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Open research questions in Fibromyalgia and Chronic Fatigue Syndrome Research

50 unresolved questions extracted from the limitations and future-work sections of 505 Fibromyalgia and Chronic Fatigue Syndrome Research papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Repeated handgrip strength (HGS) testing may quantify neuromuscular fatigability in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), but interpretation of within-subject variability as an effort-validity marker remains controversial.

    Repeated Handgrip Strength Variability in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Separating Disease-Related Fatigability from Force Gradation · 2026 · DOI

  • Currently, the impact of gender on acute-phase fatigue in stroke patients remains controversial, possibly because patients of different genders have differences in the perception or expression of fatigue symptoms, and women may be more sensitive to their discomfort (27).

    Meta-synthesis of fatigue symptom experience and influencing factors in post-stroke fatigue patients in a qualitative study · 2026 · DOI

  • Fatigue affects over half of patients with chronic liver disease (CLD) and is a major driver of impaired quality of life, yet it remains under-recognised because assessment relies almost entirely on subjective patient-reported outcomes (PROs).

    Pilot Validation of an AI-based Audiovisual Fatigue Assessment Tool (mAI Fatigue) in Chronic Liver Disease: A Multicentre Study · 2026 · DOI

  • The concomitant elevation of prefrontal TGF-β1 and cognitive deficits suggests a potential role for central TGF-β1 signaling in the pathophysiology of mental fatigue, although the precise nature of this relationship remains to be elucidated.

    Cognitive impairment and prefrontal TGF-β1 elevation in a rat model of fatigue · 2026 · DOI

  • Here, we compile evidence from literature that supports taste dysfunction, particularly alterations of taste perception mediated by Type II taste receptor cells, may be a critical underrecognized feature of ME/CFS.

    A hypothesis connecting dysgeusia due to defects in ATP-P2X3 signaling and fatigue in myalgic encephalomyelitis/chronic fatigue syndrome: lessons learned from long-COVID · 2026 · DOI

  • The exact mechanism underlying this severe outcome remains uncertain. Unlike the transient postoperative wors- ening, the post-radiation decline showed no remission. Whether interventions such as mitochondrial support (e.g., CoQ10, carnitine), anti-inflammatory approaches, or in- tensified pacing could mitigate such deterioration requires further research. Given the extreme rarity of patients with both established ME/CFS and an indication for radio- therapy, clinical experience and evidence remain virtually absent.

    Significant aggravation of pre-existing myalgic encephalomyelitis/chronic fatigue syndrome following proton beam therapy for sphenoid wing meningioma: case report · 2026 · DOI

  • This mixed-methods study integrates patient and clinician perspectives within an under-studied context and draws on a relatively large sample. Limitations include reliance on self- reported diagnoses, which were not independently validated and may introduce misclassification bias. Objective dis- ease activity measures were not included, limiting clinical contextualisation of symptom burden. However, the study aimed to capture patient-reported experiences, which may not be fully reflected by standard disease activity indices, particularly in the presence of persistent symptoms despite controlled disease. The predominantly female sample limits generalisability. Participants were recruited in part through patient organisations and may therefore represent a more engaged, health-literate, or advocacy-oriented group, intro- ducing potential selection bias. Analyses were descriptive and unadjusted for potential confounders; findings should therefore be interpreted as associations rather than causal relationships.

    Fibromyalgia in systemic autoimmune rheumatic diseases: a mixed-methods study of patient and clinician perspectives · 2026 · DOI

  • Participants were recruited via ME/CFS self‑help groups and the two German treatment centers in Berlin and Munich. As recruitment was based on self‑selection and snowballing, selection and homogeneity effects may have occurred, but with a sample size of n = 748 these can be considered moderate. A comparison with the actual gen‑ der‑ and age‑related prevalence/incidence in Germany was not possible due to a lack of reliable data. Women are likely slightly overrepresented (611 women vs. 138 men), but prevalence and incidence peaks correspond to Habermann-Horstmeier and Horstmeier Journal of Translational Medicine (2026) 24:606 Page 14 of 16 international findings (incidence peak: 30–39 years; prev‑ alence peak: 40–59 years) [44, 45]. Participants’ medical diagnoses and symptoms were self‑reported and did not rely on clinical verification. This may introduce selection and diagnostic bias. However, the aim of the study was not to estimate prevalence or evaluate diagnostic accuracy but to examine the internal structure of symptom clusters. Factor‑analytic methods are comparatively robust to such sampling heterogeneity. Self‑report Data may also be affected by recall bias. In addition, the pathophysiological classifications discussed in this study are derived from existing literature, rather than from direct biological measurements. Given the limited sample size, exploratory and confirmatory fac‑ tor analyses (EFA and CFA) could not be conducted on independent subsamples; instead, the full dataset was used. To assess the robustness of the findings, additional analyses were performed using a randomized, stratified training subsample stratified by sex and disease duration. While this procedure improves representativeness and reduces the risk of systematic bias, it does not replace validation in fully independent samples. The dichotomization of symptoms (yes/no) further constitutes a methodological constraint, as binary indi‑ cators reduces reduce variability and statistical power in structural equation modeling (SEM) and may attenuate factor loadings. This likely contributed to the moderate loadings observed in domains such as the Brain cluster. Dichotomous items are nevertheless common in clinical epidemiology because they reduce respondent burden and minimize recall bias. However, they capture sever‑ ity gradients only indirectly. Despite this limitation, all CFA and SEM models demonstrated excellent global fit indices, indicating that the underlying latent structure is robust. Future phases of this research program will therefore employ polytomous symptom scales to capture severity more precisely and further strengthen measure‑ ment sensitivity.

    Symptom clusters in ME/CFS reflect distinct neuroimmune and autonomic pathophysiological mechanisms: a translational model · 2026 · DOI

  • At present, there is no curative or approved disease-specific treatment for ME/CFS, and clinical management remains largely supportive, with the primary goals of symptom relief and functional maintenance. According to the latest CDC clinical guidance, current management focuses on post-exertional malaise, sleep disturbance, pain, orthostatic intolerance, and cognitive diÿculties, together with supportive care for coexisting anxiety, depression, and stress-related symptoms (Unger et al., 2016).

    Chronic stress and cognitive dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome: HPA axis dysregulation and hippocampal plasticity · 2026 · DOI

  • Illness intrusiveness and perceived control have been identified in studies of single illnesses as modifiable mechanisms for QOL, but are understudied in older adults with arthritis and MM.

    Illness Intrusiveness, Perceived Control, and Quality of Life in Older Adults with Arthritis and Multimorbidity · 2025 · DOI

  • Major findings Due to factors such as methodological shortcomings of existing studies, and the lack of evidence on individual modalities, it is difficult to draw definitive conclusions as to which is the most appropriate rehabilitation approach in FMS.

    Evidence-based approaches for the management of fibromyalgia syndrome: a scoping review · 2023 · DOI

  • Although its aetiology is not fully understood, complex interactions between biological, genetic and various psycho-sociological factors are thought to be effective in the onset and maintenance of FM.

    Social cognition and attachment profiles of women with fibromyalgia syndrome: a case-control study · 2023 · DOI

  • The pathogenesis of FMS is still not fully understood, but an increasing amount of evidence supports the link between childhood/adulthood emotional, physical, sexual abuse or neglect and the development of FMS.

    The Challenge of Fibromyalgia Efficacy of Hypnosis in Alleviating the Invisible Pain: <i>A Narrative Review</i> · 2023 · DOI

  • Aims: Little is known about the prevalence and characteristics of functional somatic syndromes (FSS) such as irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), whiplash associated disorders (WAD), multiple chemical sensitivity (MCS), and bodily distress syndrome (BDS) in the general population when they are investigated simultaneously.

    Prevalence of functional somatic syndromes and bodily distress syndrome in the Danish population: the DanFunD study · 2019 · DOI

  • Given that anxiety has been inadequately studied (and perhaps evaluated and treated) in rehabilitation populations, the current findings suggest that researchers and clinicians should broaden their scope when assessing and treating psychological distress to incorporate anxiety and related disorders.

    Anxiety, depression, and function in individuals with chronic physical conditions: A longitudinal analysis. · 2018 · DOI

  • Despite flourishing interest in the topic of fatigue—as indicated by the many presentations on fatigue at the 2015 annual meeting of the American College of Sports Medicine—surprisingly little is known about its impact on human performance.

    Translating Fatigue to Human Performance · 2016 · DOI

  • The emerging pattern of changes in the percentages of circulating monocyte subpopulations concomitant with higher ratings of perceived pain and the correlation between stress and pain found in the FM group warrant further investigation.

    Stress, Inflammation and Pain: A Potential Role for Monocytes in Fibromyalgia-related Symptom Severity · 2015 · DOI

  • The low prevalence of FM is considered an underestimation and results from insufficient knowledge about FM In order to increase the general awareness of the unique nature of pain in fibromyalgia and the right of patients to receive specific attention, EFIC (European Federation of the IASP Chapters) launched the European campaign against pain in fibromyalgia.

    Fibromyalgia: Up to date aspects of patophysiology, diagnosis and treatment · 2010 · DOI

  • Future research should examine longitudinal changes in quality of social support and the corresponding changes in health status and psychological well‐being, as well as the effects of integrating manipulations designed to affect the quality of social support into community interventions designed to enhance the well‐being of women with FMS.

    Social support in women with fibromyalgia: Is quality more important than quantity? · 2004 · DOI

  • However, the current evidence is limited, and further high-quality studies are needed to confirm its effects on quality of life and long- term outcomes.

    Efficacy and safety of hyperbaric oxygen therapy for women with fibromyalgia: a systematic review and meta-analysis of randomized controlled trials · 2026 · DOI

  • 0) are clinically notable, but the broader applicability of this single observation is limited by the unique dual-disease context, the absence of a control condition, the unblinded single-assessor design, the absence of objective biomarkers, and the short follow-up period.

    Sequential Clinical Changes Following Autologous Mesenchymal Stem Cell Therapy in a Patient With Concurrent Huntington's Disease and Ankylosing Spondylitis: A Case Report · 2026 · DOI

  • However, there was insufficient support for short-term accumulation or sensitisation effects, implying that higher levels of workload on previous days did not directly affect or amplify the effect of workload on fatigue on that day.

    It’s a new day – is it? Testing accumulation and sensitisation effects of workload on fatigue in daily diary studies · 2023 · DOI

  • To provide an optimal treatment strategy, insight into a patient’s current physical activity level and pattern is necessary and identification of reliable and valid measures or scales measuring physical activity level and pattern in this population is warranted.

    Measuring the physical activity level and pattern in daily life in persons with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic review · 2017 · DOI

  • Emotional processing predicted outcome for patients with chronic fatigue and therefore future research might explore this in more depth, in order to understand better how it can be facilitated.

    Investigating the active ingredients of cognitive behaviour therapy and counselling for patients with chronic fatigue in primary care: Developing a new process measure to assess treatment fidelity and predict outcome · 2006 · DOI

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50 open questions have been extracted from the limitations and future-work passages of 505 Fibromyalgia and Chronic Fatigue Syndrome Research papers in our library. Each one below links back to the study that raised it, so you can read the original claim in context.

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