The pivotal role of central sensitization in long COVID, fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Introduction: Long COVID is a condition characterized by persistent unexplained symptoms following COVID-19 infection. These symptoms are not related to another disease or organ damage and are similar to those in fibromyalgia and myslgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Areas covered: The similar clinical and pathophysiological features and management of long COVID, fibromyalgia and ME/CFS are explored from the unifying framework of central sensitivity syndromes. The article is based on a literature search utilizing PubMed for content published between 2021 and 1 May 2025, using search terms: long COVID, long COVID syndrome, post-COVID-19, post-acute SARS-CoV-2, fibromyalgia, ME/CFS, post-exertional malaise and central sensitization.

Expert opinion: Once long COVID is redefined to exclude patients with well-defined organ disease, it fits best as a model of central sensitization. Long COVID is a single syndrome, rather than many distinct diseases. Optimal management of long COVID and similar central sensitivity

Source: Goldenberg DL. The pivotal role of central sensitization in long COVID, fibromyalgia and myalgic encephalomyelitis/chronic fatigue syndrome. Expert Rev Neurother. 2025 Jun 13:1-17. doi: 10.1080/14737175.2025.2516097. Epub ahead of print. PMID: 40512228. https://www.tandfonline.com/doi/full/10.1080/14737175.2025.2516097

Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

AIM: To identify subtypes in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) based on DNA methylation profiles and health scores.

METHODS: DNA methylome profiles in immune cells were integrated with symptomatology from 70 women with ME/CFS using similarity network fusion to identify subtypes.

RESULTS: We discovered four ME/CFS subtypes associated with DNA methylation modifications in 1939 CpG sites, three RAND-36 categories and five DePaul Symptom Questionnaire measures. Methylation patterns of immune response genes and differences in physical functioning and postexertional malaise differentiated the subtypes.

CONCLUSION: ME/CFS subtypes are associated with specific DNA methylation differences and health symptomatology and provide additional evidence of the potential relevance of metabolic and immune differences in ME/CFS with respect to specific symptoms.

Source: de Vega WC, Erdman L, Vernon SD, Goldenberg A, McGowan PO. Integration of DNA methylation & health scores identifies subtypes in myalgic encephalomyelitis/chronic fatigue syndrome. Epigenomics. 2018 Apr 25. doi: 10.2217/epi-2017-0150. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29692205

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Abstract:

The diagnosis of fibromyalgia continues to generate heated debate. The presence of multiple lifetime psychiatric diagnoses was not intrinsically related to fibromyalgia but rather to the decision of patients to seek specialty medical care. Better outcome measures in fibromyalgia were tested. Neurally mediated hypotension may be associated with chronic fatigue syndrome (CFS). Treatment of patients with fibromyalgia and CFS continues to be of limited success, although the role of multidisciplinary group intervention appears promising. Two position papers focused on the adverse aspects of the medicolegal issues in fibromyalgia and CFS.

 

Source: Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 1997 Mar;9(2):135-43. http://www.ncbi.nlm.nih.gov/pubmed/9135918

 

Fibromyalgia, chronic fatigue syndrome, and myofascial pain

Abstract:

The prevalence of fibromyalgia in the general population was found to be 2% and increased with age. Multiple traumatic factors, including sexual and physical abuse, may be important initiating events. The most important pathophysiologic studies in fibromyalgia included evidence of altered blood flow to the brain and hypothalamic-pituitary-adrenal dysfunction. The prevalence of chronic fatigue syndrome is much less than that of fibromyalgia. Epidemiologic studies demonstrated that chronic fatigue and symptoms of fibromyalgia are distributed as continuous variables in the general population. No association between chronic fatigue and initial infections was seen in primary care practices.

 

Source: Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain. Curr Opin Rheumatol. 1996 Mar;8(2):113-23. http://www.ncbi.nlm.nih.gov/pubmed/8732795

 

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Abstract:

Two important studies in which nuclear magnetic resonance spectroscopy was used convincingly demonstrated that muscle is not the primary pathologic factor in fibromyalgia. There were further studies reporting that fibromyalgia-chronic fatigue syndrome may follow well treated Lyme disease or mimic Lyme disease. The longest therapeutic trial to date in fibromyalgia demonstrated an initial modest effect of tricyclic medications, but at 6 months that efficacy was no longer evident. Investigation in both fibromyalgia and chronic fatigue syndrome now focuses on the central nervous system. The use of new technology, eg, neurohormonal assays and imaging such as single-photon emission computed tomography scan, may be important in understanding these elusive conditions.

 

Source: Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 1995 Mar;7(2):127-35. http://www.ncbi.nlm.nih.gov/pubmed/7766493

 

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Abstract:

No major pathophysiologic or therapeutic findings have appeared over the past year regarding fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome, three poorly understood, controversial, and overlapping syndromes. The frequent prevalence of these disorders in association with Lyme disease and other medical and psychiatric illness was emphasized. New studies demonstrated the potential role for central nervous system activation in fibromyalgia and chronic fatigue syndrome.

 

Source: Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 1994 Mar;6(2):223-33. http://www.ncbi.nlm.nih.gov/pubmed/8024971

 

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Abstract:

Operational diagnostic criteria for fibromyalgia were applied to most clinical studies during the past year. Similar diagnostic criteria for chronic fatigue syndrome are being revised, but criteria for myofascial pain have not been agreed on or tested. Intense research efforts focused on the role of neurohormones and the hypothalamic-pituitary-adrenal axis in fibromyalgia and chronic fatigue syndrome over the past year.

 

Source: Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 1993 Mar;5(2):199-208. http://www.ncbi.nlm.nih.gov/pubmed/8452771

 

Comorbidity of fibromyalgia with medical and psychiatric disorders

Abstract:

PURPOSE: Patients with fibromyalgia have been reported to display high rates of several concomitant medical and psychiatric disorders, including migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. To test further these and other possible associations, we assessed the personal and family histories of a broad range of medical and psychiatric disorders in patients with fibromyalgia.

PATIENTS AND METHODS: Subjects were 33 women (mean age 42.1 years) who each met American College of Rheumatology criteria for fibromyalgia and presented to a rheumatologist at a tertiary referral center. They received the Structured Clinical Interview for DSM-III-R (SCID); a supplemental interview, in SCID format, for other medical and psychiatric disorders, including migraine, irritable bowel syndrome, and chronic fatigue syndrome; and an interview for family history of medical and psychiatric disorders.

RESULTS: Patients with fibromyalgia displayed high lifetime rates of migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder. They also exhibited high rates of familial major mood disorder.

CONCLUSIONS: The finding that migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder are frequently comorbid with fibromyalgia is consistent with the hypothesis that these various disorders may share a common physiologic abnormality.

 

Source: Hudson JI, Goldenberg DL, Pope HG Jr, Keck PE Jr, Schlesinger L. Comorbidity of fibromyalgia with medical and psychiatric disorders. Am J Med. 1992 Apr;92(4):363-7. http://www.ncbi.nlm.nih.gov/pubmed/1558082

 

Fibromyalgia, chronic fatigue, and myofascial pain syndromes

Abstract:

During the past year many studies have been published on fibromyalgia and chronic fatigue syndromes. Randomized clinical trials using current operational diagnostic criteria were reported, but no single therapy has been highly effective in either condition. The working case definition of chronic fatigue syndrome has been criticized and suggestions for a new case definition have been made. Further understanding of the overlap of these three common disorders will also require that uniform diagnostic criteria be tested in chronic fatigue syndrome and myofascial pain syndrome.

 

Source: Goldenberg DL. Fibromyalgia, chronic fatigue, and myofascial pain syndromes. Curr Opin Rheumatol. 1992 Apr;4(2):247-57. http://www.ncbi.nlm.nih.gov/pubmed/1581154

 

Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome

Abstract:

There continues to be an emerging body of literature related to fibromyalgia and the related conditions chronic fatigue syndrome and myofascial pain.

During the past year, the most notable contributions included a large multicenter study providing new diagnostic criteria for the classification of fibromyalgia and clinical studies describing the overlap of fibromyalgia, chronic fatigue syndrome, and myofascial pain.

Pathophysiologic studies were often preliminary and uncontrolled but the focus of these studies on abnormal nociception, neurohormones, and muscle metabolism provides an exciting hypothesis to unify pain, fatigue, and sleep disturbances, the primary symptoms of fibromyalgia. Unfortunately, new therapeutic trials were neither innovative nor especially encouraging.

 

Source: Goldenberg DL. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 1991 Apr;3(2):247-58. http://www.ncbi.nlm.nih.gov/pubmed/2064904