Pharmacological treatments for fatigue in patients with multiple sclerosis: A systematic review and meta-analysis
Introduction
Multiple sclerosis (MS) is a chronic immune-mediated inflammatory disease that causes demyelination of the central nervous system (CNS). The pathological cascades of MS are characterized by penetration of immune cells into the CNS, triggering inflammation, leading to demyelination of neurons, and eventually axonal degeneration. Fatigue, characterizing by tiredness, weakness or lack of energy, is the most common symptom of MS patients, affecting over 80% of MS patients [1]. Fatigue can significantly impact the quality of life in MS patients, as it greatly restricts their everyday activities, energy levels and productivity. Due to subjective nature of fatigue manifestations, symptoms of fatigue were always clinically overlooked during MS treatment.
In clinical practice, a variety of tests including Modified Fatigue Impact Scale (MFIS), Fatigue Impact Scale (FIS), Fatigue Severity Scale (FSS) and Visual Analogue Scale (VAS) are used to assess the severity of fatigue. Among these scales, FSS is the widely used as it is more easily and fast to screen MS fatigue relative to other scales.
Several drugs such as amantadine, modafinil, pemoline, aspirin, acetyl-l-carnitine and 4-aminopyridine have been used clinically on MS patients. Among these drugs, amantadine was the most widely used in treatment of MS fatigue. Additionally, other aforementioned pharmaceuticals excluding amantadine have also been used to treat fatigue by differential clinical institution. However, it is required to systematically determinate the efficacy and side effects of these drugs.
Section snippets
Search strategy
According to clinical practice experience and previous search protocols [2], these drugs (amantadine, modafinil, aspirin, acetyl-l-carnitine, pemoline and 4-aminopyridine) were selected in this study. We researched PubMed, Embase, Medline, Google Scholar, Cochrane Library (31 September 2016), the search terms included multiple sclerosis, fatigue, pharmacological treatments, amantadine, modafinil, aspirin, acetyl-l-carnitine, pemoline, 4-aminopyridine and randomized controlled trial. We
Study characteristics
A total of 690 citations were identified from the databases, of which 645 were excluded after a preliminary review. The remaining 45 studies were retrieved for detailed assessment. Upon further screening, 11 articles (total number of participants 723) were included in the review [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13] (see Tables 1 and 2). Pharmacological treatments were recorded, including amantadine (n = 7), modafinil (n = 4), acetyl-l-carnitine (n = 2), aspirin (n = 1), pemoline (n =
Discussion
Fatigue is a common, multidimensional, complex and highly subjective symptom of MS. It significantly impedes patients' daily life, personal relationships and work quality. Therefore, effective manages of MS fatigue were of great clinical values. Currently, a few studies have examined the efficacy of amantadine, modafinil, aspirin, acetyl-l-carnitine, pemoline, and 4-aminopyridine in treatment of MS fatigue. In this review, we included 11 articles that involves these drugs, and conducted 5
Acknowledgments
This work was supported by the National Science Foundation of Chongqing Science and Technology Commission (CSTC, cstc2016jcyjA1406).
References (20)
- et al.
Comparison of the effects of acetyl-l-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial
J. Neurol. Sci.
(2004) - et al.
Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients
Clin. Neurol. Neurosurg.
(2015) MS Practice – For Health Professionals
Management of fatigue in patients with multiple sclerosis
Drugs
(2004)- et al.
The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis
Arch. Neurol.
(1996) - et al.
Fatigue therapy in multiple sclerosis results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo
Neurology
(1995) A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. The Canadian MS Research Group
Can. J. Neurol. Sci.
(1987)- et al.
Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study
Neurology
(2005) - et al.
Fampridine-SR in multiple sclerosis: a randomized, double-blind, placebo-controlled, dose-ranging study
Mult. Scler.
(2007) - et al.
Modafinil effects in multiple sclerosis patients with fatigue
J. Neurol.
(2009)
Cited by (59)
Amantadine-induced corneal edema: A case and literature review
2023, American Journal of Ophthalmology Case ReportsWhat Special Considerations Are Needed for Individuals with Amyotrophic Lateral Sclerosis, Parkinson’s Disease, and Multiple Sclerosis?
2023, Evidence-Based Practice of Palliative Medicine, Second EditionTreatment of multiple sclerosis fatigue with the synthetic psychoactive drug modafinil
2022, Experimental NeurologyCitation Excerpt :Some studies have shown that modafinil at a dose of 200 mg/day may be beneficial in MS fatigue (Möller et al., 2011) but a more recent study showed no effect in comparison with placebo (Ford-Johnson et al., 2016). A systematic review and meta-analysis (Yang et al., 2017) evaluating pharmacological treatment for fatigue in MS showed that only amantadine has sufficient evidence for MS fatigue treatment, while modafinil does not. They found six to eight studies in three reviews (Lee et al., 2008; Brown et al., 2010; Branas, et al., 2000) with significant improvements in MS fatigue by modafinil; conversely, another review (Newton et al., 2020) found frail signs supporting the use of modafinil in MS. Considering the available data, the National Institute for Health and Care Excellence (NICE), which is a UK organization evaluating the cost/effectiveness ratio of drugs and other approaches in health and disease by a careful analysis of available evidence, does not encourage the use of modafinil in MS in their guidelines.
Quality of life in multiple sclerosis is dominated by fatigue, disability and self-efficacy
2021, Journal of the Neurological SciencesCitation Excerpt :The key finding in the current study is that fatigue, disability and self-efficacy show a strong inference for impact upon QoL, which has several clinical implications. With respect to fatigue, several medications have been trialled [32] and for non-pharmacological interventions, there is some evidence that physical exercise and Cognitive Behavioural Therapy may have some clinical benefit [33]. Occupational Therapy-led fatigue management programmes have also shown a moderate level of evidence [34].
- 1
These authors contributed equally to this study.