gov, the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), the Cochrane Central Register of Controlled Trials (CENTRAL), and the specialized registers of Cochrane Review Groups, including the Cochrane Epilepsy Group. We previously searched the WHO ICTRP separately when loading of ICTRP records into CRS Web was temporarily suspended. SELECTION CRITERIA: Randomized studies comparing any medication to placebo, another medication, or a behavioral intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We contacted study authors for additional data. We collected data on adverse events from the included trials. MAIN RESULTS: We included three trials, with a total of 112 participants. Risk of bias was low for the included studies. Two pharmaceutical company-sponsored trials compared modafinil with placebo, involving 102 participants, nearly all of whom had idiopathic hypersomnia without long sleep time. Modafinil significantly improved self-reported sleepiness on the Epworth Sleepiness Scale by 5.08 points more than placebo (95% confidence interval (CI) 3.01 to 7.16; 2 studies, 101 participants; high-certainty evidence). Modafinil also significantly improved disease severity on the Clinical Global Impression of Severity scale by 1.02 points (95% CI 0.11 to 1.93; 1 study, 30 participants; moderate-certainty evidence) and resulted in a greater proportion of participants who were "much improved" or "very much improved" on the Clinical Global Impression of Change (odds ratio (OR) for improvement 5.14, 95% CI 1.76 to 15.00; 1 study, 70 participants; moderate-certainty evidence). Ability to remain awake on the Maintenance of Wakefulness Test was significantly improved with modafinil, by 4.74 minutes more than with placebo (95% CI 2.46 to 7.01; 2 studies, 99 participants; high-certainty evidence). Ratings of exhaustion and effectiveness/performance were improved with modafinil compared to placebo in one study. Number of naps per week was no different between modafinil and placebo across two studies. Participants receiving modafinil experienced more side effects, although the difference did not reach statistical significance (OR 1.68, 95% CI 0.28 to 9.94; 2 studies, 102 participants; low-certainty evidence). One trial studying 20 participants with different disorders of sleepiness included 10 participants with idiopathic hypersomnia, with or without long sleep time, and compared clarithromycin to placebo. We only included the subset of trial data for those participants with idiopathic hypersomnia, per our protocol. There were no significant differences between clarithromycin and placebo for the Epworth Sleepiness Scale, psychomotor vigilance testing, sleep inertia, other subjective ratings, or side effects. AUTHORS' CONCLUSIONS: Modafinil is effective for the treatment of several aspects of idiopathic hypersomnia symptomatology, based on studies predominantly including participants with idiopathic hypersomnia without long sleep times, with low risk of bias, and evidence certainty ranging from high to low. There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia. There is a clear need for additional studies testing interventions for the treatment of idiopathic hypersomnia.

A practical guide to the pharmacological and behavioral therapy of Narcolepsy.

Narcolepsy is a rare, chronic, and disabling central nervous system hypersomnia; two forms can be recognized: narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2). Its etiology is still largely unknown, but studies have reported a strong association between NT1 and HLA, as well as a pathogenic association with the deficiency of cerebrospinal hypocretin-1. Thus, the most reliable pathogenic hypothesis is an autoimmune process destroying hypothalamic hypocretin-producing cells. A definitive cure for narcolepsy is not available to date, and although the research in the field is highly promising, up to now, current treatments have aimed to reduce the symptoms by means of different pharmacological approaches. Moreover, overall narcolepsy symptoms management can also benefit from non-pharmacological approaches such as cognitive behavioral therapies (CBTs) and psychosocial interventions to improve the patients' quality of life in both adult and pediatric-affected individuals as well as the well-being of their families. In this review, we summarize the available therapeutic options for narcolepsy, including the pharmacological, behavioral, and psychosocial interventions.

Idiopathic Hypersomnia and Other Hypersomnia Syndromes.

There are numerous disorders of known or presumed neurologic origin that result in excessive daytime sleepiness, collectively known as the central disorders of hypersomnolence. These include narcolepsy types 1 and 2, idiopathic hypersomnia, Kleine-Levin syndrome, and hypersomnia due to or associated with medical disease, neurologic disease, psychiatric disease, medications or substances, and insufficient sleep durations. This chapter focuses on the treatment of nonnarcoleptic hypersomnia syndromes, from those that are commonly encountered in neurologic practice, such as hypersomnia due to Parkinson's disease, to those that are exceedingly rare but present with dramatic manifestations, such as Kleine-Levin syndrome. The level of evidence for the treatment of sleepiness in these disorders is generally lower than in the well-characterized syndrome of narcolepsy, but available clinical and randomized, controlled trial data can provide guidance for the management of each of these disorders. Treatments vary by diagnosis but may include modafinil/armodafinil, traditional psychostimulants, solriamfetol, pitolisant, clarithromycin, flumazenil, sodium oxybate, melatonin, methylprednisolone, and lithium.