Disorders A Systematic Review and MetaAnalysis文档格式.docx

1、A comprehensive literature review was conducted in order to identify published studies assessing the effects of modafinil on fatigue and EDS associated with neurological disorders. Primary outcomes included fatigue and EDS. Secondary outcomes included depression and adverse effects.FindingsTen rando

2、mized controlled trials were identified including 4 studies of Parkinsons disease （PD）, 3 of multiple sclerosis （MS）, 2 of traumatic brain injury （TBI） and 1 of post-polio syndrome （PPS）. A total of 535 patients were enrolled. Our results suggested a therapeutic effect of modafinil on fatigue in TBI

3、 （MD -0.82 95% CI -1.54 - -0.11p=0.02, I2=0%）, while a beneficial effect of modafinil on fatigue was not confirmed in the pooled studies of PD or MS. Treatment results demonstrated a clear beneficial effect of modafinil on EDS in patients with PD （MD -2.45 95% CI -4.00 - -0.91p=0.002 I2=14%）, but no

4、t with MS and TBI. No difference was seen between modafinil and placebo treatments in patients with PPS. Modafinil seemed to have no therapeutic effect on depression. Adverse events were similar between modafinil and placebo groups except that more patients were found with insomnia and nausea in mod

5、afinil group.ConclusionsExisting trials of modafinil for fatigue and EDS associated with PD, MS, TBI and PPS provided inconsistent results. The majority of the studies had small sample sizes. Modafinil is not yet sufficient to be recommended for these medical conditions until solid data are availabl

6、e.Figures12Citation:Sheng P, Hou L, Wang X, Wang X, Huang C, et al. （2013） Efficacy of Modafinil on Fatigue and Excessive Daytime Sleepiness Associated with Neurological Disorders: A Systematic Review and Meta-Analysis. PLoS ONE 8（12）: e81802. doi:10.1371/journal.pone.0081802Editor:Friedemann Paul,

7、Charit University Medicine Berlin, GermanyReceived:June 3, 2013;Accepted:October 16, 2013;Published:December 3, 2013Copyright: 2013 Sheng et al. This is an open-access article distributed under the terms of theCreative Commons Attribution License, which permits unrestricted use, distribution, and re

8、production in any medium, provided the original author and source are credited.Funding:Dr. Yan Dong is supported by Natural Science Foundation from Science and Technology Commission of Shanghai Municipality （11ZR1448700） and Research Foundation for Returned Scholars from Ministry of Education of Chi

9、na. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Competing interests:The authors have declared that no competing interests exist.IntroductionExcessive daytime sleepiness （EDS） and fatigue are frequently encountered sympt

10、oms in neurological practice, which may arise from a variety of disorders such as Parkinsons disease （PD）, multiple sclerosis （MS）, Alzheimers disease （AD）, depression, stroke and traumatic brain injury （TBI） 1-13. EDS is defined as not being able to keep alert or awake in daytime hours and might fa

11、ll asleep in inappropriate situations. Different definitions have been proposed for fatigue. For example, in MS, fatigue has been defined as “A subjective lack of physical and/or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities” 14. In gen

12、eral, fatigue is considered as a subjective feeling of tiredness, weakness, or lack of energy 15. Fatigue and EDS not only severely impair productivity and performance, but may also have detrimental effects on social functioning and overall quality of life. The mechanisms of fatigue and EDS remain p

13、oorly defined, which seem to be multifactorial, arising from primary diseases related factors and other secondary ones. Recently growing evidence indicates that sleep disturbances, which are common in MS patients, may be an important contributing factor and treatment of sleep disturbances can improv

14、e fatigue and EDS in patients with MS 16-20. Therapies for fatigue and EDS should address causal mechanisms if possible. Unfortunately, the potential mechanisms of fatigue and EDS in clinical practice are often hard to be understood and many factors may be involved. Hence, both pharmacological and n

15、on-pharmacological therapies have been applied in the management of fatigue and EDS 21-24.Modafinil is a novel wake-promoting agent that is pharmacologically different from those of amphetamine and methylphenidate, the two classical psychostimulants. Its exact mode of action remains unclear. Modafin

16、il may promote wakefulness through activation of noradrenergic and dopaminergic systems, probably through interaction with the hypocretin/orexin system 25,26. Modafinil ameliorates EDS in all three disorders， i.e. narcolepsy, shift work sleep disorder （SWSD） and obstructive sleep apnea （OSA）, and ha

17、s been approved by the FDA 27,28. Of note, the European Medicines Agency has recently recommended the use of Modafinil be restricted to the treatment of narcolepsy due to severe psychiatric side effects and skin reactions 29. Furthermore, modafinil has been used in investigational treatment of EDS a

18、nd fatigue associated with PD, MS, AD, stroke, TBI and post-polio syndrome （PPS） 30-46. However, existing trials of modafinil for these neurological disorders provided inconsistent results. Although there have been some clinical trials on the effect of modafinil on fatigue and EDS associated with ps

19、ychiatric disorders, such as attention deficit hyperactivity disorder, depression, schizophrenia and cocaine addiction, they are beyond the scope of the present study.The current study employed meta-analysis to integrate the available literature on the treatment of modafinil on fatigue and EDS assoc

20、iated with neurological disorders and assessed the efficacy of modafinil on fatigue and EDS and its safety in patients with neurological diseases with a rigorous methodological quality assessment.Selection of StudiesA comprehensive literature review based on Ovid Medline, EMBASE, the Cochrane and PS

21、YCHInfo databases was conducted to identify published studies on the effect of modafinil on fatigue and EDS associated with neurological disorders. Search terms used were listed in supplement S1. The search was limited to articles written in English and published in peer-reviewed journals from Janua

22、ry 1980 to December 2012. Studies must involve human subjects and primary data must be presented. Reference lists from the relevant studies were searched for additional literature.Inclusion criteriaOriginal studies were considered for inclusion in the meta-analysis if they met with the following cri

23、teria: （1） they were randomized controlled trials （RCT）; （2） patients over 18 years old with neurological diseases such as PD, AD, MS, stroke, TBI, PPS and brain tumor were investigated; （3） the efficacy of modafinil on fatigue and EDS was examined; （4） results were sufficient to allow calculation o

24、f effect sizes.Data extraction and quality assessmentTwo authors （PS and LJH） independently reviewed the full manuscripts of eligible studies. Data were extracted in standardized data-collection forms. Extracted data included first authors name, year of publication, sample size, patients characteris

25、tics （mean age, gender）, duration of treatment, dosage, type of disease, duration of disease, outcomes, baseline findings, country, study design and Jadad score. Any discrepancy was resolved by discussion with a third author （XH）. Selected RCTs were critically appraised using the Jadad scale, which

26、assesses the methodology of the study such as randomization （2 points）, blinding （2 points） and attrition information （1 point） 47.Study outcomesPrimary outcomes included self-reported fatigue, which is then measured by single item scale and questionnaire instruments, as well as subjective EDS measu

27、red by Epworth Sleepiness Scale and objective EDS measured by Multiple Sleep Latency Test （MSLT） or Maintenance of Wakefulness Test （MWT）. Secondary outcomes included depression and adverse effects.Statistical analysisFor dichotomous data, the impact of the intervention was expressed as relative ris

28、k （RR） with 95% confidence intervals （CI） using the Mantel-Haenszel method. For continuous data, the difference in change from baseline to follow-up between intervention and control groups was expressed as mean differences with 95% CI （if the same scale was used in all studies） or standardized mean

29、differences with 95% CI （when different scales were used） using inverse variance method otherwise. Heterogeneity of treatment effects between studies was statistically explored by the I2statistic, in which 0%40% indicates unimportant heterogeneity, 30%60% indicates moderate heterogeneity, 50%90% ind

30、icates substantial heterogeneity, and 75%100% indicates considerable heterogeneity 48. The sensitivity analyses were carried out by excluding studies successively. All reportedPvalues were two-sided, andPvalues less than 0.05 were deemed as statistically significant. The publication bias was statist

31、ically examined using the Eggers regression model, calculated by Stata 12.0 （Stata Corporation, College Station, TX, USA）.ResultsStudy characteristicsA total of 427 citations were identified from the electronic searches and 3 through other sources, of which 338 were excluded after a preliminary review. The remaining 92 studies we