Fibromyalgia syndrome is a common soft tissue pain condition, typically presenting with chronic widespread pain and tenderness to palpation. For years, people with fibromyalgia pain have been doubted, criticized, mocked, negated, and marginalized because of their unique presentation of chronic widespread pain. They have been considered unduly sensitive, complainers, drug dependent, or seekers of primary and secondary gain.
The apparent cause of the pain is a low pain threshold with comorbid dysfunctional sleep, fatigue, morning stiffness, cognitive dysfunction, depression, anxiety, recurrent headaches, dizziness, irritable bowel syndrome, and urogenital pain.
The mechanism underlying the low pain threshold appears to be central sensitization leading to an amplified perception of pain. There is now growing evidence that inflammation may play a role in the pathogenesis of fibromyalgia syndrome (FMS).
Various cytokines, both pro- and anti-inflammatory, are increased in the serum and cerebral spinal fluid of individuals with FMS. These substances have been implicated in some of the associated symptoms of FMS, including allodynia (pain hypersensitivity), fatigue, anorexia, and sleep disturbances, and may relate to the depressive syndromes seen in FMS as well.
Other areas of interest include fascial dysfunction, oxidative stress, and mitochondrial dysfunction. The release of pro-inflammatory cytokines from glial cells in the central nervous system can result in behavioral changes that have been termed the “sickness syndrome,” which exhibits symptoms of exaggerated pain response as well as anorexia, fatigue, loss of interests in social activities, anhedonia, decreased concentration ability and sleep disturbances.
Normally, this constellation of symptoms is thought to promote recovery after infection, although its perpetuation in a chronically activated state may cause or exacerbate a depressive syndrome. It is possible that the clinically significant depressive symptoms seen in about one third of FMS patients could be associated with activation of the inflammatory response system.
Notwithstanding the controversial nature of FMS and evidence of its inflammatory nature, it is almost certain that psychiatrists, regardless of their practice setting, will come into contact with patients who have FMS. A better understanding of the possible inflammatory nature of these conditions and their potential associations is important as physicians attempt to better understand and provide treatment to their patients.
Fibromyalgia syndrome is a common, chronically painful, soft tissue pain condition, typically presenting with chronic widespread pain and tenderness to palpation. The apparent cause of the tenderness is a low pain threshold. Associated, or comorbid manifestations can include chronically dysfunctional sleep, fatigue, morning stiffness, cognitive dysfunction, depression, anxiety, recurrent headaches, dizziness, irritable bowel syndrome, and urogenital pain.
Epidemiology studies indicate that FMS is present in about 2% of the general population, is four to seven times more prevalent in women than in men, and its prevalence increases with the age of the population. Its natural history is to persist unchanged for many years and not to induce, or change into, another painful condition.1
Two different criteria have been established for the diagnosis of fibromyalgia, and they should be used appropriately (see Sidebar 1 and Sidebar 2). The 1990 American College of Rheumatology Research Classification Criteria (1990 ACR RCC) were developed for application to research study and remain the gold standard.
1990 ACR Research Classification Criteria for Fibromyalgia Syndrome
- 3 months of widespread pain in four quadrants
- Pain (induced by 4 kg of palpation pressure at 11 of 18 anatomically defined tender points)
Anatomically Defined Tender Points:
Occiput: suboccipital muscle insertions
Low cervical: anterior aspects of C5–7 inter-transverse spaces
Trapezius: midpoint of upper border
Supraspinatus: origins, above the scapula spine, near medial border
Second rib: upper lateral surface of second costochondral junction
Lateral epicondyle: 2 cm distal to the epicondyles
Gluteal: upper outer buttock, anterior fold of muscle
Greater trochanter: posterior to trochanteric prominence
Knees: medial fat pad, just proximal to medial condyle
ACR = American College of Rheumatology.
2010 ACR Fibromyalgia Diagnostic Criteria
Presentation of widespread pain and symptoms for 3 or more months
Widespread Pain Index (WPI) score ≥ 7 AND Symptom Severity Scale (SSS) ≥5
WPI Score from 3 to 6 AND SSS ≥9
No other disorder present that would otherwise explain the pain
Sum of WPI and SSS = total score
Diagnosis of fibromyalgia syndrome supported if total score ≥13
Validity: 93% correct or accurate (sensitivity = 97%, specificity = 92%)
ACR = American College of Rheumatology.
These criteria required two simple components: a history of widespread pain for at least 3 months and pain sensitivity to 4 kg of digital pressure (allodynia) at 11 or more of 18 anatomically defined tender points. That approach exhibits a moderately high sensitivity (88.4%) and specificity (81.1%) for identifying patients with FMS when compared with normal controls and disease controls with other painful conditions.
Drawbacks of these criteria are: they focus exclusively on the widespread pain/tenderness domain, ignoring the other important clinical domains; and they were never validated for community clinical use. The 1990 ACR RCC (see Sidebar 1) have now been supplemented in the clinical care arena by the 2010 ACR Fibromyalgia Diagnostic Criteria (2010 ACR FDC), which include widespread pain and other comorbid clinical domains, and which have been validated for the purpose of community medical care (see Sidebar 2). The new 2010 ACR FDC involves two components; a widespread pain index (WPI) and a symptom severity scale (SSS), with each having nearly equal weight toward making the diagnosis of FMS.2 The ACR FDC form can be seen in Figure 1.
Figure 1. 2010 American College of Rheumatology diagnostic criteria for fibromyalgia.
A substantial advantage of the 2010 ACR FDC for those psychiatrists who do not perform physical examinations is that the information needed for making a diagnosis by these criteria can be obtained entirely from a self-report questionnaire; a physical examination to document allodynia is not required by the 2010 ACR FDC, as is the case for the 1990 ACR RCC (see Sidebar 1 and Sidebar 2,).
Causes of FMS
The precipitating causes of FMS may vary among individuals and may require a genetically susceptible host.3,4 The mechanism underlying the painful symptoms appears to involve central sensitization leading to an amplified perception of pain.4 As a result, this condition is recognized as the human model for chronic widespread allodynia, defined as pain that results from stimuli that are not normally painful.5 Figure 2 offers a hypothetical expansion of an earlier model to explain the pathogenesis of fibromyalgia.
Figure. Proposed neuro-bio-physiopathogenesis model of fibromyalgia syndrome (FMS). Based on an earlier model by Russell and Larson,7 this model begins with the theory that there are certain genetic predispositions and genetic associations that increase the risk of FMS. (IFN = interferon; IL = interleukin; NGF = nerve growth factor; SP = substance P; TNF = tumor necrosis factor.)Image courtesy of I. Jon Russell, MD, PhD, ACR Master. Reprinted with permission.
Biologic abnormalities that are detected in most patients include the following: dysfunctional sleep by polysomnography; physiologic/biochemical evidence for central sensitization; temporal summation of second pain; and lowered thresholds to pressure-induced pain detected by brain imaging.
Other factors include lower-than-normal levels of the biogenic amines to drive descending inhibition of nociception (nociception is the biological process underlying the ability to feel pain), and elevated spinal fluid levels of substance P; in primary FMS, elevated spinal fluid levels of nerve growth factor are another factor.1,4,5
The allodynia of FMS results, at least in part, from a form of central nervous system (CNS) sensitization. Physiologically, the phenomenon of facilitated temporal summation, or wind-up, predicts that biochemical changes have occurred centrally at the level of the N-methyl-D-aspartate (NMDA) receptor in the dorsal horn of the spinal cord. Nociception can be viewed as having two opposed components — pronociception and antinociception.
A sensory signal generated by a stimulus to the peripheral tissue is carried to the dorsal horn of the spinal cord by an unmyelinated afferent nerve (a-delta and c-fiber). In the dorsal horn, a number of interactions occur. A synapse receives released glutamate and substance P, providing a mechanism (involving an NMDA receptor, with or without temporal summation) for activation of the wide dynamic range spinal neuron.
The axon of that central neuron crosses to the other side and carries the signal cephalically through the spinothalamic track to the thalamus, from which it is directed to the somatosensory cortex and other brain locations. This set of processes is called pronociception.
At the same time, the second process is activated when cortical (probably originating in the rostral anterior cingulate cortex [rACC]6) and brainstem signals descend caudally to the relevant segment of the dorsal horn where they interact, mainly preganglionically, to inhibit, counterbalance, or at least determine the magnitude of the pronociceptive signal. This second process is referred to as descending inhibition or antinociception.7
Misperceptions of FMS
It is not uncommon for people with FMS pain to be doubted because of their unique presentation of chronic widespread pain. One of the reasons for this reaction from friends, family, and even health care providers, has been that some form of pain is common in the general population, at almost any age, so people who complain frequently about pain might be considered unduly sensitive or seekers of primary or secondary gain. They have been variously labeled with an affective disorder, an anxiety disorder, a psychosomatic illness, or as being malingerers.
Although methods for validating an individual’s experience of pain have been historically crude, a sample of patients with FMS has been studied via functional magnetic resonance imaging (fMRI), documenting “objective allodynia.”8 That being said, FMS can exhibit comorbid psychiatric conditions. At least a third of individuals with FMS will have a comorbid depressive or anxiety disorder.1 Even when there is no apparent psychiatric component, it is likely that psychiatrists will come into contact with these individuals.
Pain (chronic, widespread pain as well as localized pain such as headache), sleep disturbances, fatigue, and cognitive dysfunction have been described as prominent features of FMS, which can be seen in a host of affective and anxiety disorders as well.1
Typically, FMS is not considered an inflammatory disorder. Rheumatologists might view the conditions within their realm of expertise to be “very inflammatory” or “mildly inflammatory” as exemplified by rheumatoid arthritis and osteoarthritis, respectively. They would tend to view FMS as being noninflammatory. One problem with viewing these conditions as discrete is that they can overlap with one another and perhaps even predispose an individual patient to comorbidity.
Inflammation in FMS
Cytokines are nonantibody proteins released by inflammatory cells when they come in contact with a foreign antigen and act as intercellular mediators of an inflammatory response (see Table). Classically, cytokines can be viewed as target-specific, nonantibody peptide/proteins released by activated inflammatory cells and serving as intercellular mediators of an inflammatory response. They represent a form of communication between cells charged with the task of either amplifying or down-regulating the immune response.
Table. Inflammatory or Anti-Inflammatory Mediators in Fibromyalgia Syndrome
The most obvious players in this game of immunologic tag are the cytokine-secreting cells, the cytokines molecules, and the target cells bearing receptors for specific cytokines.
Less intuitive are a class of molecules that can specifically bind to the cytokines and prevent their binding to the target cell receptors. These molecules include soluble cytokine receptor molecules that presumably have broken free from the target cells and immunoglobulin antibodies that are specific for a given cytokine.
The effectiveness of each cytokine in properly influencing the target cell depends on many factors, such as: the timing of the cytokine’s release; the cytokine’s ability to allude inactivation or destruction; the avidity of soluble inactivating agents; the cytokine’s concentration; the cytokine’s half-life in solution; the proximity of the secreting cell to the target cell; and the cell cycle receptiveness of the target cell.
According to Togo and colleagues,9 the levels of certain cytokines are higher than normal in the serum of patients with FMS. For example, the levels of interleukin-10 (IL-10), IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) were elevated in FMS. The FMS patients secreted significantly more IL-10 (anti-inflammatory in nature), which the authors suggested was a tilt away from the normal balance to one favoring anti-inflammatory activity in FMS. They further indicated that the increased nocturnal IL-10 might explain the non-refreshing sleep which is usually quite prominent in FMS.9
Cytokines and Growth Factors
According to Gur and Oktayoglu,10 cytokines are essential to immune responses, inflammation, hematopoiesis, and a variety of other physiologic processes. They further indicate that cytokine levels can be altered by physiologic stress and propose that cytokines may cause many of the comorbid manifestations of FMS, such as: allodynia; pain, fatigue; sleep dysfunction; blunted responses to physiologic or psychological stress; anxiety; myalgias; and cognitive dysfunction. Substance P (SP) is increased in the CSF and may stimulate the release of IL-6, inducing allodynia, but it is also important to know that IL-6 can function in the hypothalamus as a mimic of corticotrophin releasing factor.11
Wallace and colleagues12 found increased levels of serum IL-8 and IL-1Ra that appeared to increase with symptom duration. It is possible that the pathophysiologic feature of FMS may differ in the acute and chronic forms.12
Bazzichi and colleagues13 found plasma levels of IL-10, IL-8, and TNF-alpha to be elevated in FMS; IL-8 was considered to be particularly important because of its involvement in sympathetic pain, the sympathetic nervous system, and the hypothalamic-pituitary-adrenal (HPA) axis. TNF-alpha promotes fatigue and anorexia. The increase in IL-10 may represent a compensatory mechanism, albeit inadequate, in response to the persistent symptoms in FMS.
FMS and Depression
In a study of the pro-inflammatory cytokines IL-1beta and IL-8 in CSF, a negative correlation between IL-5 and depressive symptoms was observed in depressed patients with FMS.14 The authors were interested in the activation of glial cells and their potential impact on the development and maintenance of chronic pain.
Previously, levels of the anti-inflammatory cytokine IL-5 had been shown to be reduced in depressed patients. Furthermore, the release of proinflammatory cytokines from glial cells in the CNS can result in behavioral changes that have been termed the “sickness syndrome,” which exhibits symptoms of exaggerated pain response as well as anorexia, fatigue, loss of interests in social activities, anhedonia, decreased concentration ability, and sleep disturbances.13
Neopterin is present in the reticuloendothelial system where it is produced by activated macrophages in response to interferon-gamma (IFN-gamma) stimulation. Patients with major depression have been found to have significantly higher concentrations of neopterin in their urine as well as a higher neopterin/biopterin ratio.15
Although the significance of this observation is not clear, biopterin is the final catabolic product in the tetrahydrobio-pterin (BH4) pathway. BH4 is the essential cofactor in enzymatic hydroxylation of the aromatic amino acids phenylalanine, tyrosine, and tryptophan.16 One could speculate, therefore, that the production of serotonin from tryptophan is ultimately dependent on the response of an activated macrophage to a cytokine.
The serum from people with FMS exhibited higher than normal levels of soluble IL-6 receptor (sIL-6R) and sIL-1RA, which correlated with increased Hamilton Depression Rating Scale (HDRS) scores when compared with the values obtained from healthy volunteers.13 It is possible that the clinically relevant depressive symptoms seen in some patients with FMS could be associated with activation products of an inflammatory response system (IRS).
Activation of an IRS is characterized by immune and acute phase response changes including: increased numbers of leukocytes; activated T cells and neutrophils; lower lymphocyte proliferation, neutrophil phagocytosis and natural killer (NK) cell activity; and increased production of proinflammatory cytokines.17
Depression has been characterized by an increase in proinflammatory cytokines such as IL-1, IL-2, IL-6, IL-8, IL-12, IFN-gamma, and TNF-alpha.18 Animal models of depression have linked cell-mediated immunity (CMI) with “depressive-like behaviors” through the depressongenic activities of T cell-derived (IFN-gamma and IL-2) and monocytic-derived (IL-1, IL-6, IL-12 and TNF-alpha) cytokines.
According to Maes and colleagues,17 a significant correlation exists between serum neopterin levels and the levels of pro-inflammatory cytokines.
Serum and urinary neopterin are increased in depression, particularly melancholic depression. The increase is higher in patients that have experienced more than one depressive episode although chronicity, treatment resistance, and the presence of chronic fatigue did not seem to influence neopterin levels.19
There was a positive correlation between serum neopterin and TNF-alpha in depressed patients not present in non-depressed patients. Similarly to the neo-pterin levels, TNF-alpha was higher in melancholic patients and was related to the HDRS score. In depressed patients with elevated levels of chronic fatigue, as measured by the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale, IL-1 was elevated and exhibited a relationship to having experienced more than three depressive episodes.
Indeed, CMI, which is indicated by increased levels of plasma sIL-2R and sCD8, increased numbers of activated T cells such as CD25+ and HLA-DR+, and increased serum neopterin and stimulated production of IFN-gamma, is positively associated with recurrent depressive episodes.18
Bazzichi and colleagues13 reported that activation of the humoral and neural pathways of cytokine transmission from the periphery to the CNS can be implicated in the depressive and anxiety symptoms associated with FMS, and suggests that subinflammation may play a specific role in fibromyalgia.
Chronic Fatigue Syndrome
In a study of peripheral blood mononuclear cells from patients with chronic fatigue syndrome (CFS), the cytokines IL-1beta, IL-6, and TNF-alpha were associated with inflammation.19 The same was true for fatigue, fever, muscle pain, and weakness. The relevance of that finding to the current topic is unclear because CFS and FMS appear to be very different conditions. Serum levels of IL-2R and IL-8 were significantly lower in FMS patients with HDRS scores greater than 16 when compared with FMS patients who had HDRS scores less than 16.20
Maes and colleagues20 found that the presence of clinically relevant depressive symptoms (HDRS score >16) was associated with signs of IRS activation as indicated by higher serum IL-6R and IL-1RA of FMS patients when compared with both normal volunteers and FMS patients who had an HDRS score of less than 16.20 This study also explained a significant portion of the variance in CD8 and IL-1RA levels by depressive symptoms (HDRS score).
Additionally, this study indicated that FMS patients without depression (HDRS < 16) show indications of immunosuppression, such as lower CD8, while the authors reiterated previous findings of increased IL-1RA and IL-6R in depressed individuals that possibly indicate activation of the monocytic arm of CMI.20
Nerve growth factor (NGF), a protein that stimulates the growth of sympathetic and sensory nerve cells, and brain-derived neurotrophic factor (BDNF), involved in the stimulation and control of neurogenesis, were elevated in the CSF of individuals with FMS.21 This is notable because NGF is considered a key factor for inflammation-induced allodynia beause it regulates the proinflammatory mediators IL-1beta, TNF-alpha, and IL-6.22
A review of the biochemical origin of pain suggests that sympathetic pain (via IL-8) and pain hypersensitivity, fatigue, and depression (via IL-6) are increased in FMS.23 Skin biopsies from FMS patients show mononuclear and fibroblast-like cells near nociceptive neuronal fibers that stained positive for inflammatory cytokines.24 CNS concentrations of IL-8 have been found to be elevated in FMS.25
A recent study by Malhotra and colleagues26 showed significant elevations in the proinflammatory cytokine IL-6 along with increased levels of the T-helper cell-2 cytokine, IL-4, in the serum of patients with FMS. Remarkably, the levels of these cytokines correlated positively with subjective measures of pain in the FMS patients. The levels of IL-10 were found to be decreased in this study (inconsistent with previous studies), which the authors opined may be due to an attempt at homeostasis.
This study also looked at the levels of proinflammatory IL-2 and IFN-gamma, both of which were found to be decreased when compared with individuals without FMS.
It has been hypothesized that fascial inflammation may lead to fascial dysfunction, widespread pain, and the central sensitization of FMS, namely from inadequate growth hormone stimulation impairing fascial healing.26
N-methyl-D-aspartate receptor subtype 2D (NMDA 2D) expression was increased in the skin of FMS patients which may be suggestive of a more generalized increase in other peripheral nerves along with higher values of immunoglobulin G (IgG) deposits in the dermis and vessel walls.24
When investigators sought evidence for altered levels of adhesion molecule expression, FMS patients were found to have significantly decreased L-selectin (CD62L) and beta2-integrin (CD11b/CD18) on the surface of their polymorphonuclear leukocytes (PMN), which may decrease PMN migration to sites of inflammation and compromise the body’s defense against infection and pain.28
Immunoglobulins and Antibodies
Some interesting studies have documented the presence of antipolymer antibodies (APA) in the serum of patients with FMS.29,30 Those studies were conducted because of an observed overlap between FMS symptoms and those seen in some women with silicone gel-filled breast implants.
Wilson and colleagues29 found that 47% of FMS patients were seropositive for APA. Additionally it was found that APA seropositivity was higher in FMS than in rheumatic disorders such as rheumatoid arthritis and systemic lupus erythematosis. Finally, a positive correlation was noted with FMS severity and APA status.
In contrast, Bazzichi and colleagues30 found no significant difference in APA seropositivity between FMS patients and controls, although they did find qualitatively higher (though again, not significant) levels of APA in FMS patients with moderate-to-severe symptoms when compared with FMS patients with mild symptoms.
Lund and colleagues31 found significant elevations in C-reactive protein in FMS patients, further suggesting a possible inflammatory component of FMS. Xiao and colleagues32 made a similar observation in patients with FMS and documented that the C-reactive protein levels correlated with the erythrocyte sedimentation rate, IL-6, IL-8, and the basal metabolic rate, implying that fat cells in obese patients are contributing to the inflammatory process.
There is some evidence that inflammation may cause or contribute to the FMS-like symptoms that are seen when FMS overlaps with rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, osteoarthritis, and other pain syndromes.33
Oxidative stress (OS) has been proposed as a contributor to the etiology of FMS. Among the effects of OS are increases in lipid and protein oxidation products associated with depletion of endogenous antioxidant substances. Imbalances between reactive oxygen species and antioxidants have been implicated in a variety of conditions, including aging, atherosclerosis, carcinogenesis, infarction, osteoporosis, and muscle diseases.34
Decreased antioxidants and increased oxidants have been found in FMS patients, suggesting that these patients may have been chronically exposed to increased OS. Although the role of OS in the pathogenesis of FMS is still uncertain, it is clear that the findings of abnormal OS are reproducible in many clinical settings.
In a study of FMS patients by Altindag and colleagues,35 lower paraoxonase and arylesterase along with increased lipid hydroperoxides (evidence of decreased antioxidant status) were seen in the FMS patients when compared with healthy controls. Another study showed that total antioxidant capacity in the plasma of FMS patients was decreased as evidenced by an increase in the ROS hydrogen peroxide when compared to healthy controls.36 This study also demonstrated an inverse correlation between total antioxidant capacity and the Pain Visual Analogue Scale that which was being used to document the intensity of current perceived pain.
There is evidence of free radical damage in FMS patients, as evidenced by increased levels of malondiadehyde, which has been used as a marker for free radical damage to lipid molecules, and decreased levels of superoxide dismutase, which is a naturally occurring antioxidant in the body. Eisenger and colleagues37 found abnormalities of reactive oxygen species (decreased thiols correlated with increased protein peroxidation) in FMS patients, although this study did not show an increase in malondiadehyde.
Ozgocmen and colleagues38 found elevated thiobarbituric acid reactive substances (TBARS), an end product of lipid peroxidation, which did not differ with treatment with amitriptyline or sertraline. There was also a demonstrable negative correlation between HDRS and TBARS, suggesting a role for OS in depression.
Cordero and colleagues39 made a convincing case for mitochondrial dysfunction in FMS and pointed to morphologic alterations and histochemical abnormalities as etiologies of OS in FMS. They postulated that the OS seen in FMS may arise as a consequence of mitochondrial dysfunction or that its presence may interfere with critical aspects of mitochondrial function.
In either case, there would seem to be value in reducing this OS in FMS as a potentially curative or preventive treatment.
Cordero and colleagues39 advocate the use of coenzyme Q10 (CoQ) in FMS because of its potential to improve mitochondrial function. They postulated that because CoQ is a mitochondrial cofactor as well as a free radical scavenger because it can mitigate lipid and protein oxidation as well as DNA damage caused by OS.
Obesity in FMS
An inflammatory process may associated with or even exacerbate certain clinical problems in FMS, including obesity. Trock40 reported that obese patients have higher levels of inflammatory cytokines, possibly from the cytokine production by the visceral adipose tissue itself. An increased level of C-reactive protein has also been associated with FMS that correlates with body mass index.32
Fibromyalgia is significantly correlated with obesity, potentially from reduced physical activity, disturbances of sleep, depression, or neuroendocrine abnormalities.41
FMS is a common disorder of significant importance to physicians. This may be particularly true for psychiatrists because of its comorbidity with psychiatric illnesses. There is a growing body of evidence implicating inflammation in the pathogenesis of FMS as well as with certain psychiatric disorders such as depression. Notwithstanding the controversial nature of FMS and evidence of its inflammatory nature, it is almost certain that psychiatrists will come into contact with patients who have FMS regardless of their practice setting.
A better understanding of the possible inflammatory nature of these conditions and their potential associations with each other, are important as we attempt to better understand and provide rational treatment for our patients.
- Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Arthritis Rheum. 1990;33:160–172.. doi:10.1002/art.1780330203 [CrossRef]
- Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res. 2010;62:600–610. doi:10.1002/acr.20140 [CrossRef]
- Xiao Y, He W, Haynes WN, Russell IJ: Genetic polymorphisms of the beta 2-adrenergic receptor relate to Gs protein dysfunction in fibromyalgia syndrome. J Rheumatol. 2011; 38(6):1095–1103. doi:10.3899/jrheum.101104 [CrossRef]
- Arnold L, Fan J, Russell I, et al. The fibromyalgia family study: a genome-scan linkage study. 2012.
- Turk D, Okifuji A. Pain Terms and Taxonomies of Pain. In Fishman S, Bonica’s Management of Pain. Philadelphia, PA: Lippincott Williams & Wilkins; 2010:13–23.
- Jensen K, Kosek E, Petzke F, et al. Evidence of dysfunctional pain inhibition in fibromyalgia reflected in rACC during provoked pain. Pain. 2009;144:95–100. doi:10.1016/j.pain.2009.03.018 [CrossRef]
- Russell IJ, Larson AA: Neurophysiopathogenesis of fibromyalgia syndrome: a unified hypothesis. Rheum Dis Clin N Am. 2009;35:421–435. doi:10.1016/j.rdc.2009.06.005 [CrossRef]
- Nebel M, Gracely R: Neuroimaging of fibromyalgia. Rheum Dis Clin N Am. 2009;35:313–327. doi:10.1016/j.rdc.2009.06.004 [CrossRef]
- Togo F, Natelson BH, Adler GK, et al. Plasma cytokine fluctuations over time in healthy controls and patients with fibromyalgia. Exp Biol Med. 2009;234:232–240. doi:10.3181/0808-RM-254 [CrossRef]
- Gur A, Oktayoglu P: Status of immune mediators in fibromyalgia. Curr Pain Headache Rep. 2008; 12:175–181. doi:10.1007/s11916-008-0031-4 [CrossRef]
- Torpy DJ, Papanicolaou DA, Lotsikas AJ, Wilder RL, Chrousos GP, Pillemer SR: Responses of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis to interleukin-6: a pilot study in fibromyalgia. Arthritis Rheum. 2000;43:872–880. doi:10.1002/1529-0131(200004)43:4<872::AID-ANR19>3.0.CO;2-T [CrossRef]
- Wallace DJ, Linker-Israeli M, Hallegua D, Silverman S, Silver D, Weisman MH: Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology. 2001;40(7):743–749. doi:10.1093/rheumatology/40.7.743 [CrossRef]
- Bazzichi L, Rossi A, Massimetti G, et al. Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clin Exp Rheumatol. 2007;25:225–230.
- Maletic V, Raison CL: Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci. 2009;14:5291–5338. doi:10.2741/3598 [CrossRef]
- Song C, Lin A, Bonaccorso S, et al. The inflammatory response system and the availability of plasma tryptophan in patients with primary sleep disorders and major depression. J Affect Disord. 1998;49:211–219. doi:10.1016/S0165-0327(98)00025-1 [CrossRef]
- Shintaku H: Disorders of tertrahydrobiopterin metabolism and their treatment. Curr Drug Metab. 2002;3:123–131. doi:10.2174/1389200024605145 [CrossRef]
- Maes M, Yirmyra R, Noraberg J, et al. The inflammation and neurodegenerative (I&ND) hypothesis of depression: leads for future research and new drug developments in depression. Metab Brain Dis. 2009;24:27–53. doi:10.1007/s11011-008-9118-1 [CrossRef]
- Maes M, Mihaylova I, Kubera M, Ringel K: Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012; 36:169–175. doi:10.1016/j.pnpbp.2011.09.006 [CrossRef]
- Chao CC, Janoff EN, Hu SX, et al. Altered cytokine release in peripheral blood mononuclear cell cultures from patients with the chronic fatigue syndrome. Cytokine. 1991;3:292–298. doi:10.1016/1043-4666(91)90497-2 [CrossRef]
- Maes M, Libbrecht I, Van HF, et al. The immune-inflammatory pathophysiology of fibromyalgia: increased serum soluble Gp130, the common signal transducer protein of various neurotrophic cytokines. Psychoneuroendocrinology. 1999; 24:371–383. doi:10.1016/S0306-4530(98)00087-0 [CrossRef]
- Seidel MF, Herguijuela M, Forkert R, Otten U: Nerve growth factor in rheumatic diseases. [review]. Sem Arthritis Rheum. 2010;40:109–126. doi:10.1016/j.semarthrit.2009.03.002 [CrossRef]
- Giovengo SL, Russell IJ, Larson AA: Increased concentrations of nerve growth factor (NGF) in cerebrospinal fluid of patients with fibromyalgia. J Rheumatol. 1999;26:1564–1569.
- Omoigui S: The biochemical origin of pain: the origin of all pain is inflammation and the inflammatory response. Part 2 of 3 — inflammatory profile of pain syndromes. Med Hypoth. 2007;69:1169–1178. doi:10.1016/j.mehy.2007.06.033 [CrossRef]
- Kim SH: Skin biopsy findings: implications for the pathophysiology of fibromyalgia. Med Hypoth. 2007;69:141–144. doi:10.1016/j.mehy.2006.10.057 [CrossRef]
- Kadetoff D, Lampa J, Westman M, Andersson M, Kosek E: Evidence of central inflammation in fibromyalgia-increased cerebrospinal fluid interleukin-8 levels. J Neuroimmunol. 2012;242:33–38. doi:10.1016/j.jneuroim.2011.10.013 [CrossRef]
- Malhotra D, Saxena AK, Das SA, et al. Evaluation of cytokine levels in fibromyalgia syndrome patients and its relationship to the severity of chronic pain. J Musculoskel Pain. 2012; In press. doi:10.3109/10582452.2012.704141 [CrossRef]
- Liptan GL: Fascia: A missing link in our understanding of the pathology of fibromyalgia. J Bodywork Mov Ther. 2010;14:3–12. doi:10.1016/j.jbmt.2009.08.003 [CrossRef]
- Kaufmann I, Schelling G, Eisner C, et al. Decrease in adhesion molecules on polymorphonuclear leukocytes of patients with fibromyalgia. Rheumatol Int. 2009;29:1109–1111. doi:10.1007/s00296-008-0803-5 [CrossRef]
- Wilson RB, Gluck OS, Tesser JR, et al. Antipolymer antibody reactivity in a subset of patients with fibromyalgia correlates with severity. J Rheumatol. 1999; 26:402–407.
- Bazzichi L, Giacomelli C, De FF, et al. Antipolymer antibody in Italian fibromyalgic patients. Arthr Res Ther. 2007; 9:R86. doi:10.1186/ar2285 [CrossRef]
- Lund HL, Nafstad P, Olsen I, Schwarze P, Ronningen KS: C-reactive protein variations for different chronic somatic disorders. Scand J Pub Health. 2009;37:640–646. doi:10.1177/1403494809104358 [CrossRef]
- Xiao Y, Haynes WL, Michalek JE, Russell IJ: Elevated serum high-sensitivity C-reactive protein levels in fibromyalgia syndrome patients correlate with body mass index, inter-leukin-6, interleukin-8, erythrocyte sedimentation rate. J Clin Immunol. 2012; in press.
- Wolfe F, Cathey MA: Prevalence of primary and secondary fibrositis. J Rheumatol. 1983;10:965–968.
- Bagis S, Lulufer T, Sahin G, et al. Free radicals and antioxidants in primary fibromyalgia: an oxidative stress disorder?Rheumatol Int. 2005; 25:188–190. doi:10.1007/s00296-003-0427-8 [CrossRef]
- Altindag O, Gur A, Calgan N, et al. Paraoxonase and arylesterase activities in fibromyalgia. Redox Rep. 2007;12(3):134–138.
- Altindag O, Celik H, Jenkins DJA, et al. Total antioxidant capacity and the severity of the pain in patients with fibromyalgia. Redox Rep. 2006;11:131–135. doi:10.1179/135100006X116628 [CrossRef]
- Eisinger J, Gandolfo C, Zakarian H, Ayavou T: Reactive oxygen species, antioxidant status and fibromyalgia. J Musculoskel Pain. 1997; 5(4):5–15. doi:10.1300/J094v05n04_02 [CrossRef]
- Ozgocmen S, Ozyurt H, Sogut S, et al. Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns. Rheumatol Int. 2006;26:598–603. doi:10.1007/s00296-005-0079-y [CrossRef]
- Cordero M, de Miguel M, Alcazar J: The role of oxidative stress and mitochondrial dysfunction in the pathogenesis of fibromyalgia. In: Wilke WS, ed. New Insights into Fibromyalgia. Rijeka, Croatia: InTech; 2012:77–98.
- Trock D: Tired, achy, and overweight, the inflammatory nature of obesity. J Clin Rheumatol. 2009;15:50. doi:10.1097/RHU.0b013e31819559f7 [CrossRef]
- Ursini F, Naty S, Grembiale R: Fibromyalgia and obesity: the hidden link. Rheumatol Int. 2011;31:1403–1408. doi:10.1007/s00296-011-1885-z [CrossRef]
Inflammatory or Anti-Inflammatory Mediators in Fibromyalgia Syndrome
||Proinflammatory; pain hypersensitivity, fatigue, and depression
||Proinflammatory; sympathetic pain
||Anti-inflammatory; non-refreshing sleep
||Proinflammatory; fatigue and anorexia
||Proinflammatory; sympathetic pain
||Altered defense against infection and pain