Efficacy of modafinil on fatigue and excessive daytime sleepiness associated with neurological disorders: a systematic review and meta-analysis

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methylphenidate 1 sleepmedicinediseasesdrugs
modafinil 83 sleepmedicinediseasesdrugs
sleep disorder 8 sleepmedicinediseases

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Select Drug Character Offset Drug Term Instance
methylphenidate 4597 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. Modafinil may promote
modafinil 1023 three disorders: narcolepsy, shift work sleep disorder and obstructive sleep apnea. Existing trials of modafinil for fatigue and EDS associated with neurological disorders provided inconsistent results. This meta-analysis
modafinil 1189 disorders provided inconsistent results. This meta-analysis was aimed to assess drug safety and effects of modafinil on fatigue and EDS associated with neurological disorders.MethodsA comprehensive literature review was
modafinil 1376 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.
modafinil 1840 syndrome (PPS). A total of 535 patients were enrolled. Our results suggested a therapeutic effect of modafinil on fatigue in TBI (MD -0.82 95% CI -1.54 - -0.11 p=0.02, I2=0%), while a beneficial effect of modafinil
modafinil 1944 modafinil on fatigue in TBI (MD -0.82 95% CI -1.54 - -0.11 p=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
modafinil 2078 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 - -0.91 p=0.002 I2=14%), but not with MS and TBI.
modafinil 2219 -2.45 95% CI -4.00 - -0.91 p=0.002 I2=14%), but not 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.
modafinil 2372 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 modafinil group.ConclusionsExisting
modafinil 2466 between modafinil and placebo groups except that more patients were found with insomnia and nausea in modafinil group.ConclusionsExisting trials of modafinil for fatigue and EDS associated with PD, MS, TBI and PPS
modafinil 2512 more patients were found with insomnia and nausea in modafinil group.ConclusionsExisting trials of modafinil for fatigue and EDS associated with PD, MS, TBI and PPS provided inconsistent results. The majority
modafinil 5256 treatment of narcolepsy due to severe psychiatric side effects and skin reactions [[29]]. Furthermore, modafinil has been used in investigational treatment of EDS and fatigue associated with PD, MS, AD, stroke, TBI
modafinil 5439 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
modafinil 5576 disorders provided inconsistent results. Although there have been some clinical trials on the effect of modafinil on fatigue and EDS associated with psychiatric disorders, such as attention deficit hyperactivity disorder,
modafinil 5889 study.The current study employed meta-analysis to integrate the available literature on the treatment of modafinil on fatigue and EDS associated with neurological disorders and assessed the efficacy of modafinil on
modafinil 5986 of modafinil on fatigue and EDS associated 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
modafinil 6309 EMBASE, the Cochrane and PSYCHInfo 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
modafinil 7037 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 of effect sizes.Data
modafinil 10425 processes.10.1371/journal.pone.0081802.t001Table 1Design and patient characteristics for studies included in the meta analysis.SourceSamplesize modafinil placeboSex (male)Mean age (year)Duration of treatment (week)Maximum dosage (mg/d)Type of diseaseDuration
modafinil 10594 (week)Maximum dosage (mg/d)Type of diseaseDuration of disease (year)OutcomesBaseline findings (mean±SD, modafinil /placebo)CountryStudy designJadad scoreLou JS (2009)91074%678200PD6.1EDS ESS: 8.3±4.8 / 9.8±4.7USAparallel3DepressionCES-D:
modafinil 11960 / 5.5±1.3USAcrossover5(2007)EDSESS:8.1±3.8 / 8.4±5.7DepressionBDI: 10.5±8.0 / 8.8±6.7*For both modafinil and placebo groups.Abbreviations: PD = Parkinson’s Disease; MS = Multiple Sclerosis; TBI = Traumatic
modafinil 12459 BDI = Beck Depression Inventory; CES-D = Center of Epidemiological Study-Depression ScaleEfficacy of modafinil on fatigue associated with neurological disordersEight RCTs were included to investigate the effect
modafinil 12572 fatigue associated with neurological disordersEight RCTs were included to investigate the effect of modafinil on fatigue associated with neurological disorders, with 2 studies on PD, 3 on MS, 2 on TBI and 1 on
modafinil 12878 studies of PD, with a pooled mean of -0.22 (95% CI -1.23 - 0.79), suggesting no significant effect of modafinil on fatigue associated with PD (p=0.66) (Figure 2A). Three studies were available for meta-analyses comparing
modafinil 12997 fatigue associated with PD (p=0.66) (Figure 2A). Three studies were available for meta-analyses comparing modafinil in MS with placebo. FSS was employed in 2 studies and Modified Fatigue Impact Scale (MFIS) in 2 studies
modafinil 13214 well. Meta-analyses of fatigue measured by FSS and MFIS both failed to prove a beneficial effect of modafinil on fatigue associated with MS (-6.56, 95% CI -19.67 - 6.55, p=0.33, I2=92% for FSS; 0.20, 95% CI -5.24
modafinil 13549 al and Kaiser et al, respectively. Meta-analysis of these two studies showed a therapeutic effect of modafinil on fatigue associated with TBI, with a mean difference of -0.82 (95% CI -1.54 - -0.11 p=0.02, I2=0%)
modafinil 13741 -0.11 p=0.02, I2=0%) (Figure 2D). Vasconcelos OM et al. conducted an RCT to investigate the effect of modafinil on fatigue associated with PPS, in which improvements were seen in FSS with both placebo and modafinil
modafinil 13844 modafinil on fatigue associated with PPS, in which improvements were seen in FSS with both placebo and modafinil without significant differences between the two groups [[46]]. Owing to a limited number of trials,
modafinil 14109 publication bias for each type of neurological disorders.10.1371/journal.pone.0081802.g002Figure 2Effects of modafinil on fatigue in PD (A), MS (B) and TBI (D) measured by Fatigue Severity Scale and in MS (C) measured by
modafinil 14263 measured by Fatigue Severity Scale and in MS (C) measured by Modified Fatigue Impact Scale.Efficacy of modafinil on EDS associated with neurological disordersSubjective measurement of EDS was employed in 4 studies
modafinil 14563 -4.03 - -0.79) with unimportant heterogeneity (I2=20%), demonstrating a clear beneficial effect of modafinil on EDS associated with PD (p=0.004) (Figure 3A). The results were not affected by the sensitivity analysis
modafinil 14882 objectively examined with MSLT in the study by Ondo et al, which didn’t support the beneficial effect of modafinil . No indication of publication bias was observed for studies of PD (Egger’s test, p=0.50).10.1371/journal.pone.0081802.g003Figure
modafinil 15035 observed for studies of PD (Egger’s test, p=0.50).10.1371/journal.pone.0081802.g003Figure 3Effects of modafinil on excessive daytime sleepiness measured by Epworth Sleepiness Scale in PD (A), MS (B) and TBI (C).The
modafinil 15160 daytime sleepiness measured by Epworth Sleepiness Scale in PD (A), MS (B) and TBI (C).The efficacy of modafinil on EDS in patients with MS was investigated in two large studies. As shown in Figure 3B, beneficial
modafinil 15280 patients with MS was investigated in two large studies. As shown in Figure 3B, beneficial effect of modafinil on EDS was not confirmed in the pooled studies. Likewise, the effect of modafinil on EDS in TBI has
modafinil 15362 beneficial effect of modafinil on EDS was not confirmed in the pooled studies. Likewise, the effect of modafinil on EDS in TBI has been tested in two studies using subjective measures. The study of Jha et al. with
modafinil 15546 The study of Jha et al. with a larger number of participants didn’t prove the therapeutic effect of modafinil , while data from Kaiser et al. demonstrated a clear beneficial effect of modafinil on EDS. Meta-analysis
modafinil 15629 therapeutic effect of modafinil, while data from Kaiser et al. demonstrated a clear beneficial effect of modafinil on EDS. Meta-analysis of these two studies showed no significant effect of modafinil with a mean difference
modafinil 15714 beneficial effect of modafinil on EDS. Meta-analysis of these two studies showed no significant effect of modafinil with a mean difference of -1.77 (95% CI -4.26 - 0.72). The result had a substantial heterogeneity (I2=70%)
modafinil 15933 (Figure 3C). Moreover, the study of Kaiser et al. examined EDS with MWT, demonstrating superiority of modafinil versus placebo. The effect of modafinil on EDS in patients with PPS was investigated by Vasconcelos
modafinil 15973 et al. examined EDS with MWT, demonstrating superiority of modafinil versus placebo. The effect of modafinil on EDS in patients with PPS was investigated by Vasconcelos OM et al. Improvements were seen in ESS
modafinil 16105 with PPS was investigated by Vasconcelos OM et al. Improvements were seen in ESS with both placebo and modafinil with no significant differences between the two treatments [[46]].Efficacy of modafinil on depression
modafinil 16193 placebo and modafinil with no significant differences between the two treatments [[46]].Efficacy of modafinil on depression associated with neurological disordersFive RCTs examining the effect of modafinil on depression
modafinil 16289 of modafinil on depression associated with neurological disordersFive RCTs examining the effect of modafinil on depression associated with neurological disorders came up with consistent outcomes, in which Beck
modafinil 16628 Study-Depression Scale (CES-D) in another. The pooled standardized mean difference demonstrated no impact of modafinil on depression associated with neurological disorders (SMD 0.01, 95% CI -0.27 - 0.29, p=0.93, I2=0%)
modafinil 16883 indication of publication bias (Egger’s test, p=0.542).10.1371/journal.pone.0081802.g004Figure 4Effect of modafinil on depression associated with neurological disorders.Adverse effectsOf 10 studies included, the adverse
modafinil 17041 disorders.Adverse effectsOf 10 studies included, the adverse effects were described in 9% of patients in modafinil group and 2% of patients in placebo group. The overall risk ratio for study discontinuation due to side
modafinil 17200 overall risk ratio for study discontinuation due to side effects suggested that patients treated with modafinil were more likely to withdraw from treatment compared to patients with placebo (RR 3.68, 95% CI 1.46
modafinil 17396 3.68, 95% CI 1.46 - 9.27, p=0.006, I2=0%) (Figure 5).10.1371/journal.pone.0081802.g005Figure 5Effect of modafinil on study discontinuation due to adverse events.Occurrence of adverse events reported in the included
modafinil 17599 included studies was summarized in Table 2. Generally, more patients reported insomnia and nausea in modafinil group compared to placebo group. Other rates of adverse events were similar between the two groups.10.1371/journal.pone.0081802.t002Table
modafinil 17778 similar between the two groups.10.1371/journal.pone.0081802.t002Table 2The pooled adverse effects of modafinil in included studies.Adverse effectNo. of studiesNo. of patients modafinil/placeboRisk Ratio and 95%CIP
modafinil 17852 pooled adverse effects of modafinil in included studies.Adverse effectNo. of studiesNo. of patients modafinil /placeboRisk Ratio and 95%CIP valueI2 (%)Insomnia5172 / 1754.20 [1.52, 10.60]0.0020Headache4160 / 1631.19
modafinil 18590 weakness and depleted energy [[49]]. Our primary research question was aimed at assessing the effects of modafinil on fatigue and EDS associated with neurological disorders and its safety. This review identified 10
modafinil 18884 with MS, 115 with TBI and 66 with PPS were enrolled. Our results suggested the therapeutic effect of modafinil on fatigue in TBI, with a clear beneficial effect of modafinil on EDS in patients with PD, while the
modafinil 18947 suggested the therapeutic effect of modafinil on fatigue in TBI, with a clear beneficial effect of modafinil on EDS in patients with PD, while the beneficial effect of modafinil on fatigue could not be confirmed
modafinil 19016 with a clear beneficial effect of modafinil on EDS in patients with PD, while the beneficial effect of modafinil on fatigue could not be confirmed in the pooled studies of PD or MS, and the therapeutic effect of modafinil
modafinil 19125 on fatigue could not be confirmed in the pooled studies of PD or MS, and the therapeutic effect of modafinil on EDS was not seen in patients with MS and TBI as well. For PPS, improvements were seen in FSS and
modafinil 19261 patients with MS and TBI as well. For PPS, improvements were seen in FSS and ESS with both placebo and modafinil without significant differences between the two groups. Modafinil seemed to have no therapeutic effect
modafinil 19437 seemed to have no therapeutic effect on depression. In general, adverse events were similar between modafinil and placebo groups except that more patients reported insomnia and nausea in modafinil group compared
modafinil 19524 similar between modafinil and placebo groups except that more patients reported insomnia and nausea in modafinil group compared to the placebo group.Modafinil is an oral wake-promoting agent, which has been approved
modafinil 19771 in patients with narcolepsy, OSA and SWSD. Previous meta-analysis suggested a therapeutic effect of modafinil on EDS, but not cataplexy in narcoleptic patients [[50]]. In that study, EDS was assessed thoroughly
modafinil 20044 somnolence, sleep attacks and naps per day. Additionally, their results indicated a beneficial impact of modafinil on quality of life according to the SF-36 questionnaire. In the current study, our data did not demonstrate
modafinil 20185 the SF-36 questionnaire. In the current study, our data did not demonstrate a consistent effect of modafinil on EDS in the neurological disorders. Superior effect estimate was observed only in PD, but not in MS
modafinil 22015 sleep disorders such as OSA, which can be a major confounder in the interpretation of the effect of modafinil on EDS associated with neurological disorders. Hence, polysomnographical investigations are needed to
modafinil 22254 OSA and it will be probably useful to exclude patients with sleep disorders from randomized trials on modafinil in the future to avoid a confounder.Besides EDS, fatigue is another frequent complaint among patients
modafinil 22960 together. The meta-analyses of fatigue, examined by either FSS or MFIS, did not show beneficial effect of modafinil . Our data were in accordance with the Cochrane review by Peuckmann-Post V et al. [[54]]. In our study,
modafinil 23121 review by Peuckmann-Post V et al. [[54]]. In our study, we pooled two studies to evaluate the effect of modafinil on fatigue in TBI. Although meta-analysis showed superior effect estimate for modafinil in TBI compared
modafinil 23209 the effect of modafinil on fatigue in TBI. Although meta-analysis showed superior effect estimate for modafinil in TBI compared to placebo, the result should be interpreted with caution due to a limited number of
modafinil 23902 intermittent hypoxemia might be primarily responsible for the increased fatigue [[20]]. The effects of modafinil on sleep in OSA were conducted with overnight polysomnography in 3 RCTs [[55]-[57]]. Sleep efficiency
modafinil 24069 polysomnography in 3 RCTs [[55]-[57]]. Sleep efficiency and the architecture of the sleep were not affected by modafinil . The number of arousals was not significantly changed by modafinil in two trials, while the mean arousal
modafinil 24136 of the sleep were not affected by modafinil. The number of arousals was not significantly changed by modafinil in two trials, while the mean arousal index was statistically higher with modafinil than with placebo
modafinil 24220 significantly changed by modafinil in two trials, while the mean arousal index was statistically higher with modafinil than with placebo in the third trial. Although modafinil is proven to be effective in ameliorating EDS
modafinil 24277 arousal index was statistically higher with modafinil than with placebo in the third trial. Although modafinil is proven to be effective in ameliorating EDS in some specific conditions [[27],[28]], it doesn’t
modafinil 24556 associated with increased fatigue [[55]-[57]]. This might be one of the potential explanations why modafinil failed to decrease fatigue in neurological disorders. Owing to the fact that sleep disorders may be
modafinil 24812 disorder related fatigue, it will be probably useful to exclude patients with sleep disorders from modafinil -RCT in the future to avoid a confounder.Depression is highly associated with fatigue and EDS [[58]-[60]].
modafinil 24956 confounder.Depression is highly associated with fatigue and EDS [[58]-[60]]. Previous evidence suggested modafinil in association with antidepressant medication can improve overall clinical condition including depressive
modafinil 25152 including depressive symptoms, fatigue and EDS (61,62). Our results indicated that administration of modafinil alone could not ameliorate depressive symptoms, supporting the opinion that modafinil can be regarded
modafinil 25238 administration of modafinil alone could not ameliorate depressive symptoms, supporting the opinion that modafinil can be regarded as an agent in augmentation therapy of depression. There are some limitations in our
modafinil 26810 solution to evaluate disorder related fatigue. This may indicate that the major problem might not be that modafinil does not work, but the lack of capacity to develop sound trial concepts and to homogenize patients with
modafinil 26976 trial concepts and to homogenize patients with presumably different fatigue pathogenesis. Finally, modafinil in the identified studies was administrated in short-term settings. Despite the fact that no severe
modafinil 27155 Despite the fact that no severe adverse events were presented in the current research, the safety of modafinil in the long-term administration, especially the potential of abuse and addiction, need to be investigated
modafinil 27321 potential of abuse and addiction, need to be investigated in the future trials.ConclusionExisting trials of modafinil for fatigue and EDS associated with Parkinson’s disease, multiple sclerosis, traumatic brain injury
modafinil 27732 data are available. It would be ideal to perform large RCTs in MS and PD investigating the effect of modafinil on either fatigue or sleepiness and sleep disorders should be excluded as a major confounder by polysomnography
Select Disease Character Offset Disease Term Instance
sleep disorder 960 the FDA ameliorating excessive daytime sleepiness (EDS) in three disorders: narcolepsy, shift work sleep disorder and obstructive sleep apnea. Existing trials of modafinil for fatigue and EDS associated with neurological
sleep disorder 4944 system [[25],[26]]. Modafinil ameliorates EDS in all three disorders, i.e. narcolepsy, shift work sleep disorder (SWSD) and obstructive sleep apnea (OSA), and has been approved by the FDA [[27],[28]]. Of note, the
sleep disorder 21915 the studies included, few patients underwent polysomnographical investigations to identify persistent sleep disorder s such as OSA, which can be a major confounder in the interpretation of the effect of modafinil on EDS
sleep disorder 22212 are needed to screen out patients with OSA and it will be probably useful to exclude patients with sleep disorder s from randomized trials on modafinil in the future to avoid a confounder.Besides EDS, fatigue is another
sleep disorder 23500 al. and Kaminska et al. described a clear and significant relationship between MS-related fatigue and sleep disorder s and found an especially strong association between severe fatigue and severe OSA [[19],[20]]. Furthermore,
sleep disorder 24643 explanations why modafinil failed to decrease fatigue in neurological disorders. Owing to the fact that sleep disorder s may be one of the causes responsible for neurological disorder related fatigue, it will be probably
sleep disorder 24791 responsible for neurological disorder related fatigue, it will be probably useful to exclude patients with sleep disorder s from modafinil-RCT in the future to avoid a confounder.Depression is highly associated with fatigue
sleep disorder 27778 perform large RCTs in MS and PD investigating the effect of modafinil on either fatigue or sleepiness and sleep disorder s should be excluded as a major confounder by polysomnography in these studies.Supporting InformationChecklist

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