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Neurotherapeutics : the Journal of the... Jan 2021There are numerous disorders of known or presumed neurologic origin that result in excessive daytime sleepiness, collectively known as the central disorders of... (Review)
Review
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.
Topics: Central Nervous System Stimulants; Disorders of Excessive Somnolence; Humans; Idiopathic Hypersomnia; Wakefulness-Promoting Agents
PubMed: 32901432
DOI: 10.1007/s13311-020-00919-1 -
American Family Physician Nov 2008Fatigue, a common presenting symptom in primary care, negatively impacts work performance, family life, and social relationships. The differential diagnosis of fatigue... (Review)
Review
Fatigue, a common presenting symptom in primary care, negatively impacts work performance, family life, and social relationships. The differential diagnosis of fatigue includes lifestyle issues, physical conditions, mental disorders, and treatment side effects. Fatigue can be classified as secondary to other medical conditions, physiologic, or chronic. The history and physical examination should focus on identifying common secondary causes (e.g., medications, anemia, pregnancy) and life-threatening problems, such as cancer. Results of laboratory studies affect management in only 5 percent of patients, and if initial results are normal, repeat testing is generally not indicated. Treatment of all types of fatigue should include a structured plan for regular physical activity that consists of stretching and aerobic exercise, such as walking. Caffeine and modafinil may be useful for episodic situations requiring alertness. Short naps are proven performance enhancers. Selective serotonin reuptake inhibitors, such as fluoxetine, paroxetine, or sertraline, may improve energy in patients with depression. Patients with chronic fatigue may respond to cognitive behavior therapy. Scheduling regular follow-up visits, rather than sporadic urgent appointments, is recommended for effective long-term management.
Topics: Behavior Therapy; Benzhydryl Compounds; Caffeine; Central Nervous System Stimulants; Chronic Disease; Fatigue; Female; Humans; Male; Modafinil; Primary Health Care; Sleep; Surveys and Questionnaires
PubMed: 19035066
DOI: No ID Found -
JAMA Oncology Jul 2017Cancer-related fatigue (CRF) remains one of the most prevalent and troublesome adverse events experienced by patients with cancer during and after therapy. (Comparative Study)
Comparative Study Meta-Analysis Review
IMPORTANCE
Cancer-related fatigue (CRF) remains one of the most prevalent and troublesome adverse events experienced by patients with cancer during and after therapy.
OBJECTIVE
To perform a meta-analysis to establish and compare the mean weighted effect sizes (WESs) of the 4 most commonly recommended treatments for CRF-exercise, psychological, combined exercise and psychological, and pharmaceutical-and to identify independent variables associated with treatment effectiveness.
DATA SOURCES
PubMed, PsycINFO, CINAHL, EMBASE, and the Cochrane Library were searched from the inception of each database to May 31, 2016.
STUDY SELECTION
Randomized clinical trials in adults with cancer were selected. Inclusion criteria consisted of CRF severity as an outcome and testing of exercise, psychological, exercise plus psychological, or pharmaceutical interventions.
DATA EXTRACTION AND SYNTHESIS
Studies were independently reviewed by 12 raters in 3 groups using a systematic and blinded process for reconciling disagreement. Effect sizes (Cohen d) were calculated and inversely weighted by SE.
MAIN OUTCOMES AND MEASURES
Severity of CRF was the primary outcome. Study quality was assessed using a modified 12-item version of the Physiotherapy Evidence-Based Database scale (range, 0-12, with 12 indicating best quality).
RESULTS
From 17 033 references, 113 unique studies articles (11 525 unique participants; 78% female; mean age, 54 [range, 35-72] years) published from January 1, 1999, through May 31, 2016, had sufficient data. Studies were of good quality (mean Physiotherapy Evidence-Based Database scale score, 8.2; range, 5-12) with no evidence of publication bias. Exercise (WES, 0.30; 95% CI, 0.25-0.36; P < .001), psychological (WES, 0.27; 95% CI, 0.21-0.33; P < .001), and exercise plus psychological interventions (WES, 0.26; 95% CI, 0.13-0.38; P < .001) improved CRF during and after primary treatment, whereas pharmaceutical interventions did not (WES, 0.09; 95% CI, 0.00-0.19; P = .05). Results also suggest that CRF treatment effectiveness was associated with cancer stage, baseline treatment status, experimental treatment format, experimental treatment delivery mode, psychological mode, type of control condition, use of intention-to-treat analysis, and fatigue measures (WES range, -0.91 to 0.99). Results suggest that the effectiveness of behavioral interventions, specifically exercise and psychological interventions, is not attributable to time, attention, and education, and specific intervention modes may be more effective for treating CRF at different points in the cancer treatment trajectory (WES range, 0.09-0.22).
CONCLUSIONS AND RELEVANCE
Exercise and psychological interventions are effective for reducing CRF during and after cancer treatment, and they are significantly better than the available pharmaceutical options. Clinicians should prescribe exercise or psychological interventions as first-line treatments for CRF.
Topics: Benzhydryl Compounds; Central Nervous System Stimulants; Cognitive Behavioral Therapy; Dexmethylphenidate Hydrochloride; Dextroamphetamine; Exercise Therapy; Fatigue; Glucocorticoids; Humans; Methylphenidate; Methylprednisolone; Modafinil; Neoplasms; Paroxetine; Psychotherapy; Selective Serotonin Reuptake Inhibitors; Wakefulness-Promoting Agents
PubMed: 28253393
DOI: 10.1001/jamaoncol.2016.6914 -
CNS Drugs Jan 2020Narcolepsy is a chronic, disabling neurologic disorder characterised by excessive daytime sleepiness (EDS) and, in up to 60% of patients, cataplexy. Treatments for... (Review)
Review
Narcolepsy is a chronic, disabling neurologic disorder characterised by excessive daytime sleepiness (EDS) and, in up to 60% of patients, cataplexy. Treatments for narcolepsy are aimed at improving wakefulness (e.g. modafinil, armodafinil, stimulants), reducing cataplexy attacks (e.g. sodium oxybate, venlafaxine), and treating the symptoms of disturbed nocturnal sleep, sleep paralysis and sleep-related hallucinations (e.g. sodium oxybate). In general, medications that increase the release, or inhibit the reuptake, of norepinephrine or dopamine have wake-promoting effects and are useful in managing EDS, whereas medications that inhibit serotonin or norepinephrine reuptake have anticataplectic effects. Modulation of γ-aminobutyric acid B (GABA) receptors or histamine H receptors (H3Rs) has effects on both EDS and cataplexy. Pitolisant, an H3R antagonist, and solriamfetol, a dopamine and norepinephrine reuptake inhibitor, are the most recently approved treatments for EDS associated with narcolepsy in the European Union (pitolisant) and the USA (pitolisant and solriamfetol). Several new agents are being developed and tested as potential treatments for EDS and cataplexy associated with narcolepsy; these agents include novel oxybate formulations (once-nightly [FT218]; low sodium [JZP-258]), a selective norepinephrine reuptake inhibitor (AXS-12), and a product combining modafinil and an astroglial connexin inhibitor (THN102). This review summarises the mechanisms of action, pharmacokinetics, efficacy, and safety/tolerability of recently approved and emerging treatments for narcolepsy.
Topics: Animals; Central Nervous System Stimulants; Humans; Narcolepsy
PubMed: 31953791
DOI: 10.1007/s40263-019-00689-1 -
Journal of Sleep Research Dec 2021Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based... (Review)
Review
BACKGROUND AND PURPOSE
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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
PubMed: 34173288
DOI: 10.1111/jsr.13387 -
Annals of the American Thoracic Society May 2021Many patients with obstructive sleep apnea (OSA) experience excessive daytime sleepiness (EDS), which can negatively affect daily functioning, cognition, mood, and other... (Review)
Review
Many patients with obstructive sleep apnea (OSA) experience excessive daytime sleepiness (EDS), which can negatively affect daily functioning, cognition, mood, and other aspects of well-being. Although EDS can be reduced with primary OSA treatment, such as continuous positive airway pressure (CPAP) therapy, a significant proportion of patients continue to experience EDS despite receiving optimized therapy for OSA. This article reviews the pathophysiology and clinical evaluation and management of EDS in patients with OSA. The mechanisms underlying EDS in CPAP-treated patients remain unclear. Experimental risk factors include chronic intermittent hypoxia and sleep fragmentation, which lead to oxidative injury and changes in neurons and brain circuit connectedness involving noradrenergic and dopaminergic neurotransmission in wake-promoting regions of the brain. In addition, neuroimaging studies have shown alterations in the brain's white matter and gray matter in patients with OSA and EDS. Clinical management of EDS begins with ruling out other potential causes of EDS and evaluating its severity. Tools to evaluate EDS include objective and self-reported assessments of sleepiness, as well as cognitive assessments. Patients who experience residual EDS despite primary OSA therapy may benefit from wake-promoting pharmacotherapy. Agents that inhibit reuptake of dopamine or of dopamine and norepinephrine (modafinil/armodafinil and solriamfetol, respectively) have demonstrated efficacy in reducing EDS and improving quality of life in patients with OSA. Additional research is needed on the effects of wake-promoting treatments on cognition in these patients and to identify individual or disorder-specific responses.
Topics: Continuous Positive Airway Pressure; Disorders of Excessive Somnolence; Humans; Modafinil; Quality of Life; Sleep Apnea, Obstructive
PubMed: 33621163
DOI: 10.1513/AnnalsATS.202006-696FR -
The Cochrane Database of Systematic... Jan 2018Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is terminal, progressive neurological condition for which there are no curative... (Review)
Review
BACKGROUND
Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is terminal, progressive neurological condition for which there are no curative treatments. Among people with ALS/MND, fatigue is a common and debilitating symptom, which is characterised by reversible motor weakness and whole-body tiredness that is only partially relieved by rest. The effectiveness of pharmacological or non-pharmacological treatments for fatigue in ALS/MND is not yet established.
OBJECTIVES
To assess the effects of pharmacological and non-pharmacological interventions for fatigue in ALS/MND.
SEARCH METHODS
We searched the following databases on 5 September 2017: Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL Plus, and ERIC. We also searched two clinical trials registries.
SELECTION CRITERIA
We selected randomised and quasi-randomised controlled trials of any intervention which sought to reduce fatigue for people with ALS/MND. We included studies if reduction in fatigue was a primary or secondary outcome of the trial.
DATA COLLECTION AND ANALYSIS
We used the standard methodological procedures expected by Cochrane.
MAIN RESULTS
We included one pharmacological (modafinil) study and three non-pharmacological studies (resistance exercise, respiratory exercise, and repetitive transcranial magnetic stimulation (rTMS)), involving a total of 86 participants with ALS/MND. None of the included studies were free from risk of bias. Since there was only one trial for each intervention, no meta-analysis was possible. All studies assessed fatigue using the Fatigue Severity Scale (FSS; scale from 9 to 63, higher scores indicate more fatigue). Information for assessing bias was often lacking in study reports, making the risk of bias unclear across several domains in all trials. Blinding of participants was not possible in exercise trials, but the outcome assessment was blinded.We found very low-quality evidence suggesting possible improvements in fatigue for modafinil treatment versus placebo (MD -11.00, 95% CI -23.08 to 1.08), respiratory exercise versus a sham intervention (MD -9.65, 95% CI -22.04 to 2.73), and rTMS versus sham rTMS (data not provided), which warrant further investigation to clarify the efficacy of these treatments for fatigue in ALS/MND. We found no clear improvements in fatigue for resistance exercise versus usual care (MD 0.20, 95% CI -10.98 to 11.38; very low-quality evidence).Three participants in the modafinil group dropped out of the modafinil study, two citing issues with headache and one with chest tightness; other adverse effects were anxiety, nausea, dizziness, and sialorrhoea (probably ALS-related). The trials reported no adverse effects of exercise or rTMS.We cannot be certain about the effects of any of the interventions studied because of imprecision (small numbers of participants, wide CI), and possible study limitations.
AUTHORS' CONCLUSIONS
It is impossible to draw firm conclusions about the effectiveness of interventions to improve fatigue for people with ALS/MND as there are few randomised studies, and the quality of available evidence is very low.
Topics: Amyotrophic Lateral Sclerosis; Benzhydryl Compounds; Breathing Exercises; Fatigue; Humans; Modafinil; Randomized Controlled Trials as Topic; Resistance Training; Transcranial Magnetic Stimulation
PubMed: 29293261
DOI: 10.1002/14651858.CD011005.pub2 -
PloS One 2020Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Attention deficit hyperactivity disorder (ADHD) affects approximately 3% of adults globally. Many pharmacologic treatments options exist, yet the comparative benefits and harms of individual treatments are largely unknown. We performed a systematic review and network meta-analysis to assess the relative effects of individual pharmacologic treatments for adults with ADHD.
METHODS
We searched English-language published and grey literature sources for randomized clinical trials (RCTs) involving pharmacologic treatment of ADHD in adults (December 2018). The primary outcome was clinical response; secondary outcomes were quality of life, executive function, driving behaviour, withdrawals due to adverse events, treatment discontinuation, serious adverse events, hospitalization, cardiovascular adverse events, and emergency department visits. Data were pooled via pair-wise meta-analyses and Bayesian network meta-analyses. Risk of bias was assessed by use of Cochrane's Risk of Bias tool, and the certainty of the evidence was assessed by use of the GRADE framework.
RESULTS
Eighty-one unique trials that reported at least one outcome of interest were included, most of which were at high or unclear risk of at least one important source of bias. Notably, only 5 RCTs were deemed at overall low risk of bias. Included pharmacotherapies were methylphenidate, atomoxetine, dexamfetamine, lisdexamfetamine, guanfacine, bupropion, mixed amphetamine salts, and modafinil. As a class, ADHD pharmacotherapy improved patient- and clinician-reported clinical response compared with placebo (range: 4 to 15 RCTs per outcome); however, these findings were not conserved when the analyses were restricted to studies at low risk of bias, and the certainty of the finding is very low. There were few differences among individual medications, although atomoxetine was associated with improved patient-reported clinical response and quality of life compared with placebo. There was no significant difference in the risk of serious adverse events or treatment discontinuation between ADHD pharmacotherapies and placebo; however, the proportion of participants who withdrew due to adverse events was significantly higher among participants who received any ADHD pharmacotherapy. Few RCTs reported on the occurrence of adverse events over a long treatment duration.
CONCLUSIONS
Overall, despite a class effect of improving clinical response relative to placebo, there were few differences among the individual ADHD pharmacotherapies, and most studies were at risk of at least one important source of bias. Furthermore, the certainty of the evidence was very low to low for all outcomes, and there was limited reporting of long-term adverse events. As such, the choice between ADHD pharmacotherapies may depend on individual patient considerations, and future studies should assess the long-term effects of individual pharmacotherapies on patient-important outcomes, including quality of life, in robust blinded RCTs.
REGISTRATION
PROSPERO no. CRD 42015026049.
Topics: Adult; Amphetamine; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Bayes Theorem; Bupropion; Central Nervous System Stimulants; Dextroamphetamine; Drug-Related Side Effects and Adverse Reactions; Female; Guanfacine; Humans; Lisdexamfetamine Dimesylate; Male; Methylphenidate; Modafinil; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic
PubMed: 33085721
DOI: 10.1371/journal.pone.0240584