Pathogenesis of fibromyalgia

doi:10.1016/j.jbspin.2007.09.010

Joint Bone Spine

Volume 75, Issue 3, May 2008, Pages 273-279

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Abstract

Fibromyalgia, a syndrome characterized by widespread pain and diffuse tenderness, is considered a multifactorial disorder. Central nervous system sensitization is a major pathophysiological aspect of fibromyalgia, while various external stimuli such as infection, trauma and stress may contribute to development of the syndrome. In addition, current evidence points towards the existence of a genetic basis for fibromyalgia and information has been accumulated regarding the role of a number of candidate genes in fibromyalgia pathogenesis. In the present review, we have summarized the clinical manifestations of fibromyalgia, as well as the necessary laboratory workup; subsequently we have attempted to cover various aspects of pathogenesis with special emphasis on the genetic aspects currently uncovered.

Introduction

Fibromyalgia seems to be here to stay. Although coined as a nosological entity only some two and a half decades ago, and adorned official American College of Rheumatology (ACR) criteria only in 1990 [1], patients suffering from syndromes such as “fibrositis” and “soft tissue rheumatism” have been described in medical literature for over a century [2]. In the past, we have witnessed spirited debates regarding the classification, pathogenesis and mere validity of the concept of fibromyalgia [3], [4]. Thousands of research articles published on the topic attest to the great interest drawn to the syndrome, which is estimated to affect a staggering 2% of the population. Significant progress has occurred over recent years regarding our understanding of the mechanisms underlying altered pain processing characteristic of fibromyalgia; this evolution of knowledge is leading towards novel strategies for management of fibromyalgia pain. As our knowledge regarding the pathogenesis and etiology of fibromyalgia increases, the historical debate regarding validity is likely to be replaced by an effort to better classify patients, to identify subgroups with unique clinical characteristics and to pinpoint therapeutic interventions, while decreasing the daunting side effects of current empirical treatment. In the following review, we shall attempt to describe what is currently known about the pathogenesis of fibromyalgia and special attention will be directed towards the genetic basis of this evidently multifactorial, intriguing syndrome.

Section snippets

Clinical presentation

ACR criteria define fibromyalgia as a chronic disorder characterized by the presence of widespread pain accompanied by tenderness upon palpation of at least 11 of 18 predefined tender points throughout the musculoskeletal system [1]. In actual clinical practice it is currently common knowledge that there is nothing particularly sacred about the number 11. A patient with eight or nine tender points may have a clinical presentation otherwise typical of (and presumably responsive to the same

Findings on physical examination

The classical tender points of fibromyalgia are distributed symmetrically over the occipital, low cervical, trapezius, supraspinatus, second rib, lateral epicondyle, gluteus, greater trochanter and at the medial fat pad of the knee. Each point is palpated with the thumb of the examiner, using gradually increasing pressure until the patient reports the pressure to be painful. A point is considered “positive” if less than 4 kg of pressure is required in order to evoke tenderness by this procedure.

Laboratory evaluation

A laboratory workup is warranted in the evaluation of fibromyalgia mainly for exclusion of alternative differential diagnoses, as there are no specific laboratory findings typical of fibromyalgia. Inflammatory indices such as Erythrocyte sedimentation rate (ESR) and CRP are expected to be normal, although fibromyalgia should not be ruled out merely on the basis of an accelerated ESR, which is not uncommon among elderly patients. Rheumatoid factor and anti nuclear antibodies (ANA) are typically

Significant progress has been made over the last decades regarding the pathogenesis of fibromyalgia. In the remainder of this review we shall briefly cover the various components of our current understanding regarding the pathogenesis of fibromyalgia and will focus our discussion on the genetic basis of that syndrome.

Hormonal imbalance

As fibromyalgia has been closely linked to various forms of stress, and since a major pathway involved in the body's reaction to stress involves the activity of the Hypothalamic–Pituitary–Adrenal (HPA) axis, searching for alterations in this system in fibromyalgia appears to be a likely goal. Perturbations in the HPA axis have been demonstrated in fibromyalgia patients [28]. Similarly, alterations in the functioning of the sympathetic nervous system, another closely related system involved in

Fibromyalgia and the concept of central sensitization

Central sensitization is an emerging biopsychosocial concept currently considered to characterize a wide spectrum of interrelated “functional” disorders, which may subsequently be better defined as central sensitivity syndromes [31]. Central sensitization constitutes a condition of general over reactivity of the central nervous system to a wide spectrum of stimulation. Clinical correlates which are particularly significant to the fibromyalgia syndrome include the phenomenon of allodynia, in

From familial aggregation to genetic clues

It is currently well established that familial aggregation is characteristic of Fibromyalgia. Arnold et al. [37] studied 533 relatives of 78 probands with fibromyalgia as well as 272 relatives of 40 probands with rheumatoid arthritis. Fibromyalgia aggregated strongly in families: the odds ratio for fibromyalgia in a relative of a fibromyalgia proband versus fibromyalgia in a relative of a rheumatoid arthritis proband was 8.5. The number of tender points was also significantly higher in

Candidate genes involved in the metabolism of serotonin

In view of the evidence regarding alterations of the serotoninergic system in the pathogenesis of fibromyalgia [23] genetic research was initially directed towards genes involved in modulation of that system. Offenbaecher et al. [46] compared the genotype of the serotonin transporter gene (5-HTT) promoter region in fibromyalgia patients with healthy controls. An increased frequency of the S/S genotype of the 5-HTT gene was demonstrated among patients versus controls.

These results were

Dopamine receptors in fibromyalgia

Dopamine is a crucial CNS neurotransmitter involved in multiple activities including pain transmission. Alterations in dopamine metabolism are involved in many disturbances of the CNS including Parkinson's disease, schizophrenia and attention deficit hyperactivity disorder [50]. Pramipexole, a dopamine-3 agonist has been tested in the treatment of fibromyalgia [51].In addition, fibromyalgia has been linked with reduced presynaptic dopamine activity demonstrated on positron emission tomography

Studies of the catechol-O-methyl transferase gene polymorphism in fibromyalgia

3-Methoxy-4-hydroxyphenethylene (MPHG), which is a major metabolite of norepinephrine, has been found to be decreased in the cerebrospinal fluid of fibromyalgia patients [23]. Since norepinephrine is considered to play an important role in spinal inhibition of pain transmission, this finding may imply a reduction in this crucial aspect of pain modulation in fibromyalgia. Thus, attempts have been made to study genetic markers involved in metabolism of catecholamines. One such major enzyme is

Substance P in fibromyalgia

Substance P is an 11-amino-acid peptide neurokinin, with diverse functions in nociception [58]. As substance P has been clearly shown to be elevated in level in the CSF of fibromyalgia patients [24], an attempt has been made to find an association between the tachykinin NK1 substance P receptor and fibromyalgia. A trend towards an increase frequency of the G>C substitution at position 1354 in the 3′ untranslated region of the NK1 receptor was identified, which did not however reach statistical

Conclusion

Fibromyalgia is a common, frustrating disorder characterized by widespread musculoskeletal pain. It frustrates physicians, due to the vagueness of the complaints, the lack of clear laboratory and imaging findings and the intransigence to treatment; it frustrates patients to a much greater degree due to the severity of the suffering, the lack of specific treatment and in many cases – the disbelief and skepticism handed out by health care professionals as well as others. As our understanding of

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Blockade of spinal α<inf>5</inf>-GABA<inf>A</inf> receptors differentially reduces reserpine-induced fibromyalgia-type pain in female rats
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The role of spinal α₅ subunit-containing GABA_A (α₅-GABA_A) receptors in chronic pain is controversial. The purpose of this study was to investigate the participation of spinal α₅-GABA_A receptors in the reserpine-induced pain model. Reserpine administration induced tactile allodynia and muscle hyperalgesia in female and male rats. Intrathecal injection of L-655,708 and TB 21007 (7 days after the last reserpine injection) decreased tactile allodynia and, at a lesser extent, muscle hyperalgesia in female rats. The effects of these drugs produced a lower antiallodynic and antihyperalgesic effect in male than in female rats. Contrariwise, these drugs produced tactile allodynia and muscle hyperalgesia in naïve rats and these effects were lower in naïve male than female rats. Intrathecal L-838,417 prevented or reversed L-655,708-induced antiallodynia in reserpine-treated female rats. Repeated treatment with α₅-GABA_A receptor small interfering RNA (siRNA), but not scramble siRNA, reduced reserpine-induced allodynia in female rats. Accordingly, α₅-GABA_A receptor siRNA induced nociceptive hypersensitivity in naïve female rats. Reserpine enhanced α₅-GABA_A receptors expression in spinal cord and dorsal root ganglia (DRG), while it increased CD11b (OX-42) and glial fibrillary acidic protein (GFAP) fluorescence intensity in the lumbar spinal cord. In contrast, reserpine diminished K⁺-Cl^- co-transporter 2 (KCC2) protein in the lumbar spinal cord. Data suggest that spinal α₅-GABA_A receptors play a sex-dependent proallodynic effect in reserpine-treated rats. In contrast, these receptors have a sex-dependent antiallodynic role in naïve rats.
A systematic review of precipitating physical and psychological traumatic events in the development of fibromyalgia
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The role of physical and psychological trauma precipitating fibromyalgia is often encountered by physicians, yet a proper systematical review of this association is lacking. Literature searches identified 51 studies which examined the association of fibromyalgia with a preceding traumatic event of physical or emotional nature. The overall quality of evidence of studies included, as assessed by the GRADE criteria, was low, however the majority of studies described a significant association between prior physically traumatic events and the onset of chronic widespread pain or fibromyalgia. Elevated rates of psychological trauma in fibromyalgia patients were demonstrated across the literature and several studies indicate a mediating effect of post-traumatic stress disorder. Potential biological mechanisms for conversion of traumatic events into a chronic pain syndrome, such as fibromyalgia, are discussed.
Comparison of the big five personality traits in fibromyalgia and other rheumatic diseases
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La personnalité des patients fibromyalgiques fait encore débat. Certaines études ont mis en évidence un score élevé de Névrosisme associé à une faible extraversion, tandis que d’autres n’ont pas trouvé de différence entre ces traits de personnalité et ceux observés dans la population générale. Les facteurs de personnalité participent à la régulation des émotions et la modulation de la douleur. Cette étude avait pour objectif de déterminer les traits de personnalité dans un groupe de patientes atteintes de fibromyalgie en comparaison avec d’autres maladies rhumatismales.
Dans le cadre d’une étude multicentrique, des patientes atteintes de fibromyalgie, de polyarthrite rhumatoïde, de spondyloarthrite ou du syndrome de Gougerot-Sjögren ont été invitées à répondre au Big Five Inventory regroupant les cinq grands traits de personnalité : (1) Extraversion vs introversion, (2) Agréabilité vs antagonisme, (3) Caractère consciencieux vs impulsivité, (4) Névrosisme vs stabilité émotionnelle et (5) Ouverture vs étroitesse d’esprit. Une analyse de la variance (Test t de Student et Anova avec comparaisons post-hoc ou correction de Bonferroni) a été réalisée. Nous avons également effectué des classifications automatiques hiérarchiques et non hiérarchiques.
Ont participé à cette étude, 163 femmes atteintes de fibromyalgie (n = 48), de polyarthrite rhumatoïde (n = 46), de spondyloarthrite (n = 46) ou du syndrome de Gougerot-Sjögren (n = 23). L’âge moyen était de 47,18 ans (± 10,81 ans, extrêmes 21–65). Les patientes fibromyalgiques présentaient des scores plus élevés pour les dimensions Agréabilité (F (3, 159) = 3,39, p < 0,05), Névrosisme (F (3, 159) = 3,79, p < 0,05) et Ouverture (F (3, 159) = 4,32, p < 0,01) comparativement à celles souffrant d’autres maladies rhumatismales. Cette étude met en exergue l’existence de traits de personnalité spécifiques dans la fibromyalgie et souligne également leur rôle protecteur : dans le groupe fibromyalgie, un fort Névrosisme et un faible Caractère consciencieux (forte impulsivité) étaient associés à un niveau élevé de douleur chronique.
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Efficacy of ozone therapy as an add-on treatment in fibromyalgia: A randomized double-blind placebo-controlled study
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ReviewPathogenesis of fibromyalgia – A review

Abstract

Introduction

Section snippets

Clinical presentation

Findings on physical examination

Laboratory evaluation