Category: Fibromyalgia

Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain

Abstract:

Fibromyalgia is a long-term pain disorder that has been related to autonomic dysfunctions and reduced cardiovascular reactivity. We aimed to assess the dynamic short-term cardiovascular responses to postural changes in fibromyalgia. Thirty-eight women with fibromyalgia and thirty-six healthy women underwent the “Chronic Pain Autonomic Stress Test”.

Electrocardiogram, blood pressure and impedance cardiography were continuously recorded during active standing and lying down. Second-by-second values were derived over the first 30 s of each posture. Lower reactivity during the beginning of each position was observed in fibromyalgia sufferers compared to healthy women, with smaller responses seen during stand up in heart rate, blood pressure, cardiac output, total peripheral resistance, and pre-ejection period, and smaller changes during lying down in heart rate, cardiac output and total peripheral resistance. The magnitude of the autonomic adjustments to postural changes was inversely associated with the severity of clinical pain.

These findings indicate an early impaired autonomic cardiovascular response to orthostatic and clinostatic challenges in fibromyalgia, suggesting less autonomic flexibility and adaptability to situational demands and challenges. Short-term second-by-second cardiovascular measures may be useful in the clinical assessment of fibromyalgia.

Source: Contreras-Merino AM, Davydov DM, Galvez-Sánchez CM, Reyes Del Paso GA. Blunted short-term autonomic cardiovascular reactivity to orthostatic and clinostatic challenges in fibromyalgia as an indicator of the severity of chronic pain. Int J Psychophysiol. 2022 May;175:61-70. doi: 10.1016/j.ijpsycho.2022.03.001. Epub 2022 Mar 11. PMID: 35283267. https://www.sciencedirect.com/science/article/pii/S0167876022000599?via%3Dihub (Full text)

The autoimmune aetiology of unexplained chronic pain

Abstract:

Chronic pain is the leading cause of life years lived with disability worldwide. The aetiology of most chronic pain conditions has remained poorly understood and there is a dearth of effective therapies. The WHO ICD-11 has categorised unexplained chronic pain states as ‘chronic primary pains’ (CPP), which are further defined by their association with significant distress and/or dysfunction. The new mechanistic term, ‘nociplasticic pain’ has been developed to illustrate their presumed generation by a structurally intact, but abnormally functioning nociceptive system.

Recently, researchers have unravelled the surprising, ubiquitous presence of pain-sensitising autoantibodies in four investigated CPP indicating autoimmune causation. In persistent complex regional pain syndrome, fibromyalgia syndrome, chronic post-traumatic limb pain, and non-inflammatory joint pain associated with rheumatoid arthritis, passive transfer experiments have shown that either IgG or IgM antibodies from patient-donors cause symptoms upon injection to rodents that closely resemble those of the clinical disorders. Targets of antibody-binding and downstream effects vary between conditions, and more research is needed to elucidate the molecular and cellular details.

The central nervous system appears largely unaffected by antibody binding, suggesting that the clinically evident CNS symptoms associated with CPP might arise downstream of peripheral processes. In this narrative review pertinent findings are described, and it is suggested that additional symptom-based disorders might be examined for the contribution of antibody-mediated autoimmune mechanisms.

Source: Goebel A, Andersson D, Helyes Z, Clark JD, Dulake D, Svensson C. The autoimmune aetiology of unexplained chronic pain. Autoimmun Rev. 2022 Mar;21(3):103015. doi: 10.1016/j.autrev.2021.103015. Epub 2021 Dec 10. PMID: 34902604. https://www.sciencedirect.com/science/article/abs/pii/S1568997221002974 (Full text)

Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia

Abstract:

Background: Catechol-O-methyltransferase (COMT) has been shown to influence clinical pain, descending modulation, and exercise-induced symptom worsening. COMT regulates nociceptive processing and inflammation, key pathophysiological features of Chronic Fatigue Syndrome and Fibromyalgia (CFS/FM). We aimed to determine the interactions between genetic and epigenetic mechanisms regulating COMT and its influence on inflammatory markers and symptoms in patients with CFS/FM.

Methods: A case-control study with repeated-measures design was used to reduce the chance of false positive and increase the power of our findings. Fifty-four participants (28 patients with CFS/FM and 26 controls) were assessed twice within 4 days. The assessment included clinical questionnaires, neurophysiological assessment (pain thresholds, temporal summation, and conditioned pain modulation), and blood withdrawal in order to assess rs4818, rs4633, and rs4680 COMT polymorphisms and perform haplotype estimation, DNA methylation in the COMT gene (both MB-COMT and S-COMT promoters), and cytokine expression (TNF-α, IFN-γ, IL-6, and TGF-β).

Results: COMT haplotypes were associated with DNA methylation in the S-COMT promoter, TGF-β expression, and symptoms. However, this was not specific for one condition. Significant between-group differences were found for increased DNA methylation in the MB-COMT promoter and decreased IFN-γ expression in patients.

Discussion: Our results are consistent with basic and clinical research, providing interesting insights into genetic-epigenetic regulatory mechanisms. MB-COMT DNA methylation might be an independent factor contributing to the pathophysiology of CFS/FM. Further research on DNA methylation in complex conditions such as CFS/FM is warranted. We recommend future research to employ a repeated-measure design to control for biomarkers variability and within-subject changes.

Source: Polli A, Hendrix J, Ickmans K, Bakusic J, Ghosh M, Monteyne D, Velkeniers B, Bekaert B, Nijs J, Godderis L. Genetic and epigenetic regulation of Catechol-O-methyltransferase in relation to inflammation in chronic fatigue syndrome and Fibromyalgia. J Transl Med. 2022 Oct 25;20(1):487. doi: 10.1186/s12967-022-03662-7. PMID: 36284330; PMCID: PMC9598022. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598022/ (Full text)

Cognitive task performance and subjective cognitive symptoms in individuals with Chronic Fatigue Syndrome or Fibromyalgia: A cross-sectional analysis of the Lifelines cohort study

Abstract:

Objective: This study examined cognitive task performance and self-reported cognitive functioning in individuals with chronic fatigue syndrome (CFS) and fibromyalgia (FM) in a population-based sample and investigated the role of mood and anxiety disorders as well as severity of the physical symptoms.

Methods: This study was performed in 79,966 participants (Mean age: 52.9, SD = ±12.6 years, 59.2% women) from the Lifelines general-population. Symptoms consistent with the diagnostic criteria for CFS and FM were assessed using questionnaires. Two comparison groups were used: participants with self-reported medical disorders with well-defined pathophysiology (i.e., multiple sclerosis and rheumatic arthritis) and controls without these diseases. Objective task-performance was based on the computerized CogState cognitive battery and subjective cognitive symptoms using the concentration subscale of the Checklist Individual Strength.

Results: Cognitive task performance was poorer in individuals with CFS vs. controls without disease and controls with a medical disorder, although the severity of cognitive dysfunction was mild. Participants meeting criteria for CFS (n = 2,461) or FM (n = 4,295) reported more subjective cognitive symptoms compared to controls without a medical disorder (d = 1.53, 95%CI = 1.49-1.57 for CFS; d = 1.25, 95%CI = 1.22-1.29 for FM) and participants with a medical disease (d = 0.62, 95%CI = 0.46-0.79 for CFS; d = 0.75, 95%CI = 0.70-0.80 for FM). These differences remained essentially the same when excluding participants with comorbid mood or anxiety disorders or adjusting for physical symptom severity.

Conclusions: Subjective cognitive symptoms and to a lesser extent suboptimal cognitive task performance are more prevalent in individuals with CFS or FM compared to controls without these conditions.

Source: Joustra ML, Hartman CA, Bakker SJL, Rosmalen JGM. Cognitive task performance and subjective cognitive symptoms in individuals with Chronic Fatigue Syndrome or Fibromyalgia: A cross-sectional analysis of the Lifelines cohort study. Psychosom Med. 2022 Aug 2. doi: 10.1097/PSY.0000000000001117. Epub ahead of print. PMID: 35980775.  https://pubmed.ncbi.nlm.nih.gov/35980775/

Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity

Abstract:

Alterations in the composition and function of the gut microbiome in women with fibromyalgia have recently been demonstrated, including changes in the relative abundance of certain bile acid metabolizing bacteria. Bile acids can affect multiple physiological processes, including visceral pain, but have yet to be explored for association to the fibromyalgia gut microbiome. In this study, 16S rRNA sequencing and targeted metabolomic approaches were used to characterize the gut microbiome and circulating bile acids in a cohort of 42 women with fibromyalgia and 42 healthy controls.

Alterations in the relative abundance of several bacterial species known to metabolize bile acids were observed in women with fibromyalgia, accompanied by significant alterations in the serum concentration of secondary bile acids, including a marked depletion of α-muricholic acid. Statistical learning algorithms could accurately detect individuals with fibromyalgia using the concentration of these serum bile acids. Serum α-muricholic acid was highly correlated with symptom severity, including pain intensity and fatigue.

Taken together, these findings suggest serum bile acid alterations are implicated in nociplastic pain. The changes observed in the composition of the gut microbiota and the concentration of circulating secondary bile acids seem congruent with the phenotype of increased nociception, and are quantitatively correlated with symptom severity.

This is a first demonstration of circulating bile acid alteration in individuals with fibromyalgia, potentially secondary to upstream gut microbiome alterations. If corroborated in independent studies, these observations may allow for the development of molecular diagnostic aids for fibromyalgia as well as mechanistic insights into the syndrome.

Source: Minerbi A, Gonzalez E, Brereton N, Fitzcharles MA, Chevalier S, Shir Y. Altered serum bile acid profile in fibromyalgia is associated with specific gut microbiome changes and symptom severity. Pain. 2022 May 19. doi: 10.1097/j.pain.0000000000002694. Epub ahead of print. PMID: 35587528. https://pubmed.ncbi.nlm.nih.gov/35587528/

Dorsal root ganglia: fibromyalgia pain factory?

Abstract:

This perspective article focuses on dorsal root ganglia (DRG) as potential fibromyalgia main pain source. Humans possess 31 pairs of DRG lying along the spine. These ganglia have unique anatomical and physiological features. During development, DRG are extruded from the central nervous system and from the blood-brain barrier but remain surrounded by meningeal layers and by cerebrospinal fluid. DRG house the pain-transmitting small nerve fiber nuclei; each individual nucleus is tightly enveloped by metabolically active glial cells. DRG possess multiple inflammatory/pro-nociceptive molecules including ion channels, neuropeptides, lymphocytes, and macrophages. DRG neurons have pseudo-unipolar structure making them able to generate pain signals; additionally, they can sequester antigen-specific antibodies thus inducing immune-mediated hyperalgesia. In rodents, diverse physical and/or environmental stressors induce DRG phenotypic changes and hyperalgesia.

Unfolding clinical evidence links DRG pathology to fibromyalgia and similar syndromes. Severe fibromyalgia is associated to particular DRG ion channel genotype. Myalgic encephalomyelitis patients with comorbid fibromyalgia have exercise-induced DRG pro-nociceptive molecules gene overexpression. Skin biopsy demonstrates small nerve fiber pathology in approximately half of fibromyalgia patients. A confocal microscopy study of fibromyalgia patients disclosed strong correlation between corneal denervation and small fiber neuropathy symptom burden. DRG may be fibromyalgia neural hub where different stressors can be transformed in neuropathic pain. Novel neuroimaging technology and postmortem inquest may better define DRG involvement in fibromyalgia and similar maladies. DRG pro-nociceptive molecules are attractive fibromyalgia therapeutic targets.

Source: Martínez-Lavín M. Dorsal root ganglia: fibromyalgia pain factory? Clin Rheumatol. 2021 Jan 6:1–5. doi: 10.1007/s10067-020-05528-z. Epub ahead of print. PMID: 33409721; PMCID: PMC7787228.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787228/ (Full text)

Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain

Abstract:

The prevalence and severity of many chronic pain syndromes differ across sex, and recent studies have identified differences in immune signalling within spinal nociceptive circuits as a potential mediator. Although it has been proposed that sex-specific pain mechanisms converge once they reach neurons within the superficial dorsal horn, direct investigations using rodent and human preclinical pain models have been lacking.

Here, we discovered that in the Freund’s adjuvant in vivo model of inflammatory pain, where both male and female rats display tactile allodynia, a pathological coupling between KCC2-dependent disinhibition and N-methyl-D-aspartate receptor (NMDAR) potentiation within superficial dorsal horn neurons was observed in male but not female rats. Unlike males, the neuroimmune mediator brain-derived neurotrophic factor (BDNF) failed to downregulate inhibitory signalling elements (KCC2 and STEP61) and upregulate excitatory elements (pFyn, GluN2B and pGluN2B) in female rats, resulting in no effect of ex vivo brain-derived neurotrophic factor on synaptic NMDAR responses in female lamina I neurons. Importantly, this sex difference in spinal pain processing was conserved from rodents to humans.

As in rodents, ex vivo spinal treatment with BDNF downregulated markers of disinhibition and upregulated markers of facilitated excitation in superficial dorsal horn neurons from male but not female human organ donors. Ovariectomy in female rats recapitulated the male pathological pain neuronal phenotype, with BDNF driving a coupling between disinhibition and NMDAR potentiation in adult lamina I neurons following the prepubescent elimination of sex hormones in females. This discovery of sexual dimorphism in a central neuronal mechanism of chronic pain across species provides a foundational step towards a better understanding and treatment for pain in both sexes.

Source: Dedek A, Xu J, Lorenzo LÉ, Godin AG, Kandegedara CM, Glavina G, Landrigan JA, Lombroso PJ, De Koninck Y, Tsai EC, Hildebrand ME. Sexual dimorphism in a neuronal mechanism of spinal hyperexcitability across rodent and human models of pathological pain. Brain. 2022 Apr 29;145(3):1124-1138. doi: 10.1093/brain/awab408. PMID: 35323848; PMCID: PMC9050559. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9050559/ (Full text)

Impaired Cardiac Autonomic Control in Women With Fibromyalgia Is Independent of Their Physical Fitness

Abstract:

Background/objective: Evidence has suggested abnormal cardiac autonomic responses to exercise in patients with fibromyalgia (FM). However, it is not clear whether the dysautonomia represents a reduced physical fitness rather directly related to FM pathogenesis. Thus, we aimed to verify the cardiac autonomic responses before, during, and after a maximal incremental exercise in women with FM and whether these hypothesized alterations would be dependent with their physical fitness.

Methods: This is a cross-sectional study with 23 FM women and 17 healthy women. The participants performed a maximal incremental cycling test to determine their maximal workload (Wmax) and were further matched by their Wmax (14 FM patients, Wmax: 128.6 ± 16.2 W; and 14 healthy women, Wmax: 131.9 ± 15.9 W). Beat-to-beat heart rate (HR) was continuously monitored to calculate HR variability indexes at rest, chronotropic reserve during exercise, and HR recovery.

Results: Heart rate variability indexes related to vagal modulation were significantly lower in FM patients than in healthy women (p < 0.05). The chronotropic reserve and the HR recovery at 30, 120, 180, 300, and 600 seconds after exercise were all lower in FM patients compared with those of healthy women (p < 0.05). Similar findings were found when analysis was performed using the matched physical fitness subgroup.

Conclusions: The documented cardiac autonomic abnormalities at rest, during, and after exercise in FM patients persist even when physical fitness status is taken in account. Thus, strategies to attenuate the dysautonomia in FM patients must be considered.

Source: Schamne JC, Ressetti JC, Lima-Silva AE, Okuno NM. Impaired Cardiac Autonomic Control in Women With Fibromyalgia Is Independent of Their Physical Fitness. J Clin Rheumatol. 2021 Sep 1;27(6S):S278-S283. doi: 10.1097/RHU.0000000000001518. PMID: 32826659. https://pubmed.ncbi.nlm.nih.gov/32826659/

Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: a controlled prospective cohort study

Abstract:

Objectives: To investigate whether acute infection with Giardia lamblia is associated with fibromyalgia 10 years after infection and whether fibromyalgia is associated with irritable bowel syndrome (IBS) and chronic fatigue (CF) in this setting.

Methods: A cohort study was established after an outbreak of G. lamblia in Bergen, Norway, 2004. Laboratory-confirmed cases and a matched control group were followed for 10 years. The main outcome was fibromyalgia 10 years after giardiasis, defined by the 2016 revisions of the fibromyalgia diagnostic criteria using the Fibromyalgia Survey Questionnaire (FSQ).

Results: The prevalence of fibromyalgia was 8.6% (49/572) among Giardia exposed compared to 3.1% (21/673) in controls (p<0.001). Unadjusted odds for having fibromyalgia was higher for Giardia exposed compared to controls (odds ratio (OR): 2.91, 95% confidence interval (CI): 1.72, 4.91), but adjusted for IBS and CF it was not (OR: 1.05, 95% CI: 0.57, 1.95). Among participants without CF the odds for fibromyalgia was 6.27 times higher for participants with IBS than those without (95% CI: 3.31, 11.91) regardless of exposure. Among participants without IBS the odds for fibromyalgia was 4.80 times higher for those with CF than those without (95% CI: 2.75, 8.37).

Conclusions: We found a higher prevalence of fibromyalgia among Giardia exposed compared to controls 10 years after the acute infection. Fibromyalgia was strongly associated with IBS and CF, and the difference between the exposed and controls can be attributed to the high prevalence of IBS and CF among the Giardia exposed. Notably, this study was not designed to establish causality between Giardia exposure and the outcomes.

Source: Hunskar GS, Rortveit G, Litleskare S, Eide GE, Hanevik K, Langeland N, Wensaas KA. Prevalence of fibromyalgia 10 years after infection with Giardia lamblia: a controlled prospective cohort study. Scand J Pain. 2021 Oct 21;22(2):348-355. doi: 10.1515/sjpain-2021-0122. PMID: 34679267. https://www.degruyter.com/document/doi/10.1515/sjpain-2021-0122/html (Full text)

Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis

Abstract:

Myalgic encephalomyelitis is an illness characterized by profound malaise after mental or physical effort occurring in patients already suffering from constant fatigue. On the other hand, widespread pain and widespread allodynia are the core fibromyalgia clinical features. There is controversy on these two syndromes alikeness. Through the years, different diagnostic and/or classification criteria have been put forward to appraise both fibromyalgia and myalgic encephalomyelitis. The epidemiology of these two illnesses, and their overlap, may vary accordingly to the used definition. The most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria incorporates three myalgic encephalomyelitis features including fatigue, waking unrefreshed and dyscognition. The objective of this meta-analysis was to define the clinical overlap between fibromyalgia and myalgic encephalomyelitis based on a systematic literature review.

Methods: PubMed, Embase, Lilacs, and Cochrane data bases were searched on January 25, 2021 linking the medical subject heading “Fibromyalgia” to the following terms “chronic fatigue syndrome”, “myalgic encephalomyelitis” and “systemic exertion intolerance disease”. Our review included all original articles in which the clinical overlap between fibromyalgia and myalgic encephalomyelitis could be quantified based on recognized diagnostic or classification criteria. Articles scrutiny and selection followed the PRISMA guidelines. Each study quality was assessed according to GRADE recommendations. The global clinical overlap was calculated using a fixed effect model with inverse variance-weighted average method.

Results: Twenty one publications were included in the meta-analysis. Reviewed studies were highly dissimilar in their design, objectives, sample size, diagnostic criteria, and/or outcomes yielding a 98% heterogeneity index. Nevertheless, the clinical overlap between fibromyalgia and myalgic encephalomyelitis was a well defined outcome that could be reliably calculated despite the high heterogeneity value. All reviewed publications had moderate GRADE evidence level. Most evaluated articles used the old 1990 Wolfe et al. fibromyalgia diagnostic criteria. Myalgic encephalomyelitis and fibromyalgia diagnoses overlapped in 47.3% (95% CI: 45.97-48.63) of the reported cases.

Conclusion: This meta-analysis found prominent clinical overlap between fibromyalgia and myalgic encephalomyelitis. It seems likely that this concordance would be even higher when using the most recent Wolfe et al. 2016 fibromyalgia diagnostic criteria.

Source: Ramírez-Morales R, Bermúdez-Benítez E, Martínez-Martínez LA, Martínez-Lavín M. Clinical overlap between fibromyalgia and myalgic encephalomyelitis. A systematic review and meta-analysis. Autoimmun Rev. 2022 Jun 8:103129. doi: 10.1016/j.autrev.2022.103129. Epub ahead of print. PMID: 35690247. https://pubmed.ncbi.nlm.nih.gov/35690247/