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The Cochrane Database of Systematic... May 2015This review updates the original review, 'Pharmacological treatments for fatigue associated with palliative care' and also incorporates the review 'Drug therapy for the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
This review updates the original review, 'Pharmacological treatments for fatigue associated with palliative care' and also incorporates the review 'Drug therapy for the management of cancer-related fatigue'.In healthy individuals, fatigue is a protective response to physical or mental stress, often relieved by rest. By contrast, in palliative care patients' fatigue can be severely debilitating and is often not counteracted with rest, thereby impacting daily activity and quality of life. Fatigue frequently occurs in patients with advanced disease (e.g. cancer-related fatigue) and modalities used to treat cancer can often contribute. Further complicating issues are the multidimensionality, subjective nature and lack of a consensus definition of fatigue. The pathophysiology is not fully understood and evidence-based treatment approaches are needed.
OBJECTIVES
To evaluate the efficacy of pharmacological treatments for fatigue in palliative care, with a focus on patients at an advanced stage of disease, including patients with cancer and other chronic diseases.
SEARCH METHODS
For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO and EMBASE, and a selection of cancer journals up to 28 April 2014. We searched the references of identified articles and contacted authors to obtain unreported data. To validate the search strategy we selected sentinel references.
SELECTION CRITERIA
We considered randomised controlled trials (RCTs) concerning adult palliative care with a focus on pharmacological treatment of fatigue compared to placebo, application of two drugs, usual care or a non-pharmacological intervention. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). We did not include studies on fatigue related to antineoplastic treatment (e.g. chemotherapy, radiotherapy, surgical intervention). We also included secondary outcomes that were assessed in fatigue-related studies (e.g. exhaustion, tiredness).
DATA COLLECTION AND ANALYSIS
Two review authors (MM and MC) independently assessed trial quality and extracted data. We screened the search results and included studies if they met the selection criteria. If we identified two or more studies that investigated a specific drug with the same dose in a population with the same disease and using the same assessment instrument or scale, we conducted meta-analysis. In addition, we compared the type of drug investigated in specific populations, as well as the frequent adverse effects of fatigue treatment, by creating overview tables.
MAIN RESULTS
For this update, we screened 1645 publications of which 45 met the inclusion criteria (20 additional studies to the previous reviews). In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials and we discuss the reasons for this in the review. There were some sources of potential bias in the included studies, including a lack of description of the methods of blinding and allocation concealment, and the small size of the study populations. We included studies investigating pemoline and modafinil in participants with multiple sclerosis (MS)-associated fatigue and methylphenidate in patients suffering from advanced cancer and fatigue in meta-analysis. Treatment results pointed to weak and inconclusive evidence for the efficacy of amantadine, pemoline and modafinil in multiple sclerosis and for carnitine and donepezil in cancer-related fatigue. Methylphenidate and pemoline seem to be effective in patients with HIV, but this is based only on one study per intervention, with only a moderate number of participants in each study. Meta-analysis shows an estimated superior effect for methylphenidate in cancer-related fatigue (standardised mean difference (SMD) 0.49, 95% confidence interval (CI) 0.15 to 0.83). Therapeutic effects could not be described for dexamphetamine, paroxetine or testosterone. There were a variety of results for the secondary outcomes in some studies. Most studies had low participant numbers and were heterogeneous. In general, adverse reactions were mild and had little or no impact.
AUTHORS' CONCLUSIONS
Based on limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Fatigue research in palliative care seems to focus on modafinil and methylphenidate, which may be beneficial for the treatment of fatigue associated with palliative care although further research about their efficacy is needed. Dexamethasone, methylprednisolone, acetylsalicylic acid, armodafinil, amantadine and L-carnitine should be further examined. Consensus is needed regarding fatigue outcome parameters for clinical trials.
Topics: Adult; Amantadine; Benzhydryl Compounds; Carnitine; Central Nervous System Stimulants; Chronic Disease; Fatigue; Humans; Kidney Failure, Chronic; Methylphenidate; Modafinil; Multiple Sclerosis; Neoplasms; Palliative Care; Pemoline; Randomized Controlled Trials as Topic
PubMed: 26026155
DOI: 10.1002/14651858.CD006788.pub3 -
Journal of Clinical Sleep Medicine :... Dec 2021Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment... (Meta-Analysis)
Meta-Analysis
STUDY OBJECTIVES
Excessive daytime sleepiness associated with obstructive sleep apnea affects 9%-22% of continuous positive airway pressure-treated patients. An indirect treatment comparison meta-analysis was performed to compare efficacy and safety of medications (solriamfetol, modafinil, and armodafinil) approved to treat excessive daytime sleepiness associated with obstructive sleep apnea.
METHODS
Efficacy and safety measures assessed in this indirect treatment comparison included Epworth Sleepiness Scale (ESS), 20-minute Maintenance of Wakefulness Test (MWT20), Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), and incidence of treatment-emergent adverse events (any, serious, or leading to discontinuation).
RESULTS
A systematic literature review identified 6 parallel-arm, placebo-controlled randomized controlled trials that randomized 1,714 total participants to placebo, solriamfetol, modafinil, or armodafinil. In this indirect treatment comparison, all comparators were associated with greater improvements than placebo on the ESS, MWT20, and CGI-C after 4, 8, and 12 weeks of treatment. Relative to comparators and placebo at 12 weeks, solriamfetol at 150 mg or 300 mg had the highest probabilities of improvement in the ESS, MWT20, and CGI-C. Modafinil (200 or 400 mg) and solriamfetol (150 or 300 mg) were associated with greater improvement on the FOSQ than placebo at 12 weeks. Less than 2% of patients using placebo or comparators experienced serious or discontinuation-related treatment-emergent adverse events.
CONCLUSIONS
The results of this indirect treatment comparison show 12 weeks of treatment with solriamfetol, modafinil, and armodafinil resulted in varying levels of improvement on the ESS, MWT20, and CGI-C and similar safety risks in participants with excessive daytime sleepiness associated with obstructive sleep apnea.
CITATION
Ronnebaum S, Bron M, Patel D, et al. Indirect treatment comparison of solriamfetol, modafinil, and armodafinil for excessive daytime sleepiness in obstructive sleep apnea. . 2021;17(12):2543-2555.
Topics: Benzhydryl Compounds; Carbamates; Disorders of Excessive Somnolence; Double-Blind Method; Humans; Modafinil; Phenylalanine; Sleep Apnea, Obstructive; Treatment Outcome
PubMed: 34402784
DOI: 10.5664/jcsm.9610 -
Chronic Respiratory Disease May 2017Fatigue is a common manifestation of sarcoidosis, often persisting without evidence of disease activity. First-line therapies for sarcoidosis have limited effect on... (Review)
Review
Fatigue is a common manifestation of sarcoidosis, often persisting without evidence of disease activity. First-line therapies for sarcoidosis have limited effect on fatigue. This review aimed to assess the treatment options targeting sarcoidosis-associated fatigue. Medline and Web of Science were searched in November 2015; the bibliographies of these papers, and relevant review papers, were also searched. Studies were included if they reported on the efficacy of interventions (both pharmacological and non-pharmacological) on fatigue scores in sarcoidosis patients. Eight studies were identified that fulfilled the inclusion criteria. These studies evaluated six different interventions (infliximab, adalimumab, ARA 290, methylphenidate, armodafinil and exercise programmes). There is evidence to support a treatment effect of anti-tumour necrosis factor (TNF)-αtherapies (adalimumab and infliximab) and neurostimulants (methylphenidate and armodafinil), but within five of the studies, the risk of bias was high within most domains and the remaining three studies included only small numbers of participants and were short in duration. Trial evidence for treating fatigue as a manifestation of sarcoidosis is limited and requires further investigation. Anti-TNF-α therapies may be beneficial in patients with organ-threatening disease. Neurostimulants have some trial evidence supporting improvements in fatigue but further investigation is needed before they can be recommended.
Topics: Adalimumab; Antirheumatic Agents; Benzhydryl Compounds; Central Nervous System Stimulants; Exercise Therapy; Fatigue; Humans; Infliximab; Methylphenidate; Modafinil; Oligopeptides; Sarcoidosis; Tumor Necrosis Factor-alpha
PubMed: 27507833
DOI: 10.1177/1479972316661926 -
The Cochrane Database of Systematic... Dec 2015Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s, resulting in severe disability in... (Review)
Review
BACKGROUND
Traumatic brain injury (TBI) is a major cause of chronic disability. Worldwide, it is the leading cause of disability in the under 40s, resulting in severe disability in some 150 to 200 million people per annum. In addition to mood and behavioural problems, cognition-particularly memory, attention and executive function-are commonly impaired by TBI. Cognitive problems following TBI are one of the most important factors in determining people's subjective well-being and their quality of life. Drugs are widely used in an attempt to improve cognitive functions. Whilst cholinergic agents in TBI have been reviewed, there has not yet been a systematic review or meta-analysis of the effect on chronic cognitive problems of all centrally acting pharmacological agents.
OBJECTIVES
To assess the effects of centrally acting pharmacological agents for treatment of chronic cognitive impairment subsequent to traumatic brain injury in adults.
SEARCH METHODS
We searched ALOIS-the Cochrane Dementia and Cognitive Improvement Group's Specialised Register-on 16 November 2013, 23 February 2013, 20 January 2014, and 30 December 2014 using the terms: traumatic OR TBI OR "brain injury" OR "brain injuries" OR TBIs OR "axonal injury" OR "axonal injuries". ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases, numerous trial registries and grey literature sources. Supplementary searches were also performed in MEDLINE, EMBASE, PsycINFO, The Cochrane Library, CINAHL, LILACs, ClinicalTrials.gov, the World Health Organization (WHO) Portal (ICTRP) and Web of Science with conference proceedings.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) assessing the effectiveness of any one centrally acting pharmacological agent that affects one or more of the main neurotransmitter systems in people with chronic traumatic brain injury; and there had to be a minimum of 12 months between the injury and entry into the trial.
DATA COLLECTION AND ANALYSIS
Two review authors examined titles and abstracts of citations obtained from the search. Relevant articles were retrieved for further assessment. A bibliographic search of relevant papers was conducted. We extracted data using a standardised tool, which included data on the incidence of adverse effects. Where necessary we requested additional unpublished data from study authors. Risk of bias was assessed by a single author.
MAIN RESULTS
Only four studies met the criteria for inclusion, with a total of 274 participants. Four pharmacological agents were investigated: modafinil (51 participants); (-)-OSU6162, a monoamine stabiliser (12 participants of which six had a TBI); atomoxetine (60 participants); and rivastigmine (157 participants). A meta-analysis could not be performed due to the small number and heterogeneity of the studies.All studies examined cognitive performance, with the majority of the psychometric sub-tests showing no difference between treatment and placebo (n = 274, very low quality evidence). For (-)-OSU6162 modest superiority over placebo was demonstrated on three measures, but markedly inferior performance on another. Rivastigmine was better than placebo on one primary measure, and a single cognitive outcome in a secondary analysis of a subgroup with more severe memory impairment at baseline. The study of modafinil assessed clinical global improvement (n = 51, low quality evidence), and did not find any difference between treatment and placebo. Safety, as measured by adverse events, was reported by all studies (n = 274, very low quality evidence), with significantly more nausea reported by participants who received rivastigmine compared to placebo. There were no other differences in safety between treatment and placebo. No studies reported any deaths.
AUTHORS' CONCLUSIONS
There is insufficient evidence to determine whether pharmacological treatment is effective in chronic cognitive impairment in TBI. Whilst there is a positive finding for rivastigmine on one primary measure, all other primary measures were not better than placebo. The positive findings for (-)-OSU6162 are interpreted cautiously as the study was small (n = 6). For modafinil and atomoxetine no positive effects were found. All four drugs appear to be relatively well tolerated, although evidence is sparse.
Topics: Adolescent; Adult; Aged; Atomoxetine Hydrochloride; Benzhydryl Compounds; Brain Injuries; Chronic Disease; Cognition; Cognition Disorders; Humans; Middle Aged; Modafinil; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic; Rivastigmine
PubMed: 26624881
DOI: 10.1002/14651858.CD009221.pub2 -
The Cochrane Database of Systematic... Oct 2015Factors contributing to subjective fatigue in people with idiopathic Parkinson's disease (PD) are not well known. This makes it difficult to manage fatigue effectively... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Factors contributing to subjective fatigue in people with idiopathic Parkinson's disease (PD) are not well known. This makes it difficult to manage fatigue effectively in PD.
OBJECTIVES
To evaluate the effects of pharmacological and non-pharmacological interventions, compared to an inactive control intervention, on subjective fatigue in people with PD.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE (via PubMed); Ovid EMBASE; EBSCO CINAHL; Ovid PsycINFO; PEDro; and the WHO International Clinical Trials Registry Platform Search Portal up to April 2015. References of included studies and identified review articles were screened for additional studies. There were no restrictions based on language, date of publication or study setting.
SELECTION CRITERIA
Randomised controlled trials (RCTs) that report on subjective fatigue in people with PD.
DATA COLLECTION AND ANALYSIS
Two review authors independently performed study selection, data collection and risk of bias assessments.
MAIN RESULTS
Eleven studies were eligible for this systematic review, with a total of 1817 people. Three studies included only people who experienced clinically relevant fatigue (Fatigue Severity Scale score ≥ 4 out of 7 or Multidimensional Fatigue Inventory total score > 48 out of 100), whereas all other studies did not select participants on the basis of experienced fatigue. Nine studies investigated the effects of medication (i.e. levodopa-carbidopa, memantine, rasagiline, caffeine, methylphenidate, modafinil or doxepin) on subjective fatigue. All studies were placebo controlled. There was insufficient evidence to determine the effect of doxepin on the impact of fatigue on activities in daily life (ADL) or fatigue severity (one study, N = 12, standardised mean difference (SMD) = -1.50, 95% confidence interval (CI) -2.84 to -0.15; low quality evidence). We found high quality evidence that rasagiline reduced or slowed down the progression of physical aspects of fatigue (one study, N = 1176, SMD = -0.27, 95% CI -0.39 to -0.16, I(2) = 0%). None of the other pharmacological interventions affected subjective fatigue in PD. With regard to adverse effects, only levodopa-carbidopa showed an increase for the risk of nausea (one study, N = 361, risk ratio (RR) = 1.85, 95% CI 1.05 to 3.27; high quality evidence). Two studies investigated the effect of exercise on fatigue compared with usual care. We found low quality evidence for the effect of exercise on reducing the impact of fatigue on ADL or fatigue severity (two studies, N = 57, SMD = -0.45, 95% CI -1.21 to 0.32, I(2) = 44%).
AUTHORS' CONCLUSIONS
Based on the current evidence, no clear recommendations for the treatment of subjective fatigue in PD can be provided. Doxepin may reduce the impact of fatigue on ADL and fatigue severity; however, this finding has to be confirmed in high quality studies. Rasagiline may be effective in reducing levels of physical fatigue in PD. No evidence was found for the effectiveness of levodopa-carbidopa, memantine, caffeine, methylphenidate, modafinil or exercise. Studies are needed to investigate the effect of exercise intensity on exercise capacity and subjective fatigue. Future studies should focus on interventions that address the maladaptive behavioural or cognitive aspects of fatigue in people with PD. Characteristics, such as severity and nature of perceived fatigue and underlying mood disorders should be considered to identify responders and non-responders when studying interventions for fatigue. The development of a core-set of self-report fatigue questionnaires with established responsiveness and known minimal important difference values will facilitate the interpretation of change in fatigue scores.
Topics: Central Nervous System Stimulants; Dopamine Agents; Exercise; Fatigue; Humans; Parkinson Disease; Randomized Controlled Trials as Topic
PubMed: 26447539
DOI: 10.1002/14651858.CD010925.pub2 -
Journal of Cachexia, Sarcopenia and... Mar 2016In palliative care patients, fatigue can be severely debilitating and is often not counteracted with rest, thereby impacting daily activity and quality of life. Further... (Review)
Review
BACKGROUND
In palliative care patients, fatigue can be severely debilitating and is often not counteracted with rest, thereby impacting daily activity and quality of life. Further complicating issues are the multidimensionality, subjective nature and lack of a consensus definition of fatigue. The review aimed to evaluate the efficacy of pharmacological treatments for fatigue in palliative care, with a focus on patients at an advanced stage of disease, including patients with cancer and other chronic diseases.
METHODS
We considered randomized controlled trials concerning adult palliative care with a focus on pharmacological treatment of fatigue compared with placebo, application of two drugs, usual care or a non-pharmacological intervention. The primary outcome had to be non-specific fatigue (or related terms such as asthenia). We searched the CENTRAL, MEDLINE, PsycINFO and EMBASE, and a selection of cancer journals up to 28 April 2014. Two review authors independently assessed trial quality and extracted the data.
RESULTS
We screened 1645 publications of which 45 met the inclusion criteria. In total, we analysed data from 18 drugs and 4696 participants. There was a very high degree of statistical and clinical heterogeneity in the trials. Meta-analysis of data was possible for modafinil, pemoline, and methylphenidate.
CONCLUSIONS
Due to the limited evidence, we cannot recommend a specific drug for the treatment of fatigue in palliative care patients. Some drugs, which may be beneficial for the treatment of fatigue associated with palliative care such as amantadine, methylphenidate, and modafinil, should be further researched.
PubMed: 27066315
DOI: 10.1002/jcsm.12101 -
The Cochrane Database of Systematic... Dec 2014Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Cognitive deficits are common in people who have received cranial irradiation and have a serious impact on daily functioning and quality of life. The benefit of pharmacological and non-pharmacological treatment of cognitive deficits in this population is unclear.
OBJECTIVES
To assess the effectiveness of interventions for preventing or ameliorating cognitive deficits in adult patients treated with cranial irradiation.
SEARCH METHODS
In August 2014. we searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO and checked the reference lists of included studies. We also searched for ongoing trials via ClinicalTrials.gov, the Physicians Data Query and the Meta Register of Controlled Trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that evaluated pharmacological or non-pharmacological interventions in cranial irradiated adults, with objective cognitive functioning as a primary or secondary outcome measure.
DATA COLLECTION AND ANALYSIS
Two review authors (JD, KZ) independently extracted data from selected studies and carried out a 'Risk of bias' assessment. Cognitive function, fatigue and mood outcomes were reported. No data were pooled.
MAIN RESULTS
Sixteen studies were identified for possible inclusion in the review, six of which were included. Three studies investigated prevention and three studies investigated amelioration. Due to differences between studies in the interventions being evaluated, a meta-analysis was not possible. Two studies investigated a pharmacological intervention for the prevention of cognitive deficits; memantine compared with placebo, and d-threo-methylphenidate HCL compared with placebo. In the first study the primary cognitive outcome of memory at six months did not reach significance, but there was significant improvement in overall cognitive function compared to placebo, with similar adverse events across groups. The second study found no statistically significant difference between arms, with few adverse events. The third study investigated a rehabilitation program for the prevention of cognitive deficits but did not carry out a statistical comparison of cognitive performance between groups.Three studies investigated the use of a pharmacological intervention for the treatment of cognitive deficits; methylphenidate compared with modafinil, two different doses of modafinil, and donepezil compared with placebo. The first study found improvements in cognitive function in both the methylphenidate and modafinil arms; few adverse events were reported. The second study combined treatment arms and found improvements across all cognitive tests, however, a number of adverse events were reported. Both studies were limited by a small sample size. The third study did not find an improvement in the primary cognitive outcome of overall performance, but did find improvement in an individual test of memory, compared to placebo; adverse events were not reported. No non-pharmacological studies for the amelioration of cognitive deficits were eligible. There were a number of limitations across studies but few without high risks of bias.
AUTHORS' CONCLUSIONS
There is supportive evidence that memantine may help prevent cognitive deficits for adults with brain metastases receiving cranial irradiation. There is supportive evidence that donepezil may have a role in treating cognitive deficits in adults with primary or metastatic brain tumours who have been treated with cranial irradiation. Patient withdrawal affected the statistical power of both studies. Further research that tries to minimise the withdrawal of consent, and subsequently reduce the requirement for imputation procedures, may offer a higher quality of evidence.There is no strong evidence to support any non-pharmacological interventions (medical or cognitive/behavioural) in the prevention or amelioration of cognitive deficits. Non-randomised studies appear promising but are as yet to be conclusive via translation into high quality evidence. Further research is required.
Topics: Adult; Benzhydryl Compounds; Cognition Disorders; Cranial Irradiation; Donepezil; Humans; Indans; Memantine; Methylphenidate; Modafinil; Nootropic Agents; Piperidines; Randomized Controlled Trials as Topic
PubMed: 25519950
DOI: 10.1002/14651858.CD011335.pub2 -
Journal of Psychiatric Research Jan 2015We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of modafinil or armodafinil (ar/mod) augmentation in schizophrenia. We searched... (Meta-Analysis)
Meta-Analysis Review
We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) of modafinil or armodafinil (ar/mod) augmentation in schizophrenia. We searched PubMed, clinical trial registries, reference lists, and other sources for parallel group, placebo-controlled RCTs. Our primary outcome variable was the effect of ar/mod on negative symptom outcomes. Eight RCTs (pooled N = 372; median duration, 8 weeks) met our selection criteria. Ar/mod (200 mg/day) significantly attenuated negative symptom ratings (6 RCTs; N = 322; standardized mean difference [SMD], -0.26; 95% CI, -0.48 to -0.04). This finding remained similar in all but one sensitivity analysis - when the only RCT in acutely ill patients was excluded, the outcome was no longer statistically significant (SMD, -0.17; 95% CI, -0.51 to 0.06). The absolute advantage for ar/mod was small: just 0.27 points on the PANSS-N (6 RCTs). Ar/mod attenuated total psychopathology ratings (7 RCTs; N = 342; SMD, -0.23; 95% CI, -0.45 to -0.02) but did not influence positive symptom ratings (5 RCTs; N = 302; mean difference, -0.58; 95% CI, -1.71 to 0.55). Although data were limited, cognition, fatigue, daytime drowsiness, adverse events, and drop out rates did not differ significantly between ar/mod and placebo groups. Fixed and random effects models yielded similar results. There was no heterogeneity in all but one analysis. Publication bias could not be tested. We conclude that ar/mod (200 mg/day) is safe and well tolerated in the short-term treatment of schizophrenia. Ar/mod reduces negative symptoms with a small effect size; the absolute advantage is also small, and the advantage disappears when chronically ill patients or those with high negative symptom burden are treated. Ar/mod does not benefit or worsen other symptom dimensions in schizophrenia.
Topics: Adult; Antipsychotic Agents; Benzhydryl Compounds; Cognition; Fatigue; Female; Humans; Male; Middle Aged; Modafinil; Randomized Controlled Trials as Topic; Schizophrenia; Sleep Stages; Wakefulness-Promoting Agents
PubMed: 25306261
DOI: 10.1016/j.jpsychires.2014.09.013 -
The Cochrane Database of Systematic... Aug 2014Shift work results in sleep-wake disturbances, which cause sleepiness during night shifts and reduce sleep length and quality in daytime sleep after the night shift. In... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Shift work results in sleep-wake disturbances, which cause sleepiness during night shifts and reduce sleep length and quality in daytime sleep after the night shift. In its serious form it is also called shift work sleep disorder. Various pharmacological products are used to ameliorate symptoms of sleepiness or poor sleep length and quality.
OBJECTIVES
To evaluate the effects of pharmacological interventions to reduce sleepiness or to improve alertness at work and decrease sleep disturbances whilst off work, or both, in workers undertaking shift work in their present job and to assess their cost-effectiveness.
SEARCH METHODS
We searched CENTRAL, MEDLINE, EMBASE, PubMed and PsycINFO up to 20 September 2013 and ClinicalTrials.gov up to July 2013. We also screened reference lists of included trials and relevant reviews.
SELECTION CRITERIA
We included all eligible randomised controlled trials (RCTs), including cross-over RCTs, of pharmacological products among workers who were engaged in shift work (including night shifts) in their present jobs and who may or may not have had sleep problems. Primary outcomes were sleep length and sleep quality while off work, alertness and sleepiness, or fatigue at work.
DATA COLLECTION AND ANALYSIS
Two authors independently selected studies, extracted data and assessed risk of bias in included trials. We performed meta-analyses where appropriate.
MAIN RESULTS
We included 15 randomised placebo-controlled trials with 718 participants. Nine trials evaluated the effect of melatonin and two the effect of hypnotics for improving sleep problems. One trial assessed the effect of modafinil, two of armodafinil and one examined caffeine plus naps to decrease sleepiness or to increase alertness.Melatonin (1 to 10 mg) after the night shift may increase sleep length during daytime sleep (mean difference (MD) 24 minutes, 95% confidence interval (CI) 9.8 to 38.9; seven trials, 263 participants, low quality evidence) and night-time sleep (MD 17 minutes, 95% CI 3.71 to 30.22; three trials, 234 participants, low quality evidence) compared to placebo. We did not find a dose-response effect. Melatonin may lead to similar sleep latency times as placebo (MD 0.37minutes, 95% CI - 1.55 to 2.29; five trials, 74 participants, low quality evidence).Hypnotic medication, zopiclone, did not result in significantly longer daytime sleep length compared to placebo in one low quality trial and we could not use the data from the study on lormetazepam.Armodafinil taken before the night shift probably reduces sleepiness by one point on the Karolinska Sleepiness Scale (KSS) (MD -0.99, 95% CI -1.32 to -0.67; range 1 to 10; two trials, 572 participants, moderate quality evidence) and increases alertness by 50 ms in a simple reaction time test (MD -50.0, 95% CI -85.5 to -15.5) at three months' follow-up in shift work sleep disorder patients. Modafinil probably has similar effects on sleepiness (KSS) (MD -0.90, 95% CI -1.45 to -0.35; one trial, 183 participants, moderate quality evidence) and alertness in the psychomotor vigilance test in the same patient group. Post-marketing, severe skin reactions have been reported. Adverse effects reported by trial participants were headache, nausea and a rise in blood pressure. There were no trials in non-patient shift workers.Based on one trial, caffeine plus pre-shift naps taken before the night shift decreased sleepiness (KSS) (MD -0.63, 95% CI -1.09 to -0.17).We judged most trials to have a low risk of bias even though the randomisation method and allocation concealment were often not described.
AUTHORS' CONCLUSIONS
There is low quality evidence that melatonin improves sleep length after a night shift but not other sleep quality parameters. Both modafinil and armodafinil increase alertness and reduce sleepiness to some extent in employees who suffer from shift work sleep disorder but they are associated with adverse events. Caffeine plus naps reduces sleepiness during the night shift, but the quality of evidence is low. Based on one low quality trial, hypnotics did not improve sleep length and quality after a night shift.We need more and better quality trials on the beneficial and adverse effects and costs of all pharmacological agents that induce sleep or promote alertness in shift workers both with and without a diagnosis of shift work sleep disorder. We also need systematic reviews of their adverse effects.
Topics: Azabicyclo Compounds; Benzhydryl Compounds; Caffeine; Humans; Hypnotics and Sedatives; Melatonin; Modafinil; Piperazines; Randomized Controlled Trials as Topic; Sleep; Sleep Disorders, Circadian Rhythm; Wakefulness; Wakefulness-Promoting Agents
PubMed: 25113164
DOI: 10.1002/14651858.CD009776.pub2 -
The Cochrane Database of Systematic... May 2021Idiopathic hypersomnia is a disorder of excessive daytime sleepiness, often accompanied by long sleep times or pronounced difficulty in awakening, in the absence of a... (Meta-Analysis)
Meta-Analysis
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.
Topics: Bias; Clarithromycin; Disorders of Excessive Somnolence; Humans; Idiopathic Hypersomnia; Modafinil; Placebos; Quality of Life; Randomized Controlled Trials as Topic; Wakefulness; Wakefulness-Promoting Agents
PubMed: 34031871
DOI: 10.1002/14651858.CD012714.pub2