Fibromyalgia, Chronic Fatigue Syndrome, and Multiple Sclerosis are associated with lower translocator protein binding affinity genotypes

Abstract:

Introduction: Neuroinflammation is a known pathophysiologic mechanism in multiple sclerosis and a proposed mechanism in fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Positron Emission Tomography (PET) imaging of the translocator protein (TSPO) has been widely used to measure neuroinflammation, though second-generation ligands are highly sensitive to a single nucleotide polymorphism, rs6971, resulting in high, mixed, and low affinity binders. It is unknown whether this polymorphism is associated with neuroinflammatory disorders.

Materials and methods: Eighty-six total participant genotypes for TSPO binding affinity were identified through Sanger sequencing (30 fibromyalgia, 21 ME/CFS, 11 multiple sclerosis, and 24 healthy controls). Associations between patient group and genotype were assessed with Fisher’s Exact test. Associations between genotype and symptom severity from self-report questionnaires were assessed with Kruskal-Wallis tests.

Results: In the present study individuals with fibromyalgia, (ME/CFS), or multiple sclerosis were more likely to have a mixed- or low-affinity genotypes compared to healthy controls. Presence of the low or mixed genotypes were also associated with greater self-reported fatigue severity and depressive symptoms.

Discussion: These findings should be confirmed in larger samples but suggest functional consequences of rs6971 polymorphism that may be related to the pathophysiology of pain and fatigue illnesses.

Source: Jones C, Younger J. Fibromyalgia, Chronic Fatigue Syndrome, and Multiple Sclerosis are associated with lower translocator protein binding affinity genotypes. medRxiv [Preprint]. 2026 Oct 21:2026.10.19.26365953. doi: 10.64898/2026.10.19.26365953. PMID: 42996068; PMCID: PMC13738865. https://pmc.ncbi.nlm.nih.gov/articles/PMC13738865/ (Full text)

Dr. Lapp on CFS versus FM: Twins, Cousins, or Just Acquaintances?

by Charles W. Lapp, MD
September 6, 2011

Ed Note: This article is reproduced with kind permission from Bruce Campbell’s CFIDS & Fibromyalgia Self-Help website (https://cfsselfhelp.org/). Dr. Lapp directed the Hunter-Hopkins Center in Charlotte, NC, one of the few medical practices in the US specializing in the treatment of ME/CFS and FM. [Dr. Lapp is now retired.]

Reprinted with the kind permission of Prohealth: 9/6/11

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Chronic Fatigue Syndrome is a disorder characterized by debilitating fatigue and recurrent flulike symptoms, such as muscle and joint aches, sore throat, swollen glands, and difficulty thinking. Fibromyalgia Syndrome is a disorder characterized by widespread muscle pain.

Can such different descriptions share anything in common?

Siamese Twins

Most experts agree that the symptoms of CFS and FM are so close that they are – for all intents – the same disorder. It’s a bit like Jekyll and Hyde, or perhaps like Chang and Eng Bunker, the Siamese twins made famous by P.T. Barnum. They were both the same “person” but had two different names, two similar but different personalities.

Assigning a Diagnosis

Patients who present to their primary care providers frequently relate a litany of complaints such as fatigue, vague aching, and trouble with memory or concentration.

Based on these complaints, the primary care doctor will most likely diagnose Chronic Fatigue Syndrome using the 1994 international case definition published by the Centers for Disease Control.

On the other hand,  the patient whose major complaint is pain will likely consult a rheumatologist who will ask, “Where does it hurt?” When it is determined that the patient hurts at the classical “tenderpoints” defined by the ACR [American College of Rheumatology] in 1990, the likely diagnosis will be Fibromyalgia.

Overlaps and Shadows

So one diagnosis is frequently given by primary care physicians and the other by rheumatologists. Both diagnoses have several features in common: exertional malaise [activity intensifying symptoms], cognitive difficulties, muscle pain (or myalgias) and a sleep disorder.

Both are frequently associated with “overlap disorders” or “shadow syndromes,” as I like to call them. The most common “shadow syndromes” are irritable bowel syndrome, irritable bladder, temperomandibular dysfunction, and mitral valve prolapse.

Others include premenstrual syndrome, primary dysmenorrhea, migraine, restless legs or periodic leg movements, Myofascial Pain Syndrome (MPS), chemical sensitivities, autonomic dysfunction (Neurally Mediated Hypotension and Postural Orthostatic Tachycardia Syndrome), Gulf War Syndrome, and possibly hyperextensibility, acne rosacea, Raynaud’s phenomenon, sicca complex (dry eyes and mouth) and vasomotor rhinitis (constant runny nose and congestion).

Note that the shadow syndromes occur predominantly in females, are defined clinically rather than by physical or laboratory findings, and many are associated with either pain or fatigue. It is likely that these disorders occur concurrently because they share a common biophysiological thread.

Fibromyalgia & CFS Compared

The symptoms are similar for both syndromes, including debilitating fatigue, post-exertional malaise, feverishness, sore throat, headache, joint aches, a feeling of generalized weakness, subjective swelling, non-radicular paresthesias (numbness or tingling that does not follow typical nerve patterns), memory loss, forgetfulness, confusion, irritability, and depressed mood.

There are some subtle differences, however. (See Table 1 at end of article.)  Historically, CFS is frequently triggered by a flulike or infectious illness, but sometimes occurs after trauma or surgery. FM, on the other hand, is frequently triggered by trauma, less often by an infectious process.

While there is a preponderance of women in both disorders, women are more likely to have FM (9:1) than CFS (7:3). The median age for both disorders is about 40 years, although all age groups are vulnerable, including children and seniors. Familial aggregations and overlapping HLA haplotypes are described for both disorders.

Physiologically, both disorders have in common reduced midbrain and cortical blood flow; autonomic dysfunction such as symptomatic orthostatic tachycardia and neurally mediated hypotension;  suppression of the hypothalamic pituitary axis; disturbed Stage 4 sleep; reduced serum or CSF serotonin levels; and suppression of growth hormone, somatomedin C, or IGF1. (Similarities are summarized in Table 2.)

Substance P, a neurotransmitter responsible for the transmission of pain is elevated in persons with FM (but not CFS); and RNaseL, a cellular antiviral enzyme is frequently elevated in CFS (but not in FM). These differences may reflect why pain is a key symptom in FM, and viral symptoms predominate in CFS.

Treatment

The treatment of CFS and FM is hampered by the absence of a known cause and pathophysiology. In such instances, treatment is generally limited to supportive care and symptomatic therapy. Thus a prudent diet, basic supplementation, and traditional management of sleep disruption, pain, and autonomic symptoms are the standard course.

Counseling is helpful in coping with chronic illness and stress, and study after study has extolled the virtues of low level progressive exercise. Activity must be approached cautiously, however.

“Pure cases” of FM seem to respond with increased endurance and improved well-being to a progressive exercise program, while “pure cases” of CFS are more likely to respond with increased cognitive and flulike symptoms to a similar regimen. Thus, persons with CFS may have to start at a lower level and progress more slowly.

Pure Cases

There are certainly cases of “pure CFS” or “pure FM.” When there is no significant complaint of muscle pain, the patient would be diagnosed as having “pure CFS,” mostly characterized by fatigue, cognitive dysfunction, sleep disruption, and flu-like symptoms including vague muscular aching during relapses.

When cognitive symptoms are minimal and widespread muscle pain is the major complaint, the patient is thought to have “pure FM.” These make up a minority of the cases,  however, since about 70% of persons with CFS meet criteria for FM, and about 70% of persons with FM also meet criteria for CFS.

In most aspects Fibromyalgia and CFS are almost identical. There are subtle differences in biochemistry, prevalence, and perhaps response to exercise that separate them ever so slightly. CFS and FM may represent the extreme ends of a spectrum of multisystem disorders characterized by fatigue, pain, and female predominance.

* * * *

Table 1: Differences
CFS                                 FM
Trigger                    Flulike > trauma        Trauma > flulike

Female to Male      7 to 3                          9 to 1
Predominance

Prevalence             400-800 per 100K    2,000 per 100K

Substance P           Normal                       Increased

RNaseL                  Increased                     Normal

Exercise
Intolerance              +++                            +

Table 2: Similarities

• Reduced cerebral blood flow in cortex and midbrain
• HPG Axis suppression
• Non-restorative sleep
• Reduced serum and/or CSF serotonin
• Low growth hormone
• Familial aggregation / haplotypes

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ProHealth Note – have you visited:

The Treating CFS & FM website (www.treatcfsfm.org). Dr. Lapp and Dr. Campbell are long-time collaborators who have also pooled their knowledge to create this website. It is a guide that can take you step-by-step through creation of a personal treatment plan.

Disclaimer: This material is posted for informational and educational purposes only and is not intended to substitute for medical or other professional advice. Consult your physician or other health care provider regarding your symptoms and medical needs.

 

Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia are overlapping chronic disorders characterized by fatigue, pain, cognitive dysfunction, sleep disturbance, and multisystem symptoms. Whether peripheral blood DNA methylation reflects diagnostic categories, quantitative symptom burden, or both remains unclear. We aimed to identify DNA methylation axes associated with diagnosis, symptom dimensions, and clinical differences between these conditions.

Methods: This cross-sectional study included 188 women: 73 healthy controls, 71 with ME/CFS, and 44 with fibromyalgia. DNA methylation was profiled in peripheral blood mononuclear cells using the Illumina MethylationEPIC v2 array. Principal component analysis identified latent methylation axes. Linear models adjusted for age, body mass index, and estimated immune-cell composition tested associations with diagnostic group and clinical measures. Region-level methylation analyses, functional enrichment, bootstrap resampling, permutation testing, leave-one-out analyses, and medication/comorbidity sensitivity analyses were performed.

Results: Both patient groups had greater symptom burden than healthy controls but differed clinically. Fibromyalgia showed greater widespread pain, pain catastrophizing, central sensitization inventory scores, and temporal summation, whereas ME/CFS showed greater post-exertional malaise, cognitive symptoms, and lower physical activity. Two methylation axes showed clinically relevant associations. PC5 differentiated ME/CFS from fibromyalgia and healthy controls and was associated mainly with post-exertional malaise and cognitive symptoms. PC6 separated both patient groups from healthy controls but not from each other, and was associated with broader symptom burden, including widespread pain, pain impact, sleep disturbance, visceral symptoms, and temporal summation. The temporal summation association, together with higher widespread pain and temporal summation in fibromyalgia, suggests that PC6 includes a pain-related component extending to experimentally assessed nociceptive summation. Region-level analyses identified 591 PC5-associated and 54 PC6-associated high-confidence differentially methylated regions. Enrichment implicated neuroimmune, metabolic, cytokine, NF-κB, JAK-STAT, TGF-β, and immune-regulatory pathways. Sensitivity analyses supported the stability of the main associations.

Conclusions: Peripheral blood DNA methylation profiles identified partly distinct but overlapping DNA methylation axes in ME/CFS and fibromyalgia. PC5 was aligned with post-exertional malaise and cognitive symptoms, whereas PC6 was aligned with broader pain-related multisystem burden. Independent replication and longitudinal studies are needed to establish clinical utility.

Source: Polli A, Hendrix J, Wyns A, Van Campenhout J, Allard S, Aerts JL, Laeremans T, Xiong H, Buntinx Y, Michiels J, Ben Amar J, Godderis L, Thienpont B, Nijs J. Epigenome-wide profiling identifies distinct DNA methylation architecture underlying ME/CFS and fibromyalgia symptom burden. J Transl Med. 2026 Aug 22;24(1):1222. doi: 10.1186/s12967-026-08824-5. PMID: 42811334. https://link.springer.com/article/10.1186/s12967-026-08824-5 (Full text)

Shared genetic risk between functional somatic syndromes, internalizing disorders, and immune-mediated diseases: a twin-sibling study

Abstract:

Functional somatic syndromes frequently co-occur with internalizing disorders such as anxiety disorders and major depressive disorder. Both show familial associations with immune-mediated diseases. Here, we estimate genetic and environmental contributions to functional somatic syndromes and their overlap with immune-mediated diseases, with internalizing disorders included for comparison.

The study sample consisted of 6,097,372 Swedish twins, full siblings, and half-siblings born between 1945 and 2003. From nationwide registers covering inpatient, outpatient and primary care, we extracted ICD diagnoses of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), fibromyalgia (FM), irritable bowel syndrome (IBS), major depression, anxiety disorders, and immune-mediated diseases (consisting of autoimmune and autoinflammatory diseases).

We used bivariate twin-sibling structural equation modeling to estimate genetic and environmental correlations. We found that the heritability of functional somatic syndromes and internalizing disorders ranged from 15 to 44%, with the unique environment explaining 49-84% of the variance. We estimated the heritability of immune-mediated diseases at 37% (95% CI 36-38%), with a unique environmental component of 63% (95% CI 62-63%). Regarding the genetic correlations with immune-mediated diseases, fibromyalgia showed the strongest genetic correlation (rA = 0.52, 95% CI 0.45-0.63), IBS, ME/CFS, and major depression showed more modest genetic correlations (rA range 0.19-0.29), and anxiety disorders showed minimal genetic correlation (rA = 0.04, 95% CI 0.00-0.08).

In summary, fibromyalgia, and to a lesser degree other functional somatic syndromes and major depression, share genetic risk factors with immune-mediated diseases. These findings suggest that immune-related genetic risk factors contribute to the etiology of fibromyalgia and, to a lesser extent, other functional disorders and major depression.

Source: Steen OD, Ohlsson H, van Ockenburg SL, Kendler KS, Rosmalen JGM, Sundquist K, van Loo HM. Shared genetic risk between functional somatic syndromes, internalizing disorders, and immune-mediated diseases: a twin-sibling study. Brain Behav Immun. 2026 May 25:106837. doi: 10.1016/j.bbi.2026.106837. Epub ahead of print. PMID: 42190845. https://www.sciencedirect.com/science/article/pii/S0889159126005854 (Full text)

Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating chronic illnesses with considerable symptom overlap. Their symptoms include profound fatigue, widespread pain, post-exertional deterioration, sleep disturbance, dysautonomia, and cognitive impairment. These illnesses frequently co-occur; ME/CFS often develops first, particularly after infection. This overlap creates a diagnostic grey area and contributes to severe reductions in quality of life. Despite these shared features, key distinctions remain essential. ME/CFS is characterised by post-exertional neuroimmune exhaustion (PENE)/post-exertional malaise (PEM), a hallmark of post-exertional worsening and multisystem involvement. Contrastingly, FM centres on chronic widespread pain and symptom variability. It is not characterised by PEM/PENE or the same extent of system dysfunction as ME/CFS. Both disorders lack a definitive biomarker as of 2025. Thus, diagnosis remains clinical and supported by objective tests where available.

Main body: Although immune dysregulation is common in patients with each condition, distinct immune signatures have been observed. ME/CFS is characterised by fluctuating pro- and anti-inflammatory cytokine levels and a frequent reduction in natural killer (NK) cell function; this is consistent with immune exhaustion. Patients with FM exhibit elevated IL-6, IL-17 A, and IL-4 levels, and a broader immune imbalance linked to pain amplification rather than immune collapse. Viral infections do not directly cause either condition, but commonly act as triggers. Shared mechanisms, such as spinal reflex arc activation and microglial sensitisation, suggest a common pathway mediated by proprioceptor-induced microglial activation for chronic pain. ME/CFS causes autoimmunity-like processes, whereas evidence of autoimmune drivers for FM is limited. Gut microbiome studies have revealed reduced microbial diversity in patients with ME/CFS. Moreover, the two disorders are characterised by shared, yet distinct, microbial alterations.

Conclusion: Given the chronic and debilitating nature of ME/CFS and FM, prevention and early intervention remain crucial, but understudied. Health education, workplace adaptations, and early diagnostic pathways may substantially reduce the disease burden. Many patients are outside formal healthcare systems. Therefore, digital tools such as symptom-tracking apps, biosensors, remote testing, and assistive technologies are becoming central to disease management and monitoring. These approaches support a transdiagnostic, patient-centred model capable of addressing both conditions and reaching populations that remain underserved.

Source: Murovska M, Krumina A, Araja D, Kujawski S, Zalewski P, Nora-Krukle Z, Berkis U. Myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia – overlap, differences, and emerging insights. J Transl Med. 2026 Feb 20. doi: 10.1186/s12967-026-07889-6. Epub ahead of print. PMID: 41715182. https://link.springer.com/article/10.1186/s12967-026-07889-6 (Full text available as PDF file)

Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are debilitating disorders with overlapping symptoms such as chronic pain and fatigue. Dysregulation of the endogenous opioid system, particularly µ-opioid receptor function, may contribute to their pathophysiology. This study examined whether epigenetic modifications, specifically µ-opioid receptor 1 gene (OPRM1) promoter methylation, play a role in this dysfunction.
Using a repeated-measures design, 28 ME/CFS/FM patients and 26 matched healthy controls visited the hospital twice within four days. Assessments included blood sampling for epigenetic analysis, a clinical questionnaire battery, and quantitative sensory testing (QST). Global DNA (hydroxy)methylation was quantified via liquid chromatography–tandem mass spectrometry, and targeted pyrosequencing was performed on promoter regions of OPRM1, COMT, and BDNF. ME/CFS/FM patients reported significantly worse symptom outcomes.
No differences in global (hydroxy)methylation were found. Patients showed significantly higher OPRM1 promoter methylation, which remained after adjusting for symptom severity and QST findings. Across timepoints, OPRM1 methylation consistently correlated with BDNF Promoter I and Exon III methylation. This is, to the best of our knowledge, the first study examining OPRM1 methylation in ME/CFS/FM. Increased OPRM1 methylation in patients, independent of symptoms or pain sensitivity measures, supports the hypothesis of dysregulated opioidergic signaling in these conditions.
Source: Wyns A, Hendrix J, Van Campenhout J, Buntinx Y, Xiong H-Y, De Bruyne E, Godderis L, Nijs J, Rice D, Chiang D, et al. Hypermethylation of OPRM1: Deregulation of the Endogenous Opioid Pathway in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Fibromyalgia. International Journal of Molecular Sciences. 2026; 27(2):826. https://doi.org/10.3390/ijms27020826  https://www.mdpi.com/1422-0067/27/2/826 (Full text)

HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity

Abstract:

Research of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology. Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored.

By using HERV-V3 high-density microarrays (including over 350k HERV elements and more than 1500 immune-related genes) to interrogate the transcriptomes of peripheral blood mononuclear cells from female patients diagnosed with ME/CFS, FM, or both, and matched healthy controls (n = 43), this study fills this gap of knowledge. Hierarchical clustering of HERV expression profiles strikingly allowed perfect participant assignment into four distinct groups: ME/CFS, FM, co-diagnosed, or healthy, pointing at a potent biomarker value of HERV expression profiles to differentiate between these hard-to-diagnose chronic syndromes.

Differentially expressed HERV-immune-gene modules revealed unique profiles for each of the four study groups and highlighting decreased γδ T cells, and increased plasma and resting CD4 memory T cells, correlating with patient symptom severity in ME/CFS. Moreover, activation of HERV sequences coincided with enrichment of binding sequences targeted by transcription factors which recruit SETDB1 and TRIM28, two known epigenetic silencers of HERV, in ME/CFS, offering a mechanistic explanation for the findings.

Unexpectedly, HERV expression profiles appeared minimally affected in co-diagnosed patients denoting a new nosological entity with low epigenetic impact, a seemingly relevant aspect for the diagnosis and treatment of this prevalent group of patients.

Source: Giménez-Orenga K, Martín-Martínez E, Nathanson L, Oltra E. HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity. Elife. 2025 May 8;14:RP104441. doi: 10.7554/eLife.104441. PMID: 40338225. https://elifesciences.org/articles/104441 (Full text)

Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Syndrome (GWS), and Fibromyalgia (FM) are complex, chronic illnesses with overlapping clinical features. Symptoms that are reported across these conditions include post-exertional malaise (PEM), fatigue, and pain, yet the etiology of these illnesses remains largely unknown. Diagnosis is challenging in patients with these conditions as definitive biomarkers are lacking; patients are required to meet clinical criteria and often undergo lengthy testing to exclude other conditions, a process that is often prolonged, costly, and burdensome for patients.

The identification of reliable validated biomarkers could facilitate earlier and more accurate diagnosis and drive the development of targeted pharmacological therapies that might address the underlying pathophysiology of these diseases. Major driving forces for biomarker identification are the advancing fields of metabolomics and proteomics that allow for comprehensive characterization of metabolites and proteins in biological specimens. Recent technological developments in these areas enable high-throughput analysis of thousands of metabolites and proteins from a variety of biological samples and model systems, that provides a powerful approach to unraveling the metabolic phenotypes associated with these complex diseases.

Emerging evidence suggests that ME/CFS, GWS, and FM are all characterized by disturbances in metabolic pathways, particularly those related to energy production, lipid metabolism, and oxidative stress. Altered levels of key metabolites in these pathways have been reported in studies highlighting potential common biochemical abnormalities. The precise mechanisms driving altered metabolic pathways in ME/CFS, GWS, and FM remain to be elucidated; however, the elevated oxidative stress observed across these illnesses may contribute to symptoms and offer a potential target for therapeutic intervention.

Investigating the mechanisms, and their role in the disease process, could provide insights into disease pathogenesis and reveal novel treatment targets. As such, comprehensive metabolomic and proteomic analyses are crucial for advancing the understanding of these conditions in-order to identify both common, and unique, metabolic alterations that could serve as diagnostic markers or therapeutic targets.

Source: Davis L, Higgs M, Snaith A, Lodge TA, Strong J, Espejo-Oltra JA, Kujawski S, Zalewski P, Pretorius E, Hoerger M, Morten KJ. Dysregulation of lipid metabolism, energy production, and oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome, Gulf War Syndrome and fibromyalgia. Front Neurosci. 2025 Mar 10;19:1498981. doi: 10.3389/fnins.2025.1498981. PMID: 40129725; PMCID: PMC11931034. https://pmc.ncbi.nlm.nih.gov/articles/PMC11931034/ (Full text)

Recognizing the role of fibromyalgia in post-exertional malaise

Letter:

The recent opinion by Charlton et al. published in Trends in Endocrinology & Metabolism [] provides a thought-provoking discussion of the overlap between long coronavirus disease (long-COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), emphasizing the centrality of post-exertional malaise (PEM) as a shared mechanism.

Here, we suggest that fibromyalgia should be included in the discussion, given the established role of PEM in this condition []. In addition, fibromyalgia not only shares symptomatic and mechanistic overlaps with ME/CFS, but also offers a complementary perspective on the pathophysiology of PEM. Considering that PEM is a key symptom in both fibromyalgia and long COVID, exploring skeletal muscle function in fibromyalgia could provide complementary insights into the muscle-specific alterations that contribute to this debilitating phenomenon.

Source: Giollo A, Salvato M, Doria A. Recognizing the role of fibromyalgia in post-exertional malaise. Trends Endocrinol Metab. 2025 Mar 11:S1043-2760(25)00045-1. doi: 10.1016/j.tem.2025.02.005. Epub ahead of print. PMID: 40074568. https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(25)00045-1

Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are comorbid disorders with overlapping symptoms. Research highlights autonomic dysfunction compared to healthy individuals, particularly involving the sympathetic branch. While past reviews focused on neurophysiological assessments, this systematic review summarises biological adrenergic markers, offering deeper insights into the observed sympathetic dysfunction in ME/CFS and FM aiming to identify targetable pathophysiological mechanisms.

Methods: A systematic search was performed on PubMed, Web of Science, Embase and Scopus. Studies investigating peripheral biological markers of adrenergic function in patients with ME/CFS or FM compared to healthy controls at baseline were included. Meta-analyses were performed using R statistical software.

Results: This meta-analysis of 37 studies, encompassing 543 ME/CFS patients and 651 FM patients, compared with 747 and 447 healthy controls, respectively, revealed elevated adrenaline (SMD = .49 [.31-.67]; Z = 5.29, p < .01) and β1 adrenergic receptor expression (SMD = .79 [.06-1.52]; Z = 2.13; p = .03) in blood of ME/CFS patients at rest. Additionally, patients with ME/CFS had a greater increase in the expression of α2A adrenergic receptor (AR, SMD = .57 [.18-.97]; Z = 2.85, p < .01), β2 AR (SMD = .41 [.02-.81]; Z = 2.04; p = .04) and COMT (SMD = .42 [.03-.81]; Z = 2.11; p = .03) after exercise and an increased response of noradrenaline to an orthostatic test (SMD = .11 [-.47 to -.70]; Z = 2.10; p = .04), both found in blood. FM patients showed no significant differences at baseline but exhibited a diminished adrenaline response to exercise (SMD = -.79 [-1.27 to -.30]; Z = -3.14; p < .01).

Conclusion: This systematic review and meta-analysis revealed adrenergic dysfunction mainly in patients with ME/CFS. Higher baseline adrenaline levels and atypical responses to exercise in ME/CFS indicate that sympathetic dysfunction, underscored by adrenergic abnormalities, is more involved in the pathophysiology of ME/CFS rather than FM.

Source: Hendrix J, Fanning L, Wyns A, Ahmed I, Patil MS, Richter E, Van Campenhout J, Ickmans K, Mertens R, Nijs J, Godderis L, Polli A. Adrenergic dysfunction in patients with myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia: A systematic review and meta-analysis. Eur J Clin Invest. 2024 Sep 25:e14318. doi: 10.1111/eci.14318. Epub ahead of print. PMID: 39319943. https://pubmed.ncbi.nlm.nih.gov/39319943/