Multiple sclerosis (MS) is a demyelinating, neurodegenerative disease of the central nervous system, with fatigue being one of its main symptoms. The aetiology of fatigue in MS is unknown. Several studies have linked coenzyme Q10 (CoQ10) supplementation to benefits in reducing fatigue in various diseases. The primary objective of this study was to determine the efficacy of CoQ10 administration for reducing fatigue in patients diagnosed with MS. As secondary objectives, we sought to estimate the existence of differences between different types of MS and to evaluate the optimal dose for the treatment of fatigue in MS.
MethodsA systematic review was conducted according to the PRISMA guidelines. The MEDLINE, Embase, and Web of Science databases were consulted, and studies including adult patients diagnosed with MS-related fatigue who had been administered CoQ10/ubidecarenone were included.
ResultsA total of 3 studies were obtained: 2 randomised clinical trials and one non-randomised experimental study. In all studies, patients were diagnosed with relapsing–remitting MS (RRMS) and received oral CoQ10 supplementation for 12 weeks, with variations in the doses administered. All studies reported a significant reduction in fatigue in the intervention group (CoQ10 supplementation).
ConclusionsThe results support the use of CoQ10 supplementation to reduce fatigue in RRMS. Further long-term studies are recommended to confirm its protective effects on fatigue and to clarify the optimal dosage.
La esclerosis múltiple (EM) es una enfermedad neurodegenerativa desmielinizante del sistema nervioso central, siendo la fatiga uno de sus principales síntomas. Se desconoce la etiología de la fatiga en la EM. Diversos estudios han relacionado la suplementación con coenzima Q10 (CoQ10) con beneficios en la reducción de la fatiga en diversas enfermedades. El objetivo principal de este estudio fue determinar la eficacia de la administración de CoQ10 para reducir la fatiga en pacientes con diagnóstico de EM. Como objetivos secundarios, se buscó estimar la existencia de diferencias entre los distintos tipos de EM y evaluar la dosis óptima para el tratamiento de la fatiga en la EM.
MétodosSe realizó una revisión sistemática según las directrices PRISMA. Se consultaron las bases de datos MEDLINE, Embase y Web of Science, y se incluyeron estudios que incluían pacientes adultos con diagnóstico de fatiga relacionada con la EM a quienes se les había administrado CoQ10/ubidecarenona.
ResultadosSe obtuvieron un total de 3 estudios: 2 ensayos clínicos aleatorizados y un estudio experimental no aleatorizado. En todos los estudios, los pacientes fueron diagnosticados con EM remitente-recurrente (EMRR) y recibieron suplementos orales de CoQ10 durante 12 semanas, con variaciones en las dosis administradas. Todos los estudios informaron una reducción significativa de la fatiga en el grupo de intervención (suplementación con CoQ10).
ConclusionesLos resultados respaldan el uso de suplementos de CoQ10 para reducir la fatiga en la EMRR. Se recomienda realizar estudios a largo plazo adicionales para confirmar sus efectos protectores sobre la fatiga y determinar la dosis óptima.
Multiple sclerosis (MS) is a chronic autoimmune disease that causes central nervous system (CNS) demyelination and neurodegeneration, resulting in irreversible axonal loss and gliosis.1 It may present with 2 basic courses: relapsing–remitting forms, and progressive forms, which are further classified as primary progressive, when MS is progressive from disease onset, and secondary progressive, when it becomes progressive after an initial relapsing phase. According to disease progression, we may classify MS into different subtypes: relapsing–remitting (RRMS), secondary progressive (SPMS), and primary progressive (PPMS). We may also include clinically isolated syndrome (CIS), which does not meet all criteria for MS but often represents the first symptom of the disease.2
In addition to the basic phenotype (relapsing–remitting or progressive), 2 additional elements are used to characterise the disease course: activity and progression. Clinical activity is defined as the existence of relapses over a given period of time. MS is characterised as radiologically active if MRI detects new lesions, a clear increase in the size of existing lesions, or the appearance of gadolinium-enhancing lesions. In the absence of relapses or MRI activity, the disease is considered not to be active. On the other hand, evidence of sustained clinical worsening (clinical history or objective findings from patient examination) over a given period of time, independently of the presence of relapses, indicates disease progression. It is important to understand that progressive MS does not progress homogeneously; rather, it varies over time.
The underlying process in MS causes a variety of symptoms, with fatigue being one of the most frequent and the most challenging for patients. Fatigue in MS, described as an overwhelming sensation of physical and mental exhaustion, is disproportionate to the activity performed and significantly limits patients' quality of life.3
With an incidence of 80% among patients with MS, fatigue not only impacts the physical sphere but also their work and social activities and is responsible for a considerable reduction in their ability to work.4 Fatigue may be classified as primary, that caused directly by MS, and secondary, that derived from various medical comorbidities and associated conditions, such as depression, sleep disorders, intercurrent processes, adverse effects of long-term medication, or muscle weakness.
The exact aetiology of fatigue in MS is unknown, although a combination of factors is thought to be involved, including structural damage to CNS grey matter and white matter, autoimmune disorders, endocrine disorders, mitochondrial dysfunction, and a pro-inflammatory state.5–7
In this context, coenzyme Q10 (coQ10) may be a potentially relevant agent. In addition to its role as a lipid-soluble antioxidant, it is essential in the mitochondrial electron transport chain, suggesting potential involvement in MS fatigue.
CoQ10, also known as ubiquinone, is synthesised naturally by the body; it is present in the majority of eukaryotic cells, and particularly in the mitochondria. CoQ10 concentrations are highest in organs with higher energy needs, such as the heart, liver, and kidneys; the molecule generates energy through its participation in the electron transport chain and ATP production in aerobic cellular respiration. Another of its multiple functions is as an antioxidant and immune system stimulant, and protecting against cardiac disease.8
CoQ10 deficiency may occur for various reasons, including deficiency of nutrients involved in its synthesis, genetic defects in CoQ10 synthesis or use, and certain diseases that increase the demand for CoQ10 in tissues.9
Although CoQ10 supplementation has demonstrated benefits in reducing fatigue in many diseases, including chronic fatigue syndrome, fibromyalgia, and fatigue associated with statin use,10–13 its efficacy in the context of MS-related fatigue is still under investigation.
In this regard, a systematic review by Mehrabani et al.13 found that CoQ10 has greater therapeutic effects in patients with fatigue related to statin use and fibromyalgia, underscoring the need for deeper exploration of its potential impact on MS-associated fatigue.
The efficacy of CoQ10 in treating fatigue in patients with MS has not yet been established.
The main objective of this review was to determine the efficacy of CoQ10 in reducing fatigue in patients diagnosed with MS. As specific objectives, we aimed to establish whether there are differences between the different types of MS and to evaluate the optimal dose in treating MS-associated fatigue.
Materials and methodsWe conducted a systematic literature review based on the PRISMA guidelines.14
The study includes systematic reviews and experimental and observational studies of adult patients with fatigue and diagnosed with MS and undergoing interventions involving the administration of CoQ10/ubidecarenone; eligible studies had to be written in English or Spanish and published in the last 10 years.
Search strategyIn February 2024, a search was conducted on the main literature databases: MEDLINE, Embase, and Web of Science.
The search involved 2 phases: a search for systematic reviews and a search for research studies. The complete strategy is included in Appendix 1.
The results of the literature search were downloaded using the Zotero bibliography management software in order to remove duplicate references. A total of 36 studies were identified.
To select articles that met the inclusion criteria, results were screened in 3 phases: by title, by abstract, and by full text. A total of 3 articles were selected. (see Fig. 1).
Assessment of methodological quality
The procedure followed in this systematic review ensured that the studies included present high levels of scientific evidence.
We established minimum levels of methodological quality for the articles selected for review. Thus, studies that did not meet at least 56% of the items in the evaluation criteria applied (CONSORT and TREND statements) were considered deficient in terms of methodology.
For randomised clinical trials (RCTs), we followed the CONSORT criteria.15 The RCTs by Bitarafan et al.16 and Sanoobar et al.17 scored 17 and 14 points, respectively, of a total of 25.
For the non-randomised experimental study, we used the TREND criteria.18 The study by Moccia et al.19 met 14 of the 22 criteria (Appendix 2).
VariablesMethodological variables-Study design: our systematic review included original, analytical, experimental studies with a high or moderate level of evidence according to the GRADE system.20
-Sample size: the study includes a minimum sample size of 100.
Clinical variables-Clinical outcome variable: fatigue was defined as a lack of physical or mental energy. Symptoms of fatigue were studied using the Fatigue Severity Scale (FSS), a unidimensional scale measuring the severity of this symptom.21 The FSS includes 9 items, each of which is scored from one point (strongly disagree) to 7 points (strongly agree). The total FSS score is the sum of all item scores divided by 9, yielding a mean score reflecting the general severity of fatigue as perceived by the patient (higher scores indicate more severe fatigue). In this case, to maintain homogeneity among the studies analysed, values are expressed as the global score, with a maximum possible value of 63 (Appendix 3).
-Type of MS: CIS, RRMS, PPMS, and SPMS.
-Intervention and/or experimental conditions: we analysed the CoQ10 dose administered, frequency of administration, and form and duration of treatment.
ResultsOverall calculation of variablesThe literature search yielded a total of 3 studies: 2 RCTs and one non-randomised experimental study.
The RCT by Sanoobar et al.,17 conducted in Iran, included a total of 48 patients: 24 in the CoQ10 group (mean age [standard deviation], 33.1 [7.6] years) and 24 in the placebo group (mean age, 30.9 [7.7] years). In this study, the baseline fatigue score was 43.1 (10) in the CoQ10 group, decreasing to 33 (12.6) after treatment (41.5 [15.6] at baseline and 45 [13.6] after treatment in the placebo group).
The RCT by Bitarafan et al.,16 also conducted in Iran, included a total of 46 patients: 23 in the multivitamin-mineral (MVM) treatment group and 23 in the placebo group, with a mean age of 35.35 (5.73) years. Patients in the intervention group presented an FSS score of 38.52 (8.01) at baseline, decreasing to 35.52 (8.23) after treatment with MVM (36.20 [6.46] at baseline and 35.80 [6.72] after treatment in the placebo group).
Both RCTs had a duration of 12 weeks, and both included samples of patients diagnosed with RRMS.
The non-randomised experimental study included for review was conducted in Italy by Moccia et al.19 This study followed a crossover design and included a total of 60 patients with RRMS under concomitant treatment with interferon beta1a (IFN-β1a) 44 μg plus CoQ10 for 3 months, and subsequently with IFN-β1a 44 μg for a further 3 months. In this study, the authors only report the coefficient of the reduction in FSS score (−4.527).
The main results of the studies reviewed are summarised below and are synthesised in Table 1.
Summary of results from the systematic review.
| Study | Design | Sample | Duration | Change in outcome variable(fatigue) | Type of MS | Experimental intervention(CoQ10 dose, frequency, administration pathway, duration) | ||
|---|---|---|---|---|---|---|---|---|
| Sanoobar et al.17 | RCT | Total = 48CoQ10 group = 24Placebo group =24 | 12 weeks | Change from baseline:-CoQ10 group:−10.09; P = .001-Placebo group:+3.4; P = .001 | RR | CoQ10 500 mg (oral) | Frequency: daily | Duration: 12 weeks |
| Bitarafan et al.16 | RCT | Total = 46MVM group =23Placebo group =23 | 12weeks | Change from baseline:-MVM group:−3.00 (4.42);P = .005-Placebo group:−0.40 (5.14);P = .730No significant difference was found between groups(P = .090). | RR | 2 MVM capsules containing:350 μg vit. A, 15 μg vit. D, 7.5 mg vit. D, 75 mg vit. C, 1.1 mg vit. B1, 1.5 mg vit. B6, 400 μg vit. B9, 2.4 μg de vit. B12, 250 mg Ca, 160 mg Mg, 27 μg Se, 200 mg CoQ10, and 100 mg L-carnitine(oral) | Frequency: daily | Duration: 12 weeks |
| Moccia et al.19 | Non-randomised, crossover experimental study | Total = 60 | 24weeks | Change after treatment (CoQ10 plus IFN-β1a vs IFN-β1a only).−4.527(95% confidence interval, −9.424 to −1.368); P = .027 | RR | CoQ10 200 mg (oral) | Frequency: daily | Duration: 12 weeks |
Ca: calcium; CoQ10: coenzyme Q10; IFN-β1a: interferon beta1a; Mg: magnesium; MS: multiple sclerosis; MVM: multivitamin-mineral supplementation; RCT: randomised clinical trial; RR: relapsing–remitting multiple sclerosis; Se: selenium; vit.: vitamin.
•Variation in the outcome variable (fatigue):
In all studies, the intervention group receiving CoQ10 presented a significant reduction in fatigue (P < .05), with a mean reduction in FSS score of −5.87 points with respect to baseline.
It should be noted that in the study by Bitarafan et al.,16 patients received vitamin supplementation in addition to CoQ10, which may also have positively contributed to the reduction in fatigue.
•Types of MS:
All patients included in all 3 studies presented RRMS.
•Experimental intervention:
In all studies, patients received CoQ10 supplementation orally for 12 weeks, with differences in the doses administered.
In the study by Sanoobar et al.,17 CoQ10 was dosed at 500 mg/day, whereas the other 2 studies used doses of 200 mg/day. It should be noted that in the study by Bitarafan et al.,16 CoQ10 was not administered in isolation but rather in combination with other vitamin supplements.
We should also note that fatigue was not the only variable analysed in the different studies. The study by Bitarafan et al.16 also measured cytokine levels before and after MVM supplementation. The study by Moccia et al.19 examined the impact on laboratory markers associated with oxidative stress and inflammation, as well as other clinical measures of MS severity. The RCT by Sanoobar et al.17 studied the impact of CoQ10 on depression in addition to the change in fatigue.
DiscussionMS is characterised by inflammation, demyelination, and destruction of axons in the CNS. However, the precise aetiology of fatigue is unknown. One hypothesis is that patients with MS need to recruit more cerebral nerve fibres compared to healthy individuals, which may cause fatigue.22
The objective of this review was to determine the efficacy of CoQ10 in reducing fatigue in patients diagnosed with MS.
The anti-inflammatory and antioxidant properties of CoQ10 were studied at different doses. Sanoobar et al.17 used a dose of 500 mg per day, whereas Moccia et al.19 dosed CoQ10 at 200 mg per day. Bitarafan et al.16 used a dose of 200 mg CoQ10 per day, as well as other vitamins and minerals (vitamins A, D, C, B1, B6, and B9; calcium, magnesium, selenium, and L-carnitine), which may have had some effect on MS-associated fatigue, potentially biasing the results. A study by Maric et al.23 reported an improvement in fatigue scale scores in patients with chronic fatigue syndrome receiving multivitamin supplementation for 2 months; it may be possible to extrapolate these results to fatigue in MS.
The articles reviewed, 2 RCTs and one non-randomised study, reported a statistically significant mean reduction in FSS scores of −5.87 points with respect to baseline (P < .05). These results support the usefulness of this supplement in the treatment of fatigue in patients with MS, expanding its potential benefits for treating better-studied fatigue conditions, such as fibromyalgia or chronic fatigue syndrome.10–13
It was not possible in this review to determine whether the efficacy of the treatment differs between different types of MS, as all studies exclusively included patients with MS.
Certain methodological limitations should be taken into account when analysing our results.
The revision included 2 RCTs and one non-randomised experimental study. The latter followed an open-label crossover design in which patients knew that they were receiving the experimental treatment, and used no washout period between treatments. This may have resulted in biases in the interpretation of the results. However, due to the crossover design, each patient acted as their own control, which enables the elimination of numerous confounding factors (covariates) and facilitates comparative analysis, with a smaller number of patients needed to demonstrate the findings.
It should also be noted that, although all the studies included used the same instrument to measure fatigue (the FSS), the conditions of the studies were not the same. In the study by Moccia et al.,19 one of the inclusion criteria was having been under treatment with IFN-β1a 44 μg for at least 6 months prior, and not previously having received any other treatment. The trial by Bitarafan et al.16 also required patients to have been receiving interferon for at least 3 months. As inflammatory cytokines released by immune cells may be another possible cause of fatigue in patients with MS, there may be a synergy between CoQ10 and IFN-β24 (interferons are endogenous glycoproteins with immunomodulatory, antiviral, and antiproliferative properties25), which may bias our study results.
Furthermore, the studies reviewed do not account for the fact that certain disease-modifying treatments indicated for MS, such as IFN-β1a, alemtuzumab, ofatumumab, ocrelizumab, natalizumab, and ponesimod,25–30 as well as other drugs used for symptom control (THC/CBD spray, baclofen31,32), may cause fatigue as an adverse effect.
Due to the multifactorial, idiopathic aetiology of MS-related fatigue, it is important to perform a comprehensive patient evaluation: we must rule out other causes of fatigue, such as intercurrent infections (which are more frequent in patients with bladder dysfunction or receiving immunosuppressive treatment) and screen for potential drug interactions that may have a synergistic effect on these symptoms. In this regard, interdisciplinary collaboration is proposed as the optimal strategy for addressing and solving problems that can cause limitations in everyday life and greatly impact patients' quality of life, independently of the type of disease.33
ConclusionsThis systematic review of 2 RCTs and one non-randomised, open-label, crossover experimental study observed a significant reduction in MS-related fatigue after 12 weeks' treatment with CoQ10. However, larger studies with longer follow-up periods are needed to confirm the protective effects of CoQ10 against fatigue.
A daily CoQ10 dose of 200 mg achieved a significant reduction in fatigue, although the best results were observed with a dose of 500 mg per day, reported in the study by Sanoobar et al.17
Given the disabling impact of fatigue in the physical, professional, and psychosocial spheres, and the lack of adverse effects of treatment with CoQ10, the supplement may be an appropriate option for treating fatigue in patients with RRMS. However, as all the studies reviewed were performed in patients with RRMS, its efficacy in progressive MS is not established; this represents a knowledge gap that should be addressed in future research.
Ethical considerationsThis review does not include patient data and, therefore, does not require informed consent or approval by the regional ethics committee.
FundingThis review has received no funding.
Conflicts of interestThe authors have no conflicts of interest to declare.
