Fibromyalgia syndrome: etiology, pathogenesis, diagnosis, and treatment.

1. Introduction

Fibromyalgia is a syndrome characterized by chronic widespread pain at multiple tender points, joint stiffness, and systemic symptoms (e.g., mood disorders, fatigue, cognitive dysfunction, and insomnia) [ 1 – 4 ] without a well-defined underlying organic disease. Nevertheless, it can be associated with specific diseases such as rheumatic pathologies, psychiatric or neurological disorders, infections, and diabetes.

What today is defined as fibromyalgia had already been described in the nineteenth century. In 1904, Gowers [ 5 ] coined the term “fibrositis” which was used until the seventies and eighties of the last century when an etiology involving the central nervous system was discovered. But it was Graham [ 6 ] in 1950 who introduced the modern concept of fibromyalgia as “pain syndrome” in the absence of a specific organic disease. Then in the mid-1970s Smythe and Moldofsky [ 7 ] coined the new term “fibromyalgia” and identified regions of extreme tenderness, the so-called “tender points.” Only in 1990 did the American College of Rheumatology committee write up the widely used diagnostic criteria [ 8 ] that have only recently been modified [ 9 , 10 ]. The prevalence of fibromyalgia has been estimated to be around 1%-2% (3.4% for women and 0.5% for men) [ 11 , 12 ]. However, it is still a poorly understood condition that is difficult to diagnose.

This paper is based on a systematic search of the PubMed database to identify articles related to fibromyalgia. The searches were restricted to English language citations from the inception of the database to June 2012. Relevant articles from the bibliographies of selected articles were also identified and used in this paper. All selected articles were published between 1904 and 2012.

This paper is primarily intended to assist orthopedic surgeons who find themselves faced with patients' referring musculoskeletal symptoms affected by (often undiagnosed) fibromyalgia. It is very important to know and to remember this syndrome so that the patient can be sent to the correct specialist.

2. Etiology and Pathogenesis

The etiology and pathogenesis of fibromyalgia are still not fully understood. Several factors such as dysfunction of the central and autonomic nervous systems, neurotransmitters, hormones, immune system, external stressors, psychiatric aspects, and others seem to be involved.

2.1. Central Nervous System (CNS)

Central sensitization is considered the main mechanism involved and it is defined by the increased response to stimulation mediated by CNS signaling [ 13 ]. Central sensitization is the consequence of spontaneous nerve activity, enlarged receptive fields, and augmented stimulus responses transmitted by primary afferent fibers [ 14 ]. An important involved phenomenon seems to be the “windup” which reflects the increased excitability of spinal cord neurons: after a painful stimulus, subsequent stimuli of the same intensity are perceived as stronger [ 15 ]; this occurs normally in everyone [ 16 ], but it is excessive in fibromyalgic patients [ 17 ]. These phenomena are an expression of neuroplasticity and are mainly mediated by N-methyl-D-aspartate (NMDA) receptors located in the postsynaptic membrane in the dorsal horn of the spinal cord [ 18 – 21 ].

Another mechanism supposedly involves the well-known descending inhibitory pain pathways, which modulate spinal cord responses to painful stimuli. They seem to be impaired in patients with fibromyalgia, helping to exacerbate the central sensitization [ 14 , 22 , 23 ].

Apart from augmented neuronal mechanisms, glial cell activation also appears to play an important role in the pathogenesis of fibromyalgia because they help to modulate pain transmission in the spinal cord. Activated by various painful stimuli, they release proinflammatory cytokines, nitric oxide, prostaglandins, and reactive oxygen species that stimulate and prolong spinal cord hyperexcitability [ 24 – 26 ].

Also, various neurotransmitters seem to be involved in the central sensitization. Serotonin (5-HT) has a significant role in the modulation of pain [ 27 ], and several studies have been carried out looking for modified levels of this molecule in the serum and in the cerebrospinal fluid (CSF). Also, 5-HT's precursor tryptophan and its metabolites have been measured in the blood and in the CSF and the urine with conflicting data. In some studies 5-HT was found at low levels either in the serum [ 28 – 30 ] or in CSF [ 31 ] while other authors have not found statistical differences in 5-HT levels between affected patients and controls either in serum [ 28 ] or in CSF [ 32 ]. Serotonin is involved also in the regulation of mood and sleep [ 33 , 34 ] and this could explain the association between fibromyalgia and sleep and mental disorders.

Other neurotransmitters also play a role. There are data suggesting the involvement of norepinephrine [ 32 ], dopamine [ 35 , 36 ], substance P (whose levels are typically high in cases of fibromyalgia as its synthesis is inhibited by 5-HT) [ 37 – 39 ], endorphins, and metenkephalins [ 40 , 41 ]. These peptides of the endogenous opioid system seem to be hyperactive but somehow are unable to modulate pain in these patients. This could explain the reduced efficacy of exogenous opiates in this population [ 42 ].

Functional neuroimaging studies support the involvement of the brain in the pathogenesis of this condition.

Single-photon-emission computed tomography (SPECT) was one of the first functional neuroimaging techniques to be used for this. After the infusion of a radioactive tracer, this technique provides a measure of regional cerebral blood flow (rCBF) throughout the brain, reflecting neural activity. The thalamus seems to be a region of interest. Mountz et al. [ 43 ] compared baseline levels of rCBF in 10 patients with 7 controls, demonstrating decreased rCBF in bilateral thalamus and caudate nucleus in the first group. The involvement of thalamus and basal ganglia was also proposed by Adigüzel et al. [ 44 ]: he demonstrated increases in rCBF in these regions after treatment with amitriptyline. Kwiatek et al. [ 45 ] showed decreased rCBF in the right thalamus, the inferior dorsal pons, and next to the right lentiform nucleus. Bradley et al. [ 46 ] also replicated the finding of low rCBF in the right thalamus.

Positron emission tomography (PET) uses radioactive tracers like SPECT, but it is characterized by increased temporal and spatial resolution. For example, Wik et al. [ 47 ] compared rCBF in 8 patients and controls at rest. Patients showed higher rCBF than controls in the retrosplenial cortex bilaterally, while lower rCBF in the left frontal, temporal, parietal, and occipital cortices. This could reflect increased attention towards subnoxious somatosensory signaling and a dysfunction of the normal cognitive processing of pain in patients affected by fibromyalgia. PET with [ 18 F] fluorodeoxyglucose (FDG) helps to assess variations in glucose metabolism. Yunus et al. [ 48 ] did not find significant differences at rest between 12 fibromyalgic patients and 7 controls, while Walitt et al. [ 49 ] showed an association between the increased metabolic activity in limbic structures and the improvement in a comprehensive treatment program. Using the radiolabeled opioid [ 11 C] carfentanil, Harris et al. [ 40 ] tried to explain the apparently paradoxical hyperactivity of the endogenous opioid system. He showed a significantly reduced overall μ opioid receptor binding potential in patients affected by fibromyalgia. The right and left nucleus accumbens and the left amygdale were the regions most significantly involved and a trend towards reduction was also seen in the right dorsal anterior cingulate cortex. These findings could reflect occupancy by endogenous opioids released in response to the ongoing pain and a receptor downregulation.

Functional magnetic resonance imaging (fMRI) has greater temporal and spatial resolution than either SPECT or PET. In the first fMRI study of fibromyalgia [ 50 ] 16 patients and 16 controls underwent fMRI during painful stimulation. First the 2 groups were stimulated with the same pressure; then the intensity of stimulation of controls was increased to deliver a subjective level of pain similar to that experienced by the patients. Neural activation patterns were similar only under the second condition of painful stimulation. These findings support the hypothesis of a model of centrally augmented pain processing. Cook et al. [ 51 ] examined with fMRI the response of two groups of women (9 patients and 9 controls) to both painful and nonpainful stimuli. In response to nonpainful stimuli patients showed significantly greater activity than controls in insular, prefrontal, supplemental motor and anterior cingulate cortices. In response to painful stimuli the contralateral insular cortex was significantly activated to a greater extent in patients than it was in controls. Other recent studies have suggested the role of cortical structures, such as the insular cortex [ 52 , 53 ], the right premotor cortex, the supplementary motor area, the midcingulate cortex, and the right inferior frontal gyrus [ 52 ].

The role of the thalamus has been recently underlined by Foerster et al. [ 54 ] who explored correlations between rCBF and levels of both clinical and evoked pain. They showed a significant correlation between the rCBF in the bilateral thalami and the BPCQ-INT scale [ 55 ], a self-report questionnaire used to evaluate personal control of pain. In addition the rCBF values of the thalamus appeared less correlated with the values detected in other brain regions in patients than in controls.

Functional magnetic resonance imaging seems also to be useful to better understand the role of the descending inhibitory pain system. In the study done by Jensen et al. [ 56 ] 16 patients and 16 controls underwent fMRI during individually calibrated painful pressure. They did not find different activities in brain regions involved in attention or affectivity, or regions with sensory connections with the stimulated body area. Interestingly, they showed attenuated response to pain in the rostral anterior cingulate cortex, an important region of the descending pain regulating system. This may explain the impairment of this system, as previously proposed by various authors [ 14 , 22 , 23 ]. In a subsequent study Jensen compared the functional connectivity of the descending inhibitory pain pathways in fibromyalgic patients and controls [ 57 ]. He mainly focused on the rostral anterior cingulate cortex and the thalamus. Controls showed higher rACC connectivity to the bilateral hippocampi, amygdala, brainstem, and the rostral ventromedial medulla (regions involved in the pain inhibitory network); they also showed higher thalamus connectivity to the orbitofrontal cortex (the region involved in pain and emotion regulation through both cognitive evaluative processes and homeostatic control).

Additional neuroimaging methods have been used to understand central pathogenesis of fibromyalgia.

Voxel-based morphometry (VBM) uses MRI images to assess the volume of specific brain regions. Various studies have shown loss of grey matter in fibromyalgic patients involving the amygdala, the cingulate cortex, and the hippocampus [ 58 – 61 ]. The significance of this atrophy is not clear.

Diffusion tensor imaging (DTI) is based on the movement of water through brain tissue and provides information about the integrity of white matter. Sundgren et al. [ 62 ] showed a reduced signal in the right thalamus in patients affected by fibromyalgia and the reduction was statistically greater in patients referring worse pain.

Magnetic resonance spectroscopy (MRS) evaluates a signal that reflects the concentration of various molecules (e.g., glycine, glutamate, and aspartate) in relation to a standard molecule. Patients affected by fibromyalgia showed a different ratio of choline/creatine within the dorsolateral prefrontal cortex and a different ratio of glutamate/glutamine within the insula and the posterior gyrus [ 63 – 65 ].

Arterial spin labeling (ASL) is similar to fMRI, but uses magnetized blood as contrast agent. The signal of rCBF is mostly from the parenchyma improving the spatial localization. Few authors have used ASL: Owen found abnormal activations in the bilateral insula, the secondary somatosensory cortex, the cingulate cortex, the contralateral primary somatosensory cortex, and the ipsilateral thalamus [ 66 ]; Hernandez found decreased rCBF in the bilateral thalamus in fibromyalgic patients [ 67 ].

2.2. Neuroendocrine System and Autonomic Nervous System

As fibromyalgia is considered a stress-related disorder, it is easy to understand that the hypothalamic-pituitary-adrenal (HPA) axis is involved [ 68 ]. Different studies showed elevated cortisol levels, particularly in the evening, associated with a disrupted circadian rhythm [ 69 , 70 ]. In addition, these patients showed high values of adrenocorticotropic hormone (ACTH) both basally [ 71 , 72 ] and in response to stress—most likely as a consequence of a chronic hyposecretion of corticotropin-releasing hormone (CRH) [ 73 ]. These alterations are probably related to low levels of 5-HT observed in cases of fibromyalgia, because serotoninergic fibers regulate the HPA axis function [ 71 ].

Growth hormone (GH) levels tend to be normal during the day, reduced during sleep. It is likely that the explanation is twofold. First, GH is mainly secreted during stage 4 of sleep and this phase is disrupted in patients affected by fibromyalgia. Second, these patients have high levels of somatostatin, a GH inhibitor, induced by ACTH whose levels are high as previously mentioned [ 74 ]. Thyroid hormone levels are usually normal, even if the patients often show symptoms of hypothyroidism and there is some evidence suggesting an association with abnormal thyrotropin-releasing hormone (TRH) stimulation tests [ 75 ]. Gonadotropin and gonadal steroid secretion is usually normal [ 76 – 78 ], apparently without any correlation to the higher incidence of fibromyalgia in females.

Various studies, the most recent of which is based on methodologies such as power spectrum analysis of heart rate variability [ 79 , 80 ] and tilt table tests [ 81 ], seem to confirm that in fibromyalgia the sympathetic nervous system is persistently hyperactive, but hyporeactive to stress. This could explain some clinical symptoms such as fatigue, morning stiffness, sleep disorders, anxiety, pseudo-Raynaud's phenomenon, sicca symptoms, and bowel irritability [ 42 ]. High serum levels of neuropeptide Y, which is normally secreted along with norepinephrine, are supposed to be a sign of this dysautonomic state [ 82 ].

2.3. Sleep Disturbances

Patients with fibromyalgia often complain of sleep disorders [ 83 ] and these are probably involved in its pathogenesis [ 1 ]. As revealed by electroencephalographic examinations, the fourth phase of sleep is the most disturbed and a direct consequence should be a deficit of GH and insulin-like growth factor 1 (IGF-1) [ 84 , 85 ]. Given that these hormones are involved in muscle microtrauma repair, the healing of this tissue could be affected by sleep disturbances [ 86 ].

2.4. Genetic Factors

Genetic predisposition is likely to be an important factor as suggested by several familial studies [ 87 , 88 ] and transmission is thought to be polygenic [ 89 ]. Among the various genes investigated, the most important are associated with neurotransmitters. The serotonin transporter gene is characterized by a single nucleotide polymorphism; the “S” (short) allele is more frequent in patients affected by fibromyalgia and by psychological distress [ 90 , 91 ]. Other genes presumed to be involved are the catechol-O-methyltransferase gene [ 92 , 93 ], the dopamine D4 receptor gene [ 94 ], and the HLA-region [ 95 ].

2.5. Immune System

Fibromyalgia is common in patients affected by autoimmune disease [ 96 – 98 ]. Different studies in the literature deal with autoantibodies in fibromyalgia [ 99 – 102 ] with equivocal results. In particular several authors have investigated the association between this disease and antipolymer antibodies (APAs) [ 103 , 104 ]: the results are controversial and APAs cannot be used as a marker for diagnosis [ 105 ].

2.6. Psychiatric Aspects

Psychiatric problems seem to contribute considerably to the development of fibromyalgia. The prevalence of psychiatric conditions among patients affected by fibromyalgia is higher than among subjects complaining of other rheumatic diseases [ 3 ]. The most common disorders associated are anxiety, somatization, dysthymia, panic disorders, posttraumatic stress, and overall depression [ 106 – 110 ]. Depression is more frequently associated with fibromyalgia than with other musculoskeletal diseases [ 111 ] and the dysfunction of the 5-HT system might play a role [ 112 ]. Depression worsens fibromyalgic symptoms and vice versa, and antidepressants represent a cornerstone of fibromyalgia therapy [ 113 – 115 ].

2.7. Peripheral Tissues

Peripheral tissues such as skin, muscles, and microvessels are coming under closer investigation. Vascular dysregulation in muscles [ 116 ], inadequate response to oxidative stress [ 117 ] exacerbated by the nocturnal fall in saturation [ 118 ], increased IL-1 in cutaneous tissues, increased substance P in muscles, and DNA fragmentations of muscle fibers [ 119 ] are all suspected to possibly play a role in this condition.

2.8. Trigger Factors

Infections seem to be able to induce fibromyalgia even if a direct causal relationship is not documented [ 120 ]. In particular, viruses such as HCV, HIV, Coxsackie B, and Parvovirus [ 121 – 124 ] and bacteria like Borrelia [ 125 , 126 ] could be involved. An important role dealing with this association might be played by cytokines [ 127 – 129 ] and by glial cells, which, for example, express receptors for bacteria and viruses [ 130 , 131 ].

Physical trauma [ 132 ], vaccinations [ 120 ], and chemical substances [ 133 ] may also be trigger factors. However, it is worth recalling findings by Greenfield who noticed no precipitant factor in 72% of patients included in his research [ 134 ].

3. Diagnosis

Many cases of fibromyalgia do not precisely align with a standardized set of diagnostic criteria. However, it is not believed to be a diagnosis of exclusion, although some healthcare providers have labeled it as such. Because there is an absence of absolute, definitive diagnostic criteria with universal applicability, providers often settle upon this diagnosis following negative testing for other differentials [ 135 ].

Rather than assuming a diagnosis of fibromyalgia, carefully considering a multitude of potential diagnoses (shown in Table 1 ) will decrease the likelihood of a misdiagnosis. Five of the common differentials to consider in patients exhibiting symptoms of fibromyalgia are mental health disorders, hypothyroidism, rheumatoid arthritis, adrenal dysfunction, and multiple myeloma [ 136 ].

Diagnosis is difficult and frequently missed because symptoms are vague and generalized. Despite this, three main symptoms are referred by almost every patient: pain, fatigue, and sleep disturbance [ 137 , 138 ]. In particular the physician must investigate the features of the pain: it is typically diffuse, multifocal, deep, gnawing, or burning. It often waxes and wanes and is frequently migratory. If this is the case, fibromyalgia should be suspected since often this kind of pain is not the result of inflammation or damage in the area of the region(s) of interest. It is also important to evaluate additional symptoms, which may seem unrelated to fibromyalgia, such as weight fluctuations, morning stiffness, irritable bowel disease, cognitive disturbance, headaches, heat and cold intolerance, irritable bladder syndrome, restless legs, and Raynaud's phenomenon [ 2 ].

The musculoskeletal and neurological examinations are normal in fibromyalgia patients [ 139 ]. A detectable sign is the presence of the tender points, as explained by the American College of Rheumatology (ACR) [ 8 ].

They are specific places on the body that are painful when a standard amount of pressure (about 4 kg) is applied.

With respect to laboratory tests, they should be limited to a complete blood count, routine serum chemistries, thyroid-stimulating hormone (hypothyroidism may have symptoms similar to fibromyalgia or may accompany fibromyalgia) and erythrocyte sedimentation rate and/or C-reactive protein. Typically there are no laboratory abnormalities specifically associated with this condition. ANA (antinuclear antibody) test is quite often ordered and it may be positive, but the rate of a positive test in fibromyalgia patients is the same as normal controls [ 2 , 139 ].

As such, diagnosis is principally based on the two major diagnostic criteria defined by the ACR in 1990 [ 8 ]: (1) a history of widespread musculoskeletal pain present for at least three months, and (2) tenderness in at least 11 of 18 defined tender points shown in Figure 1 (both criteria must be satisfied). The pain must affect both sides of the body, must affect areas above and below the waist, and must be also axial. For a tender point to be considered positive it must be evaluated by digital palpation with about 4 kg of pressure (when the thumbnail bed blanches) and the subject must state that the palpation was “painful” (“irritating” is not sufficient).

A proliferation of studies followed publication of the 1990 criteria. According to PubMed ( http://www.ncbi.nlm.nih.gov/pubmed/ ), 361 English-language original articles with “fibromyalgia” as a keyword were published in the 20 years before the criteria existed, compared with 3844 in the 20-year period after the publication [ 140 ]. The 1990 ACR classification criteria have brought numerous benefits: studies have begun to unravel the etiology and impact of the disorder; treatment strategies have improved; patients have also benefited from increased recognition and diagnosis of the disorder.

Even though these criteria are useful for standardizing the diagnosis, they have been criticized: during these 20 years a number of practical and philosophical objections have been raised in relation to the 1990 ACR classification criteria. The most notable have been the criticisms about the use and interpretation of tender-point count [ 141 , 142 ], the lack of consideration of associated symptoms [ 143 – 146 ], and neglect of the possibility that fibromyalgia might represent the extreme end of a widespread musculoskeletal pain continuum [ 147 ].

To address these issues Wolfe and colleagues undertook a two-phase multicentre study to develop criteria for fibromyalgia that do not require a tender-point count and that provide a severity scale for associated fibromyalgia symptoms: the ACR 2010 criteria [ 10 ]. Thirty-two physicians, experienced in fibromyalgia and tender-points examination, interviewed and physically assessed 433 patients with a current or previous diagnosis of fibromyalgia (diagnosed using physicians' usual methods) and 396 matched controls (diagnosed with noninflammatory pain disorders). Two factors best discriminated between patients with fibromyalgia and those with other disorders: the widespread pain index (WPI), a count of number of painful body regions, and the Symptom Severity (SS) scale, a measure of cognitive symptoms, sleep, fatigue, and additional somatic symptoms.

In developing the 2010 ACR criteria, the investigators sought to simplify clinical diagnosis of fibromyalgia, but not to facilitate self-diagnosis; the criteria require a clinical assessment of the severity of comorbid symptoms [ 10 ].

The widespread distribution of pain and its chronology remain defining characteristics of fibromyalgia in the 2010 ACR criteria. Importantly, the new criteria also assess the presence and severity of associated symptoms via the SS scale; however, it has been suggested that this new part introduces ambiguity into the clinical diagnosis. For example, there is a notable subjective nature of counting somatic symptoms [ 148 ]. How many symptoms constitute “a few,” “a moderate amount,” or “a great deal?” Wolfe and colleagues [ 10 ], suggest that the diagnosing physician should make this judgment using their clinical experience to guide them.

This issue has begun to be addressed in the development and modification of the 2010 ACR criteria for use in clinical and epidemiological studies [ 149 ].

In their modified 2010 diagnostic criteria (intended for use in postal surveys), Wolfe et al. retain the 19-site WPI and the self-reported specific symptoms, but eliminate the physician estimation of SS score and replace it with three dichotomous “yes/no” answers regarding the presence of abdominal pain, depression, and headaches in the past 6 months [ 149 ].

All these criteria are pooled to give an 0–31 fibromyalgia symptoms (FS) score.

The authors report that an FS score of ≥13 correctly classified 93% of patients identified as having fibromyalgia on the basis of the 1990 criteria with a specificity of 96.6% and sensitivity of 91.8% [ 149 ].

An implicit aim of the 2010 criteria is to facilitate more rigorous study of fibromyalgia etiology [ 10 ]. In common with all complex disorders, the onset of fibromyalgia will be attributable to multiple factors that interact in intricate ways to determine outcome. Studies of etiology need to explore these interactions, although often fail to do so. This problem is neither new nor unique to fibromyalgia research. In epidemiology research, the strongest study design is arguably the prospective cohort study: putative risk factors are measured among a cohort of people without fibromyalgia, who are followed up over time to identify individuals who develop the disorder. The relationship between risk factor exposure and the onset of fibromyalgia can then be assessed, and associations inferred. However, incidence and prevalence of fibromyalgia are low in general population, and the number of disorder-free individuals who would need to be assessed is consequently high.

The 2010 ACR criteria will usefully address the problem, by removing the tender-point examination, and with the publication of modified self-completed criteria that can be included in large scale epidemiological investigations [ 148 ]; consequently future studies will be able to assess the large number of people necessary to identify sufficient numbers of incident cases of fibromyalgia.

Wolfe et al. [ 10 ] and others [ 148 ] have noted that the new criteria are “almost as good” as the previous classification, with the 2010 criteria correctly classifying 80% of subjects who would have been classified using the 1990 criteria. A comparison between 1990 and 2010 ACR classification criteria for fibromyalgia is shown in Table 2 .

4. Treatment

The goals of fibromyalgia treatment are to alleviate pain, increase restorative sleep, and improve physical function through a reduction in associated symptoms [ 150 ]. The identification and treatment of all pain sources that may be present in addition to fibromyalgia such as peripheral inflammatory or neuropathic pain generators (e.g., comorbid osteoarthritis or neuropathic pathologies) or visceral pain (e.g., comorbid irritable bowel syndrome) are central to the proper clinical management of fibromyalgia [ 151 ].

Because pain, depression, and other symptoms of fibromyalgia are linked to inherited and environmental causes, a multifaceted treatment approach is often required including both nonpharmacological pain management strategies and medication [ 152 ].

The American Pain Society (APS) and the Association of the Scientific Medical Societies in Germany (AWMF) gave the highest level of recommendation to (1) aerobic exercise, (2) cognitive-behavioral therapy (CBT), (3) amitriptyline, and (4) multicomponent therapy. The APS guideline and AWMF guideline were completed prior to the approval of pregabalin and duloxetine for the treatment of fibromyalgia by the United States Food and Drug Administration (FDA). The European League Against Rheumatism (EULAR) gave the highest level of recommendation of “A” to a set of pharmacological treatments (i.e., tramadol, amitriptyline, fluoxetine, duloxetine, milnacipran, moclobemide, pirlindol, tropisetron, pramipexole, and pregabalin), a recommendation strength of “B” to aerobic exercise, and a recommendation strength of only “D” to CBT. EULAR did not give any recommendations for cyclobenzaprine, multicomponent treatment, patient education, hypnotherapy, biofeedback, or other complementary and alternative medicine approaches (CAM), such as acupuncture or homeopathy, whereas EULAR gave a “D” recommendation for CBT, and the APS and AWMF decided on an “A” recommendation. Whereas EULAR and AWMF did not recommend strong opioids (expert opinion), APS recommendation strength was a “C”. APS and AWMF provided the same strength of recommendation (“B”) to tramadol, balneotherapy, hypnotherapy, biofeedback, massage therapy, pregabalin, fluoxetine, and duloxetine. Whereas APS recommended patient education as a single intervention (“B”), acupuncture (“C”), and trigger point injections (“C”), AWMF did not recommend patient education as a single intervention (“A”), acupuncture (“A”) (a minority report recommended acupuncture with a strength of “B”), and trigger point injections (“C”). All three guidelines recommend against the use of NSAIDs (as a single intervention) or corticosteroids [ 153 ].

4.1. Medications

Evaluating the comparative efficacy of interventions for fibromyalgia is difficult because no common definition of response in fibromyalgia exists. At present, the inclusion of assessment domains is inconsistent, and there is wide variation in the use of instruments indexing those domains. Historically, many symptoms have been thought to be associated with fibromyalgia. Because an assessment of all symptoms in each patient is not feasible; consensus was required to identify the key domains that needed to be assessed to determine clinically meaningful improvement. Much of the work in this area has been organized by the Outcome Measures in Rheumatology (OMERACT) Fibromyalgia working group [ 154 ].

It was observed that the responder definitions that best favored drug over placebo included improvement in pain and physical function as well as improvement in either sleep or fatigue (at least 30% improvement over placebo in the symptom domains) [ 155 ]. Along with pain, sleep disturbance and fatigue have been consistently ranked by patients and clinicians as being among the most common and troublesome symptoms of fibromyalgia [ 154 ]. The other responder definition that performed well in the analysis included additional symptom domains of depression, anxiety, and cognitive dysfunction to reflect the heterogeneity of the fibromyalgia population and the recognition that some treatments may affect these other domains of importance. A responder definition that includes improvement in specific key symptom domains in addition to pain evaluates the broader impact of fibromyalgia on patients and addresses the limitations of other composite responder definitions for fibromyalgia trials that focused only on the symptom of pain.

In terms of nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen have been shown to be no better than placebo [ 156 ], although there is some evidence that NSAIDs may have a synergistic effect when combined with centrally active agents like tricyclic antidepressants and anticonvulsants [ 157 ]. Furthermore, a survey of 1042 patients affected by fibromyalgia found that 66.1% deemed NSAIDs more effective than acetaminophen [ 158 ]. Given the acceptable adverse effect profile of simple analgesic drugs and, in selected populations, NSAIDS, it seems reasonable to include them in the management of fibromyalgia, despite the lack of conclusive evidence.

The prevalence of opioid use by fibromyalgia patients is unknown, although Goldenberg et al. [ 159 ] reported the use of any analgesic drug other than NSAIDs in 52% in a cross-sectional study. Opioids are not, however, recommended by any current guidelines for the management of fibromyalgia [ 153 , 160 , 161 ].

Tramadol has been found to be beneficial in fibromyalgia patients [ 160 , 162 ]. It is an atypical pain reliever that has a different action on the CNS (the reuptake of serotonin and norepinephrine) from that of other narcotics. Alone or in combination with acetaminophen, it is commonly prescribed at a dose of 200–300 mg/day to relieve fibromyalgia-related pain [ 163 , 164 ]. Significant differences ( P ≤ 0.05) were observed between the tramadol/acetaminophen and placebo groups for improvements in sleep adequacy (9.3 versus +6.7) and sleep duration (0.4 hours versus 0.2 hours), but not for the other measures of sleep. Its potential for drug abuse is fortunately negligible, but there is a theoretical risk of seizures and serotoninergic syndrome when it is combined with selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenalin reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and triptans, although only a few cases have been described [ 165 ].

Both antidepressants and neuromodulating antiepileptics substantially reduce fibromyalgia symptoms. Among antidepressants, serotonin and norepinephrine reuptake inhibitors have been found to provide the best efficacy and tolerability for fibromyalgia [ 166 , 167 ]. Both duloxetine and milnacipran belong to the serotonin-norepinephrine reuptake inhibitor class of antidepressants and reduce pain by increasing activity of noradrenergic antinociceptive pathways. Both have shown efficacy in randomized, blinded, controlled studies [ 168 ].

Duloxetine should be considered in patients with significant depression symptoms. The maximum dosage for the treatment of fibromyalgia is 60 mg daily, but, due to nausea, 30 mg daily is often started initially [ 169 ].

Milnacipran has increased selectivity for norepinephrine than for serotonin. It may be helpful in patients with significant fatigue or cognitive dysfunction. The initial dose is 12.5 mg daily which is increased over several weeks to a maximum daily dose of 100 mg, given in two separate doses. In the milnacipran trials, the composite responder definition for the treatment of fibromyalgia consisted of 3 components: (1) 30% improvement from baseline in pain, (2) a rating of “very much improved” (score 1) or “much improved” (score 2) on the Patient Global Impression of Change (PGIC) scale, and (3) six-point improvement from baseline in physical function (SF-36 Physical Component Summary (PCS) score) [ 170 ].

Pregabalin is an α 2- δ ligand that has analgesic, anxiolytic-like, and anticonvulsant activity in animal models, and biochemical studies have found that the primary binding site for pregabalin and the related gabapentin are α 2- δ (type 1). α 2- δ is an auxiliary protein associated with voltage-gated calcium channels, and the potent binding of pregabalin at the α 2- δ site reduces calcium influx at nerve terminals resulting in reduction of the release of a number of neurochemicals, including glutamate, noradrenaline, and substance P, which may explain the analgesic, anticonvulsant, and anxiolytic-like activity of pregabalin in animal models. It has also been suggested that reducing neurotransmitter release from neurons in the spinal cord and brain may be clinically beneficial for fibromyalgia patients. Pregabalin has significant side effects, including weight gain, dizziness, somnolence, and peripheral edema. When taken with angiotensin-converting-enzyme (ACE) inhibitors it may cause angioedema. The recommended dose is 300–450 mg daily, but many patients respond to lower doses. A single low dose (50–75 mg) at bedtime is frequently employed initially.

Crofford et al. [ 171 ] demonstrated in a 6-month double-blind, placebo-controlled trial that patients treated with pregabalin had statistically significant delayed time to loss of therapeutic response (LTR) versus those receiving placebo. The trial included a 6-week open label (OL) pregabalin-treatment period followed by 26-weeks double-blind treatment with placebo or pregabalin. Adults with fibromyalgia and ≥40 mm score on 100 mm pain visual analog scale (VAS) were considered. During OL weeks 1–3 patients received escalating dosage of pregabalin to determine their optimal dosage. During OL weeks 4–6, patients received their pregabalin optimal fixed dosages (300, 450, and 600 mg/d). To be randomized, they must have had ≥50% decrease in pain VAS and a self-rating of “much” or “very much” improved on Patient Global Impression of Change (PGIC) at the end of OL. Crofford et al. defined the time to LTR as <30% reduction in pain or worsening of fibromyalgia. At the end of double-blind phase, 61% placebo patients met LTR criteria versus 32% pregabalin patients. Similarly, half of placebo patients showed worsening in the Overall Sleep Problem Index of the MOS-Sleep Scale by day 14 compared with by day 42 for pregabalin patients. Regarding adverse events (AE), more pregabalin than placebo patients discontinued the study during the double-blind phase. The most common AEs in the pregabalin treatment group were insomnia (6%), sinusitis, nausea, arthralgia, anxiety, and influenza (each 5%) and weight increased (4%).

Currently duloxetine (DLX), milnacipran (MLN), and pregabalin (PGB) are the only drugs that have been approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia. A comparison of the efficacy and harms of these three drugs shows some differences: the NNTs for a 30% pain reduction (all dosages pooled together) were as follows: DLX 7.2 (95% CI 5.2, 11.4), MLN 19 (95% CI 7.4, 20.5), and PGB 8.6 (95% CI 6.4, 12.9). The NNTs for dropout due to lack of efficacy were as follows: DLX −16.5 (95% CI −43.7, −10.1), MLN −31.1 (95% CI −23.7, −16.7), and PGB −16.0 (95% CI −25.8, −11.6). The NNHs for a dropout due to side effects were as follows: DLX 14.9 (95% CI 9.1, 41.4), MLN 7.6 (95% CI 6.2, 9.9), and PGB 7.6 (95% CI 6.3, 9.4) [ 172 ].

The mechanisms of action of pregabalin, duloxetine, and milnacipran are thought to be related to proposed pathophysiologies of fibromyalgia. However, these therapeutic agents are still not effective for all fibromyalgia patients. A recent study by Katz et al. suggests that the diagnostic criteria for fibromyalgia may be partially responsible, as there is currently no gold standard for fibromyalgia diagnosis [ 173 ].

The family of tricyclic antidepressants (TCAs) are effective over the short term in the management of fibromyalgia, specifically the TCA amitriptyline and the biologically similar cyclobenzaprine. By inhibiting the reuptake of both serotonin and norepinephrine, tricyclic compounds enhance norepinephrine and serotonin neurotransmission in the descending inhibitory pain pathways, resulting in a reduction in pain. Four meta-analyses examined the efficacy of tricyclics in fibromyalgia management [ 113 , 174 – 176 ]. These tricyclic studies primarily assessed amitriptyline or cyclobenzaprine in patients with fibromyalgia and tended to be small, short-term, single-center trials. The meta-analysis by Arnold and associates [ 113 ] examined 9 placebo-controlled trials of amitriptyline, dothiepin, cyclobenzaprine, clomipramine, and maprotiline. The largest improvement was associated with measures of sleep quality, with treatment effect sizes ranging from 0.10 to 1.19; the most modest improvements were found in measures of stiffness (effect size range, 0.30 to 0.77) and tenderness (effect size range, −0.34 to 0.73). The overall degree of efficacy was modest in most studies, with a median treatment effect size of 0.44 and weighted mean treatment effect size of 0.43. The NNT of amitriptyline is 3,54 (95% CI 2,74, 5,01). Although TCAs are moderately effective, the use of these compounds is limited by a relatively narrow therapeutic index and poor tolerability due to affinity at multiple receptor systems [ 4 ]. Unlike newer dual reuptake inhibitors of serotonin and norepinephrine, TCAs possess significant affinity for histaminergic, cholinergic, and adrenergic receptor systems [ 177 , 178 ], which contribute to their strong side effects such as sedation, dry mouth, and constipation at higher doses. Tolerability of tricyclic compounds can be improved by prescribing very low doses before bedtime and by very slowly escalating the dose. However, the dose should be kept as low as possible, and they should be used with caution in patients with cardiovascular, renal, or hepatic disease [ 178 , 179 ].

4.2. Nonpharmacologic Treatments

The nonpharmacologic treatments most consistently linked to fibromyalgia improvements are aerobic exercise and strength training. Effective exercise focuses on stretching, with gradual progression to strengthening and reconditioning exercise [ 180 , 181 ].

Two randomized controlled single blind trials indicate that Tai chi holds potential as a useful modality in the multidimensional treatment of fibromyalgia [ 182 ]. Tai chi compared to wellness education and stretching improves symptoms, physical function, quality of sleep, self-efficacy, and functional mobility for people with fibromyalgia [ 183 ]. Authors observed significant improvements in static balance, dynamic balance, and timed get-up-and-go. These consistent findings of improvement in objective measures of functional mobility carry important clinical implications, suggesting that Tai chi may help decrease risk for falls and minimize difficulties in performing essential daily physical activity tasks [ 184 ].

Both aquatic exercises and balneotherapy are regarded as nonpharmacological interventions for fibromyalgia. Aquatic exercises (water-based exercises, aquatic therapy, or hydrotherapy) are exercises that are performed in the water. The Chartered Society of Physiotherapists defined aquatic exercises as a therapy program using the properties of water, designed by a suitably qualified physiotherapist, to improve function, ideally in a purpose-built and suitably heated pool [ 185 ]. It remains unclear whether aquatic exercises are more effective than other active interventions such as land-based exercises. Furthermore there is a lack of evidence for specific doses and timing of exercise programs because most RCTs and SRs did not provide enough information to address these issues. Often the intervention was rather poorly described in the original papers [ 186 ]. The term balneotherapy (seated immersion or spatherapy) is classically used in (eastern) European countries for bathing in water without exercise. Often natural mineral or thermal waters are used for bathing, drinking, and inhalation. The mechanisms by which immersion in mineral or thermal water or the application of mud alleviates chronic pain and the symptoms of fibromyalgia are not completely known [ 187 – 189 ]. A distinction can be made between the non-specific (hydrotherapeutic in a broad sense) mechanisms of simple bathing in hot tap water and the specific (hydromineral and chemotherapeutic) mechanisms, which depend on the chemical and physical properties of the water used. Hot stimuli produce analgesia on nerve endings by increasing the pain threshold. It causes relief of muscle spasms through the γ fibers of muscle spindles and activates the descending pain inhibitory system. According to the “gate theory,” pain relief may be due to the temperature and hydrostatic pressure of water on the skin [ 190 ].

Spa therapy provokes a series of endocrine reactions, particularly in the release of adrenocorticotropic hormone (ACTH), cortisol, prolactin, and growth hormone (GH), although it does not alter the circadian rhythm of these hormones. A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, marked by mild hypocortisolemia and glucocorticoid feedback resistance, has been demonstrated in fibromyalgia patients. These findings can explain the beneficial clinical effects of spa therapy in fibromyalgia. The systematic reviews on patients with fibromyalgia concluded, based on 4 RCTs, that there is moderate evidence in favor of the use of balneotherapy [ 191 ]. Unfortunately, no meta-analysis was performed, no data were presented, and most studies showed major methodological flaws.

Psychological pain management skills have also been reported to be efficacious in patients with fibromyalgia. Cognitive-behavioral therapy (CBT) outperformed other psychological treatments in short-term fibromyalgia pain intensity reduction, reaching a medium effect size. Additionally, CBT and relaxation were significantly more effective than other psychological treatments in reducing sleep problems associated with fibromyalgia. The results indicate that all psychological treatments were equally effective in decreasing depression. For pain intensity and depression, the results also indicate that psychological treatments were more effective than control conditions, with small to medium effect sizes [ 192 – 194 ].

Although not included in the recent evidence-based guidelines, EULAR recommendations additionally support inclusion of warm-water therapy, based on consistently beneficial data reported in numerous studies. Long-term studies found that warm-water exercise for 8 months was cost effective, with improvements of 8% for pain and 20% for physical function in treated patients compared with controls [ 171 , 195 – 197 ].

Over the last decade, it has been repeatedly shown that noninvasive repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) induces analgesic effects both in experimental pain [ 198 – 202 ] and in various chronic pain conditions [ 203 , 204 ], probably by activating pain modulation systems. Recently it was demonstrated that 10 daily sessions of unilateral M1 stimulation decrease chronic widespread pain and improve health-related quality of life of patients with fibromyalgia [ 204 ]. The analgesic effects of rTMS of the primary motor cortex can be maintained for up to 6 months in patients with chronic pain; the decrease in pain intensity was associated with a long-term improvement in other clinical features including fatigue, catastrophizing, and several items related to quality of life. Only a few studies in patients with neuropathic pain [ 205 , 206 ] or fibromyalgia [ 204 ] have evaluated the effects of repeated daily stimulations over a period of 5–10 days and reported analgesic effects lasting for 2-3 weeks after the last stimulation. The mechanisms underlying motor cortex rTMS-induced analgesia remain unclear, but may be similar to that of chronic motor cortex stimulation through surgically implanted epidural electrodes, which is used to treat patients with refractory neuropathic pain [ 207 – 209 ]. Mhalla et al. [ 210 ] showed that active rTMS had a significant effect on average pain intensity over the course of the treatment, as shown by comparison with a sham stimulation treatment ( F = 0.02; P = 0.007). Pairwise comparisons showed that this effect was significant from day 5 onwards and was maintained until week 25, although the magnitude of the effect tended to decrease during the period of monthly stimulation, from week 16 to 25. Active stimulation significantly improved ( F = 8.62, P = 0.005); the Brief Pain Inventory (BPI) score reported a marked decrease in the interference of pain with “general activity,” “walking,” “relations with other people,” “enjoyment of life,” and “sleep.” In contrast, the active treatment did not significantly decrease the interference of pain on “work” and “mood.” In addition, active rTMS significantly decreased both the total score ( F = 5.03; P = 0.03) of the Fibromyalgia Impact Questionnaire (FIQ) and the 3 subscores relating to fatigue ( F = 4.8; P = 0.003), stiffness ( F = 11.7; P = 0.001), and morning tiredness ( F = 7.47; P = 0.009).

Mean depression and anxiety scores (Hospital Anxiety and Depression Scale (HAD) and the 13-item short form of the Beck Depression Inventory (BDI)) were not significantly affected by active or sham stimulation. Catastrophizing score (PCS) was significantly lower ( F = 5.99, P = 0.02) after active rTMS than after sham treatment. APR, AWMF and EULAR recommendations are summarized in Table 3 .

5. Conclusions

Fibromyalgia is a complex syndrome that is often difficult to diagnose, particularly for physicians who do not usually deal with this disease. Pathogenesis is still not fully clear, but modern functional neuroimaging techniques are giving us important data about the CNS involvement. Fibromyalgia is not to be considered a diagnosis of exclusion: the recently published ACR 2010 criteria try to help us not to be confused by all the differential diagnoses for fibromyalgia. A multidisciplinary approach is optimal and the physician must take into consideration both drugs (in particular antidepressants and neuromodulating antiepileptics) and nonpharmacological treatment, such as aerobic exercise and strength training, aquatic exercises and balneotherapy, cognitive-behavioral therapy, and also the emerging brain stimulation techniques.

1 Bigatti SM Hernandez AM Cronan TA Rand KL Sleep disturbances in fibromyalgia syndrome: relationship to pain and depression Arthritis Care and Research 2008 59 7 961 967 2-s2.0-47249096704 18576297 10.1002/art.23828 PMC3691959

2 Clauw DJ Fibromyalgia: an overview American Journal of Medicine 2009 122 12, supplement S3 S13 2-s2.0-70749145982 10.1016/j.amjmed.2009.09.006 19962494

3 Giesecke T Williams DA Harris RE Subgrouping of fibromyalgia patients on the basis of pressure-pain thresholds and psychological factors Arthritis and Rheumatism 2003 48 10 2916 2922 2-s2.0-0142040426 14558098 10.1002/art.11272

4 Mease P Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment Journal of Rheumatology 2005 75 6 p. 21 2-s2.0-26444619824 16078356

5 Gowers WR A lecture on lumbago: its lessons and analogues: delivered at the national hospital for the paralysed and epileptic British Medical Journal 1904 1 117 121 20761312 10.1136/bmj.1.2246.117 PMC2352601

6 Graham W The fibrosits syndrome Bulletin on the Rheumatic Diseases 1953 3 8 33 34 2-s2.0-41949107478 13032696

7 Smythe HA Moldofsky H Two contributions to understanding of the “fibrositis” syndrome Bulletin on the Rheumatic Diseases 1977 28 1 928 931 2-s2.0-0017588905 199304

8 Wolfe F Smythe HA Yunus MB The American College of Rheumatology 1990. Criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee Arthritis and Rheumatism 1990 33 2 160 172 2-s2.0-0025266660 2306288 10.1002/art.1780330203

9 Wolfe F New American College of Rheumatology criteria for fibromyalgia: a twenty-year journey Arthritis Care and Research 2010 62 5 583 584 2-s2.0-77951739749 20461781 10.1002/acr.20156

10 Wolfe F Clauw DJ Fitzcharles MA The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity Arthritis Care and Research 2010 62 5 600 610 2-s2.0-77951735184 20461783 10.1002/acr.20140

11 Wolfe F Ross K Anderson J Russell IJ Hebert L The prevalence and characteristics of fibromyalgia in the general population Arthritis and Rheumatism 1995 38 1 19 28 2-s2.0-0028890678 7818567 10.1002/art.1780380104

12 Lindell L Bergman S Petersson IF Jacobsson LTH Herrstrom P Prevalence of fibromyalgia and chronic widespread pain Scandinavian Journal of Primary Health Care 2000 18 3 149 153 2-s2.0-0033753447 11097099 10.1080/028134300453340

13 Yunus MB Towards a model of pathophysiology of fibromyalgia: aberrant central pain mechanisms with peripheral modulation Journal of Rheumatology 1992 19 6 846 850 2-s2.0-0026747899 1404119

14 Staud R Smitherman ML Peripheral and central sensitization in fibromyalgia: pathogenetic role Current Pain and Headache Reports 2002 6 4 259 266 2-s2.0-0036690249 12095460 10.1007/s11916-002-0046-1

15 Li J Simone DA Larson AA Windup leads to characteristics of central sensitization Pain 1999 79 1 75 82 2-s2.0-0032945956 9928779 10.1016/S0304-3959(98)00154-7

16 Mendell LM Wall PD Responses of single dorsal cord cells to peripheral cutaneous unmyelinated fibres Nature 1965 206 4979 97 99 2-s2.0-0001895691 14334366 10.1038/206097a0

17 Staud R Vierck CJ Cannon RL Mauderli AP Price DD Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome Pain 2001 91 1-2 165 175 2-s2.0-0035057629 11240089 10.1016/s0304-3959(00)00432-2

18 Staud R Domingo M Evidence for abnormal pain processing in fibromyalgia syndrome Pain Medicine 2001 2 3 208 215 2-s2.0-0035215018 15102253 10.1046/j.1526-4637.2001.01030.x

19 Davies SN Lodge D Evidence for involvement of N-methylaspartate receptors in “wind-up” of class 2 neurones in the dorsal horn of the rat Brain Research 1987 424 2 402 406 2-s2.0-0023605956 2823998 10.1016/0006-8993(87)91487-9

20 Dickenson AH Sullivan AF Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation Neuropharmacology 1987 26 8 1235 1238 2-s2.0-0023189510 2821443 10.1016/0028-3908(87)90275-9

21 Dickenson AH A cure for wind up: NMDA receptor antagonists as potential analgesics Trends in Pharmacological Sciences 1990 11 8 307 309 2-s2.0-0025375531 2168102 10.1016/0165-6147(90)90228-z

22 Staud R Cannon RC Mauderli AP Robinson ME Price DD Vierck CJ Temporal summation of pain from mechanical stimulation of muscle tissue in normal controls and subjects with fibromyalgia syndrome Pain 2003 102 1-2 87 95 2-s2.0-0037333196 12620600 10.1016/s0304-3959(02)00344-5

23 Kosek E Hansson P Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects Pain 1997 70 1 41 51 2-s2.0-0030889132 9106808 10.1016/s0304-3959(96)03295-2

24 Watkins LR Milligan ED Maier SF Spinal cord glia: new players in pain Pain 2001 93 3 201 205 2-s2.0-0034882399 11514078 10.1016/S0304-3959(01)00359-1

25 Watkins LR Milligan ED Maier SF Glial activation: a driving force for pathological pain Trends in Neurosciences 2001 24 8 450 455 2-s2.0-0035426434 11476884 10.1016/s0166-2236(00)01854-3

26 Watkins LR Maier SF Immune regulation of central nervous system functions: from sickness responses to pathological pain Journal of Internal Medicine 2005 257 2 139 155 2-s2.0-13244281729 15656873 10.1111/j.1365-2796.2004.01443.x

27 Dubner R Hargreaves KM The neurobiology of pain and its modulation Clinical Journal of Pain 1989 5 supplement 2 S1 S4 2-s2.0-0024804930 10.1097/00002508-198906002-00002 2520436

28 Wolfe F Russell IJ Vipraio G Ross K Anderson J Serotonin levels, pain threshold, and fibromyalgia symptoms in the general population Journal of Rheumatology 1997 24 3 555 559 2-s2.0-0030959929 9058665

29 Yunus MB Dailey JW Aldag JC Masi AT Jobe PC Plasma tryptophan and other amino acids in primary fibromyalgia: a controlled study Journal of Rheumatology 1992 19 1 90 94 2-s2.0-0026503839 1556707

30 Hrycaj P Stratz T Muller W Russell IJ Vipraio GA Lopez Y Platelet 3H-imipramine uptake receptor density and serum serotonin levels in patients with fibromyalgia/fibrositis syndrome Journal of Rheumatology 1993 20 11 1986 1988 2-s2.0-0027786760 8308794

31 Houvenagel E Forzy G Leloire O Spinal fluid monoamines in primary fibromyalgia Revue du Rhumatisme et des Maladies Osteo-Articulaires 1990 57 1 21 23 2-s2.0-0025152726 1690912

32 Russell IJ Vaeroy H Javors M Nyberg F Cerebrospinal fluid biogenic amine metabolites in fibromyalgia/fibrositis syndrome and rheumatoid arthritis Arthritis and Rheumatism 1992 35 5 550 556 2-s2.0-0026732553 1374252 10.1002/art.1780350509

33 Ressler KJ Nemeroff CB Role of serotonergic and noradrenergic systems in the pathophysiology of depression and anxiety disorders Depression and Anxiety 2000 121 supplement 2 19 10.1002/1520-6394(2000)12:1+<2::AID-DA2>3.0.CO;2-4 11098410

34 Juhl JH Fibromyalgia and the serotonin pathway Alternative Medicine Review 1998 3 5 367 375 2-s2.0-0032185602 9802912

35 Wood PB Stress and dopamine: implications for the pathophysiology of chronic widespread pain Medical Hypotheses 2004 62 3 420 424 2-s2.0-1642380993 14975515 10.1016/j.mehy.2003.10.013

36 Malt EA Olafsson S Aakvaag A Lund A Ursin H Altered dopamine D 2 receptor function in fibromyalgia patients: a neuroendocrine study with buspirone in women with fibromyalgia compared to female population based controls Journal of Affective Disorders 2003 75 1 77 82 2-s2.0-0038012656 12781354 10.1016/s0165-0327(02)00025-3

37 Russell IJ Orr MD Littman B Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome Arthritis and Rheumatism 1994 37 11 1593 1601 2-s2.0-0028104819 7526868 10.1002/art.1780371106

38 Pillemer SR Bradley LA Crofford LJ Moldofsky H Chrousos GP The neuroscience and endocrinology of fibromyalgia Arthritis and Rheumatism 1997 40 11 1928 1939 2-s2.0-0030829256 9365080 10.1002/art.1780401103

39 Vaeroy H Helle R Forre O Kass E Terenius L Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromalgia: new features for diagnosis Pain 1988 32 1 21 26 2-s2.0-0023919037 2448729 10.1016/0304-3959(88)90019-X

40 Harris RE Clauw DJ Scott DJ McLean SA Gracely RH Zubieta JK Decreased central μ -opioid receptor availability in fibromyalgia Journal of Neuroscience 2007 27 37 10000 10006 2-s2.0-34548620789 17855614 10.1523/JNEUROSCI.2849-07.2007 PMC6672650

41 Baraniuk JN Whalen G Cunningham J Clauw DJ Cerebrospinal fluid levels of opioid peptides in fibromyalgia and chronic low back pain BMC Musculoskeletal Disorders 2004 5, article 48 2-s2.0-12344284096 10.1186/1471-2474-5-48 PMC539267 15588296

42 Stisi S Cazzola M Buskila D Etiopathogenetic mechanisms of fibromyalgia syndrome Reumatismo 2008 60 supplement 1 25 35 2-s2.0-69249235454 18852906

43 Mountz JM Bradley LA Modell JG Fibromyalgia in women: abnormalities of regional cerebral blood flow in the thalamus and the caudate nucleus are associated with low pain threshold levels Arthritis and Rheumatism 1995 38 7 926 938 2-s2.0-0029099804 7612042 10.1002/art.1780380708

44 Adigüzel O Kaptanoglu E Turgut B Nacitarhan V The possible effect of clinical recovery on regional cerebral blood flow deficits in fibromyalgia: a prospective study with semiquantitative SPECT Southern Medical Journal 2004 97 7 651 655 2-s2.0-3242672207 15301122 10.1097/00007611-200407000-00008

45 Kwiatek R Barnden L Tedman R Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami Arthritis & Rheumatism 2000 43 2823 2833 11145042 10.1002/1529-0131(200012)43:12<2823::AID-ANR24>3.0.CO;2-E

46 Bradley LA Sotolongo A Alberts KR Abnormal regional cerebral blood flow in the caudate nucleus among fibromyalgia patients and non-patients is associated with insidious symptom onset Journal of Musculoskeletal Pain 1999 7 1-2 285 292 2-s2.0-0032885166

47 Wik G Fischer H Bragée B Kristianson M Fredrikson M Retrosplenial cortical activation in the fibromyalgia syndrome NeuroReport 2003 14 4 619 621 2-s2.0-0037623357 12657898 10.1097/00001756-200303240-00019

48 Yunus MB Young CS Saeed SA Mountz JM Aldag JC Positron emission tomography in patients with fibromyalgia syndrome and healthy controls Arthritis Care and Research 2004 51 4 513 518 2-s2.0-4043145717 15334421 10.1002/art.20544

49 Walitt B Roebuck-Spencer T Esposito G The effects of multidisciplinary therapy on positron emission tomography of the brain in fibromyalgia: a pilot study Rheumatology International 2007 27 11 1019 1024 2-s2.0-34547839635 17634904 10.1007/s00296-007-0405-7

50 Gracely RH Petzke F Wolf JM Clauw DJ Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia Arthritis and Rheumatism 2002 46 5 1333 1343 2-s2.0-0036093275 12115241 10.1002/art.10225

51 Cook DB Lange G Ciccone DS Liu WC Steffener J Natelson BH Functional imaging of pain in patients with primary fibromyalgia Journal of Rheumatology 2004 31 2 364 378 2-s2.0-0742322755 14760810

52 Glass JM Williams DA Fernandez-Sanchez ML Executive function in chronic pain patients and healthy controls: different cortical activation during response inhibition in fibromyalgia Journal of Pain 2011 12 1219 1229 21945593 10.1016/j.jpain.2011.06.007 PMC3715316

53 Kim SH Chang Y Kim JH Insular cortex is a trait marker for pain processing in fibromyalgia syndrome—blood oxygenation level-dependent functional magnetic resonance imaging study in Korea Clinical and Experimental Rheumatology 2011 29 6, supplement 69 S19 S27 21813055

54 Foerster BR Petrou M Harris RE Cerebral blood flow alterations in pain-processing regions of patients with fibromyalgia using perfusion MR imaging American Journal of Neuroradiology 2011 32 1873 1878 21868622 10.3174/ajnr.A2614 PMC4337836

55 Skevington SM A standardized scale to measure beliefs about controlling pain (B.P.C.Q.): a preliminary study Psychology and Health 1990 4 221 232

56 Jensen KB Kosek E Petzke F Evidence of dysfunctional pain inhibition in Fibromyalgia reflected in rACC during provoked pain Pain 2009 144 1-2 95 100 2-s2.0-67349279598 19410366 10.1016/j.pain.2009.03.018

57 Jensen KB Loitoile R Kosek E Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network Molecular Pain 2012 8, article 32 10.1186/1744-8069-8-32 PMC3404927 22537768

58 Burgmer M Gaubitz M Konrad C Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia Psychosomatic Medicine 2009 71 5 566 573 2-s2.0-67650388607 19414621 10.1097/PSY.0b013e3181a32da0

59 Valet M Gündel H Sprenger T Patients with pain disorder show gray-matter loss in pain-processing structures: a voxel-based morphometric study Psychosomatic Medicine 2009 71 1 49 56 2-s2.0-65549122637 19073757 10.1097/PSY.0b013e31818d1e02

60 Lutz J Jäger L De Quervain D White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-tensor and volumetric imaging study Arthritis and Rheumatism 2008 58 12 3960 3969 2-s2.0-57349170177 19035484 10.1002/art.24070

61 Schmidt-Wilcke T Luerding R Weigand T Striatal grey matter increase in patients suffering from fibromyalgia—a voxel-based morphometry study Pain 2007 132 supplement 1 S109 S116 2-s2.0-35648957245 17587497 10.1016/j.pain.2007.05.010

62 Sundgren PC Petrou M Harris RE Diffusion-weighted and diffusion tensor imaging in fibromyalgia patients: a prospective study of whole brain diffusivity, apparent diffusion coefficient, and fraction anisotropy in different regions of the brain and correlation with symptom severity Academic Radiology 2007 14 7 839 846 2-s2.0-34250197576 17574134 10.1016/j.acra.2007.03.015

63 Harris RE Sundgren PC Pang Y Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia Arthritis and Rheumatism 2008 58 3 903 907 2-s2.0-40549091937 18311814 10.1002/art.23223

64 Harris RE Sundgren PC Craig AD Elevated insular glutamate in fibromyalgia is associated with experimental pain Arthritis and Rheumatism 2009 60 10 3146 3152 2-s2.0-70349776233 19790053 10.1002/art.24849 PMC2827610

65 Fayed N Garcia-Campayo J Magallón R Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate Arthritis Research and Therapy 2010 12 4, article R134 2-s2.0-77954265387 10.1186/ar3072 PMC2945024 20609227

66 Owen DG Bureau Y Thomas AW Prato FS Lawrence KSS Quantification of pain-induced changes in cerebral blood flow by perfusion MRI Pain 2008 136 1-2 85 96 2-s2.0-41749118739 17716820 10.1016/j.pain.2007.06.021

67 Nebel MB Gracely RH Neuroimaging of Fibromyalgia Rheumatic Disease Clinics of North America 2009 35 2 313 327 2-s2.0-67651216051 19647145 10.1016/j.rdc.2009.06.004

68 Crofford LJ The hypothalamic-pituitary-adrenal axis in the pathogenesis of rheumatic diseases Endocrinology and Metabolism Clinics of North America 2002 31 1 1 13 2-s2.0-0036014491 12055982 10.1016/s0889-8529(01)00004-4

69 Ferraccioli G Cavalieri F Salaffi F Neuroendocrinologic findings in primary fibromyalgia (soft tissue chronic pain syndrome) and in other chronic rheumatic conditions (rheumatoid arthritis, low back pain) Journal of Rheumatology 1990 17 7 869 873 2-s2.0-0025302257 2145431

70 McCain GA Tilbe KS Diurnal hormone variation in fibromyalgia syndrome: a comparison with rheumatoid arthritis Journal of Rheumatology 1989 16 19 154 157 2-s2.0-0024790235 2607509

71 Neeck G Neuroendocrine and hormonal perturbations and relations to the serotonergic system in fibromyalgia patients Scandinavian Journal of Rheumatology, Supplement 2000 29 113 8 12 2-s2.0-0034536613 11028824

72 Geenen R Jacobs JWG Bijlsma JWJ Evaluation and management of endocrine dysfunction in fibromyalgia Rheumatic Disease Clinics of North America 2002 28 2 389 404 2-s2.0-0035990384 12122926 10.1016/s0889-857x(01)00009-6

73 Griep EN Boersma JW de Kloet ER Altered reactivity of the hypothalamic-pituitary-adrenal axis in the primary fibromyalgia syndrome Journal of Rheumatology 1993 20 3 469 474 2-s2.0-0027416185 8386766

74 Jones KD Deodhar P Lorentzen A Bennett RM Deodhar AA Growth hormone perturbations in Fibromyalgia: a review Seminars in Arthritis and Rheumatism 2007 36 6 357 379 2-s2.0-34248651389 17224178 10.1016/j.semarthrit.2006.09.006

75 Garrison RL Breeding PC A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone Medical Hypotheses 2003 61 2 182 189 2-s2.0-0041621564 12888300 10.1016/s0306-9877(02)00294-3

76 Korszun A Young EA Engleberg NC Follicular phase hypothalamic-pituitary-gonadal axis function in women with fibromyalgia and chronic fatigue syndrome Journal of Rheumatology 2000 27 6 1526 1530 2-s2.0-0034084133 10852283

77 Samborski W Sobieska M Pieta P Drews K Brzosko M Normal profile of sex hormones in women with primary fibromyalgia Annales Academiae Medicae Stetinensis 2005 51 2 23 26 2-s2.0-33646844278 16519092

78 El Maghraoui A Tellal S Achemlal L Bone turnover and hormonal perturbations in patients with fibromyalgia Clinical and Experimental Rheumatology 2006 24 4 428 431 2-s2.0-33748535735 16956434

79 Cohen H Neumann L Kotler M Buskila D Autonomic nervous system derangement in fibromyalgia syndrome and related disorders Israel Medical Association Journal 2001 3 10 755 760 2-s2.0-0035691735 11692551

80 Kooh M Martínez-Lavín M Meza S Simultaneous heart rate variability and polysomnographic analyses in fibromyalgia Clinical and Experimental Rheumatology 2003 21 4 529 530 2-s2.0-0043201071 12942716

81 Furlan R Colombo S Perego F Abnormalities of cardiovascular neural control and reduced orthostatic tolerance in patients with primary fibromyalgia Journal of Rheumatology 2005 32 9 1787 1793 2-s2.0-24944455817 16142879

82 Anderberg UM Liu Z Berglund L Nyberg F Elevated plasma levels of neuropeptide Y in female fibromyalgia patients European Journal of Pain 1999 3 1 19 30 2-s2.0-0032895251 10700334 10.1053/eujp.1998.0097

83 Roizenblatt S Moldofsky H Benedito-Silva AA Tufik S Alpha sleep characteristics in fibromyalgia Arthritis & Rheumatism 2001 44 222 230 11212164 10.1002/1529-0131(200101)44:1<222::AID-ANR29>3.0.CO;2-K

84 Van Cauter E Plat L Copinschi G Interrelations between sleep and the somatotropic axis Sleep 1998 21 6 553 566 2-s2.0-0032530784 9779515

85 Prinz PN Moe KE Dulberg EM Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men Journals of Gerontology A 1995 50 4 M222 M226 2-s2.0-0029077962 10.1093/gerona/50a.4.m222 7614245

86 Bennett RM Clark SR Campbell SM Burckhardt CS Low levels of somatomedin C in patients with the fibromyalgia syndrome: a possible link between sleep and muscle pain Arthritis and Rheumatism 1992 35 10 1113 1116 2-s2.0-0026801234 1418002 10.1002/art.1780351002

87 Buskila D Neumann L Hazanov I Carmi R Familial aggregation in the fibromyalgia syndrome Seminars in Arthritis and Rheumatism 1996 26 3 605 611 2-s2.0-0030442453 8989805 10.1016/s0049-0172(96)80011-4

88 Arnold LM Hudson JI Hess EV Family study of fibromyalgia Arthritis and Rheumatism 2004 50 3 944 952 2-s2.0-1542313923 15022338 10.1002/art.20042

89 Buskila D Sarzi-Puttini P Ablin JN The genetics of fibromyalgia syndrome Pharmacogenomics 2007 8 1 67 74 2-s2.0-33846537316 17187510 10.2217/14622416.8.1.67

90 Offenbaecher M Bondy B de Jonge S Possible association of fibromyalgia with a polymorphism in the serotonin transporter gene regulatory region Arthritis & Rheumatism 1999 42 2482 2488 10555044 10.1002/1529-0131(199911)42:11<2482::AID-ANR27>3.0.CO;2-B

91 Cohen H Buskila D Neumann L Ebstein RP Confirmation of an association between fibromyalgia and serotonin transporter promoter region (5-HTTLPR) polymorphism, and relationship to anxiety-related personality traits Arthritis and Rheumatism 2002 46 3 845 847 2-s2.0-0036191561 10.1002/art.10103 11920428

92 Zubieta JK Heitzeg MM Smith YR COMT val158 genotype affects μ -opioid neurotransmitter responses to a pain stressor Science 2003 299 5610 1240 1243 2-s2.0-0037458277 12595695 10.1126/science.1078546

93 Gürsoy S Erdal E Herken H Madenci E Alaşehirli B Erdal N Significance of catechol-O-methyltransferase gene polymorphism in fibromyalgia syndrome Rheumatology International 2003 23 3 104 107 2-s2.0-0038512578 12739038 10.1007/s00296-002-0260-5

94 Buskila D Cohen H Neuman L Ebstein RP An association between fibromyalgia and the dopamine D4 receptor exon III repeat polymorphism and relationship to novelty seeking personality traits Molecular Psychiatry 2004 9 8 730 727 2-s2.0-4243165660 15052273 10.1038/sj.mp.4001506

95 Yunus MB Khan MA Rawlings KK Green JR Olson JM Shah S Genetic linkage analysis of multicase families with fibromyalgia syndrome Journal of Rheumatology 1999 26 2 408 412 2-s2.0-0032932447 9972977

96 Middleton GD McFarlin JE Lipsky PE The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus Arthritis and Rheumatism 1994 37 8 1181 1188 2-s2.0-0027971740 8053957 10.1002/art.1780370812

97 Tishler M Barak Y Paran D Yaron M Sleep disturbances, fibromyalgia and primary Sjogren's syndrome Clinical and Experimental Rheumatology 1997 15 1 71 74 2-s2.0-0030938441 9093776

98 Wolfe F Michaud K Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize RA patients with fibromyalgia Journal of Rheumatology 2004 31 4 695 700 2-s2.0-1842530444 15088293

99 Kötter I Neuscheler D Günaydin I Wernet D Klein R Is there a predisposition for the development of autoimmune diseases in patients with fibromyalgia? Retrospective analysis with long term follow-up Rheumatology International 2007 27 11 1031 1039 2-s2.0-34547830256 17634900 10.1007/s00296-007-0413-7

100 Ribeiro LS Proietti FA Interrelations between fibromyalgia, thyroid autoantibodies, and depression Journal of Rheumatology 2004 31 10 2036 2040 2-s2.0-5044229841 15468372

101 Pamuk ON Cakir N The frequency of thyroid antibodies in fibromyalgia patients and their relationship with symptoms Clinical Rheumatology 2007 26 1 55 59 2-s2.0-33845866350 16541203 10.1007/s10067-006-0237-y

102 Bazzichi L Rossi A Giuliano T Association between thyroid autoimmunity and fibromyalgic disease severity Clinical Rheumatology 2007 26 12 2115 2120 2-s2.0-36248968162 17487449 10.1007/s10067-007-0636-8

103 Wilson RB Gluck OS Tesser JRP Rice JC Meyer A Bridges AJ Antipolymer antibody reactivity in a subset of patients with fibromyalgia correlates with severity Journal of Rheumatology 1999 26 2 402 407 2-s2.0-0032935878 9972976

104 Jensen B Wittrup IH Wiik A Antipolymer antibodies in Danish fibromyalgia patients Clinical and Experimental Rheumatology 2004 22 2 227 229 2-s2.0-1842606533 15083892

105 Sarzi-Puttini P Atzeni F Franco MD Anti-polymer antibodies are correlated with pain and fatigue severity in patients with fibromyalgia syndrome Autoimmunity 2008 41 1 74 79 2-s2.0-38049072183 18176867 10.1080/08916930701620035

106 Katon W Sullivan M Walker E Medical symptoms without identified pathology: relationship to psychiatric disorders, childhood and adult trauma, and personality traits Annals of Internal Medicine 2001 134 9 917 925 2-s2.0-0035340084 11346329 10.7326/0003-4819-134-9_part_2-200105011-00017

107 Clauw DJ Crofford LJ Chronic widespread pain and fibromyalgia: what we know, and what we need to know Best Practice and Research 2003 17 4 685 701 2-s2.0-0038268869 12849719 10.1016/s1521-6942(03)00035-4

108 McBeth J Macfarlane GJ Benjamin S Silman AJ Features of somatization predict the onset of chronic widespread pain: results of a large population-based study Arthritis & Rheumatism 2001 44 940 946 11315933 10.1002/1529-0131(200104)44:4<940::AID-ANR151>3.0.CO;2-S

109 Cohen H Neumann L Haiman Y Matar MA Press J Buskila D Prevalence of post-traumatic stress disorder in fibromyalgia patients: overlapping syndromes or post-traumatic fibromyalgia syndrome? Seminars in Arthritis and Rheumatism 2002 32 1 38 50 2-s2.0-0036672211 12219319 10.1053/sarh.2002.33719

110 Epstein SA Kay G Clauw D Psychiatric disorders in patients with fibromyalgia: a multicenter investigation Psychosomatics 1999 40 1 57 63 2-s2.0-0032903066 9989122 10.1016/S0033-3182(99)71272-7

111 McBeth J Silman AJ The role of psychiatric disorders in fibromyalgia Current Rheumatology Reports 2001 3 2 157 164 2-s2.0-0035315894 11286672 10.1007/s11926-001-0011-8

112 Bair MJ Robinson RL Katon W Kroenke K Depression and pain comorbidity: a literature review Archives of Internal Medicine 2003 163 20 2433 2445 2-s2.0-0242455998 14609780 10.1001/archinte.163.20.2433

113 Arnold LM Keck PE Welge JA Antidepressant treatment of fibromyalgia. A meta-analysis and review Psychosomatics 2000 41 2 104 113 2-s2.0-0034117292 10749947 10.1176/appi.psy.41.2.104

114 Nørregaard J Volkmann H Danneskiold-Samsøe B A randomized controlled trial of citalopram in the treatment of fibromyalgia Pain 1995 61 3 445 449 2-s2.0-0029062173 7478688 10.1016/0304-3959(94)00218-4

115 Fishbain D Evidence-based data on pain relief with antidepressants Annals of Medicine 2000 32 5 305 316 2-s2.0-0033944573 10949061 10.3109/07853890008995932

116 Katz DL Greene L Ali A Faridi Z The pain of fibromyalgia syndrome is due to muscle hypoperfusion induced by regional vasomotor dysregulation Medical Hypotheses 2007 69 3 517 525 2-s2.0-34447286017 17376601 10.1016/j.mehy.2005.10.037

117 Ozgocmen S Ozyurt H Sogut S Akyol O Ardicoglu O Yildizhan H Antioxidant status, lipid peroxidation and nitric oxide in fibromyalgia: etiologic and therapeutic concerns Rheumatology International 2006 26 7 598 603 2-s2.0-33645847273 16283318 10.1007/s00296-005-0079-y

118 Lario BA Alonso Valdivielso JL López JA Soteres CM Viejo Bañuelos JL Cabello AM Fibromyalgia syndrome: overnight falls in arterial oxygen saturation American Journal of Medicine 1996 101 1 54 60 2-s2.0-0030198603 8686716 10.1016/s0002-9343(96)00067-8

119 Staud R Biology and therapy of fibromyalgia: pain in fibromyalgia syndrome Arthritis Research and Therapy 2006 8 3, article 208 2-s2.0-33745239716 10.1186/ar1950 PMC1526632 16684376

120 Ablin JN Shoenfeld Y Buskila D Fibromyalgia, infection and vaccination: two more parts in the etiological puzzle Journal of Autoimmunity 2006 27 3 145 152 2-s2.0-33846086560 17071055 10.1016/j.jaut.2006.09.004

121 Rivera J de Diego A Trinchet M García Monforte A Fibromyalgia-associated hepatitis C virus infection British Journal of Rheumatology 1997 36 9 981 985 2-s2.0-0030798295 9376995 10.1093/rheumatology/36.9.981

122 Nash P Chard M Hazleman B Chronic Coxsackie B infection mimicking primary fibromyalgia Journal of Rheumatology 1989 16 11 1506 1508 2-s2.0-0024845330 2557447

123 Leventhal LJ Naides SJ Freundlich B Fibromyalgia and parvovirus infection Arthritis and Rheumatism 1991 34 10 1319 1324 2-s2.0-0026000803 1657005 10.1002/art.1780341018

124 Buskila D Gladman DD Langevitz P Urowitz S Smythe HA Fibromyalgia in human immunodeficiency virus infection Journal of Rheumatology 1990 17 9 1202 1206 2-s2.0-0025027022 2290162

125 Dinerman H Steerc AC Lyme disease associated with fibromyalgia Annals of Internal Medicine 1992 117 4 281 285 2-s2.0-0026647138 1637022 10.7326/0003-4819-117-4-281

126 Hsu VM Patella SJ Sigal LH ‘Chronic Lyme disease’ as the incorrect diagnosis in patients with fibromyalgia Arthritis and Rheumatism 1993 36 11 1493 1500 2-s2.0-0027370080 8240427 10.1002/art.1780361103

127 Milligan ED O’Connor KA Nguyen KT Intrathecal HIV-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines Journal of Neuroscience 2001 21 8 2808 2819 2-s2.0-0035871357 11306633 10.1523/JNEUROSCI.21-08-02808.2001 PMC6762530

128 Holguin A O'Connor KA Biedenkapp J HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS) Pain 2004 110 3 517 530 2-s2.0-3843103991 15288392 10.1016/j.pain.2004.02.018

129 Thompson ME Barkhuizen A Fibromyalgia, hepatitis C infection, and the cytokine connection Current Pain and Headache Reports 2003 7 5 342 347 2-s2.0-0642335532 12946286 10.1007/s11916-003-0032-2

130 Gabuzda D Wang J Chemokine receptors and virus entry in the central nervous system Journal of NeuroVirology 1999 5 6 643 658 2-s2.0-0033387213 10602405 10.3109/13550289909021293

131 Rock RB Gekker G Hu S Role of microglia in central nervous system infections Clinical Microbiology Reviews 2004 17 4 942 964 2-s2.0-5644271409 15489356 10.1128/CMR.17.4.942-964.2004 PMC523558

132 Waylonis GW Perkins RH Post-traumatic fibromyalgia: a long-term follow-up American Journal of Physical Medicine and Rehabilitation 1994 73 6 403 412 2-s2.0-0028577686 7993614 10.1097/00002060-199411000-00005

133 Bell IR Baldwin CM Schwartz GE Illness from low levels of environmental chemicals: relevance to chronic fatigue syndrome and fibromyalgia American Journal of Medicine 1998 105 3 74S 82S 2-s2.0-0032575968 9790486 10.1016/s0002-9343(98)00162-4

134 Greenfield S Fitzcharles MA Esdaile JM Reactive fibromyalgia syndrome Arthritis and Rheumatism 1992 35 6 678 681 2-s2.0-0026651296 1599521 10.1002/art.1780350612

135 Sim J Madden S Illness experience in fibromyalgia syndrome: a metasynthesis of qualitative studies Social Science and Medicine 2008 67 1 57 67 2-s2.0-44349123310 18423826 10.1016/j.socscimed.2008.03.003

136 Schneider MJ Brady DM Perle SM Commentary: differential diagnosis of fibromyalgia syndrome: proposal of a model and algorithm for patients presenting with the primary symptom of chronic widespread pain Journal of Manipulative and Physiological Therapeutics 2006 29 6 493 501 2-s2.0-33746803245 16904498 10.1016/j.jmpt.2006.06.010

137 Aaron LA Burke MM Buchwald D Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder Archives of Internal Medicine 2000 160 2 221 227 2-s2.0-0034707662 10647761 10.1001/archinte.160.2.221

138 Aaron LA Buchwald D A review of the evidence for overlap among unexplained clinical conditions Annals of Internal Medicine 2001 134 9 868 881 2-s2.0-0035341150 11346323 10.7326/0003-4819-134-9_part_2-200105011-00011

139 Gilliland BC Kasper DL Harrison TR Fibromyalgia, arthritis associated with systemic disease, and other arthritides Harrison's Principles of Internal Medicine 2005 2 16th edition New York, NY, USA McGraw-Hill, Medical Publication Division 2055 2064

140 McBeth J Mulvey MR Fibromyalgia: mechanisms and potential impact of the ACR, 2010 classification criteria Nature Reviews Rheumatology 2012 8 108 116 22270077 10.1038/nrrheum.2011.216

141 Buskila D Neumann L Fibromyalgia syndrome (FM) and nonarticular tenderness in relatives of patients with FM Journal of Rheumatology 1997 24 5 941 944 2-s2.0-0030989985 9150086

142 Fitzcharles MA Boulos P Inaccuracy in the diagnosis of fibromyalgia syndrome: analysis of referrals Rheumatology 2003 42 2 263 267 2-s2.0-0344837922 12595620 10.1093/rheumatology/keg075

143 Choy EH Arnold LM Clauw DJ Content and criterion validity of the preliminary core dataset for clinical trials in fibromyalgia syndrome Journal of Rheumatology 2009 36 10 2330 2334 2-s2.0-70450208166 19820222 10.3899/jrheum.090368 PMC3412585

144 Mease PJ Arnold LM Bennett R Fibromyalgia syndrome Journal of Rheumatology 2007 34 6 1415 1425 2-s2.0-34250176930 17552068

145 Mease PJ Clauw DJ Arnold LM Fibromyalgia syndrome Journal of Rheumatology 2005 32 11 2270 2277 2-s2.0-27744590935 16265715

146 Mease PJ Clauw DJ Gendreau RM The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial Journal of Rheumatology 2009 36 2 398 409 2-s2.0-64849117499 19132781 10.3899/jrheum.080734

147 Wolfe F Michaud K Outcome and predictor relationships in fibromyalgia and rheumatoid arthritis: evidence concerning the continuum versus discrete disorder hypothesis Journal of Rheumatology 2009 36 4 831 836 2-s2.0-66149122979 19228653 10.3899/jrheum.080897

148 Toda K Preliminary diagnostic criteria for fibromyalgia should be partially revised: comment on the article by Wolfe et al Arthritis Care and Research 2011 63 2 308 309 2-s2.0-79551533799 10.1002/acr.20358 20890978

149 Wolfe F Clauw DJ Fitzcharles MA Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia Journal of Rheumatology 2011 38 6 1113 1122 2-s2.0-79957809749 21285161 10.3899/jrheum.100594

150 Bennett RM Jones J Turk DC Russell IJ Matallana L An internet survey of 2,596 people with fibromyalgia BMC Musculoskeletal Disorders 2007 8, article 27 2-s2.0-33947366834 10.1186/1471-2474-8-27 PMC1829161 17349056

151 Arnold LM Strategies for managing fibromyalgia American Journal of Medicine 2009 122 supplement 12 S31 S43 2-s2.0-70749146730 19962495 10.1016/j.amjmed.2009.09.009

152 Goldenberg DL The interface of pain and mood disturbances in the rheumatic diseases Seminars in Arthritis and Rheumatism 2010 40 1 15 31 2-s2.0-77955279351 19217649 10.1016/j.semarthrit.2008.11.005

153 Häuser W Thieme K Turk DC Guidelines on the management of fibromyalgia syndrome—a systematic review European Journal of Pain 2010 14 1 5 10 2-s2.0-72049123263 19264521 10.1016/j.ejpain.2009.01.006

154 Mease P Arnold LM Choy EH Fibromyalgia syndrome module at OMERACT 9: domain construct Journal of Rheumatology 2009 36 10 2318 2329 2-s2.0-70450177636 19820221 10.3899/jrheum.090367 PMC3419373

155 Farrar JT Young JP LaMoreaux L Werth JL Poole RM Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale Pain 2001 94 2 149 158 2-s2.0-0034748159 11690728 10.1016/S0304-3959(01)00349-9

156 Goldenberg DL Burckhardt C Crofford L Management of fibromyalgia syndrome Journal of the American Medical Association 2004 292 19 2388 2395 2-s2.0-8544239393 15547167 10.1001/jama.292.19.2388

157 Goldenberg DL Felson DT Dinerman H A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia Arthritis and Rheumatism 1986 29 11 1371 1377 2-s2.0-0022998505 3535811 10.1002/art.1780291110

158 Wolfe F Zhao S Lane N Preference for nonsteroidal antiinflammatory drugs over acetaminophen by rheumatic disease patients: a survey of 1, 799 patients with osteoarthritis, rheumatoid arthritis, and fibromyalgia Arthritis & Rheumatism 2000 43 378 385 10693878 10.1002/1529-0131(200002)43:2<378::AID-ANR18>3.0.CO;2-2

159 Goldenberg Schaefer DL Ryan C Chandran K Zlateva Gergana A What Is the true cost of fibromyalgia to our society: results from a cross-sectional survey in the United States Arthritis & Rheumatism 2009 60, supplement 10 p. 104

160 Carville SF Arendt-Nielsen S Bliddal H EULAR evidence-based recommendations for the management of fibromyalgia syndrome Annals of the Rheumatic Diseases 2008 67 4 536 541 2-s2.0-41849093775 17644548 10.1136/ard.2007.071522

161 American Pain Society Guideline for the Management of Pain in Fibromyalgia, American Pain Society Clinical Practice Guidelines Program 2011, http://www.ampainsoc.org/

162 Clauw DJ Pharmacotherapy for patients with fibromyalgia Journal of Clinical Psychiatry 2008 69 supplement 2 25 29 2-s2.0-45849093290 18537460

163 Biasi G Manca S Manganelli S Marcolongo R Tramadol in the fibromyalgia syndrome: a controlled clinical trial versus placebo International Journal of Clinical Pharmacology Research 1998 18 1 13 19 2-s2.0-0031693130 9604730

164 Bennett RM Kamin M Karim R Rosenthal N Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study American Journal of Medicine 2003 114 7 537 545 2-s2.0-0037716856 12753877 10.1016/s0002-9343(03)00116-5

165 Llinares-Tello F Escrivá-Moscardó S Martínez-Pastor F Martínez-Mascaraque P Possible serotoninergia syndrome associated with coadministration of paroxetine tramadol Medicina Clinica 2007 128 11 p. 438 2-s2.0-34247472223 10.1016/s0025-7753(07)72615-5 17394862

166 Littlejohn GO Guymer EK Fibromyalgia syndrome: which antidepressant drug should we choose Current Pharmaceutical Design 2006 12 1 3 9 2-s2.0-33644855526 16454718

167 Arnold LM Duloxetine and other antidepressants in the treatment of patients with fibromyalgia Pain Medicine 2007 8 supplement 2 S63 S74 2-s2.0-34548099465 17714117 10.1111/j.1526-4637.2006.00178.x

168 Holman AJ Pragmatic consideration of recent randomized, placebo-controlled clinical trials for treatment of fibromyalgia Current Pain and Headache Reports 2008 12 6 393 398 2-s2.0-65249121996 18973730 10.1007/s11916-008-0067-5

169 Perahia DGS Pritchett YL Desaiah D Raskin J Efficacy of duloxetine in painful symptoms: an analgesic or antidepressant effect? International Clinical Psychopharmacology 2006 21 6 311 317 2-s2.0-33749315762 17012978 10.1097/01.yic.0000224782.83287.3c

170 Ware JE Sherbourne CD The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection Medical Care 1992 30 6 473 483 2-s2.0-0026877917 1593914

171 Crofford LJ Mease PJ Simpson SL Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin Pain 2008 136 3 419 431 2-s2.0-43549104210 18400400 10.1016/j.pain.2008.02.027

172 Häuser W Petzke F Sommer C Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome Journal of Pain 2010 11 6 505 521 2-s2.0-77952742362 20418173 10.1016/j.jpain.2010.01.002

173 Katz RS Wolfe F Michaud K Fibromyalgia diagnosis: a comparison of clinical, survey, and American College of Rheumatology criteria Arthritis and Rheumatism 2006 54 1 169 176 2-s2.0-31044442025 16385512 10.1002/art.21533

174 O’Malley PG Balden E Tomkins G Santoro J Kroenke K Jackson JL Treatment of fibromyalgia with antidepressants: a meta-analysis Journal of General Internal Medicine 2000 15 9 659 666 2-s2.0-0033770655 11029681 10.1046/j.1525-1497.2000.06279.x PMC1495596

175 Tofferi JK Jackson JL O’Malley PG Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis Arthritis Care and Research 2004 51 1 9 13 2-s2.0-1242269398 14872449 10.1002/art.20076

176 Häuser W Bernardy K Üçeyler N Sommer C Treatment of fibromyalgia syndrome with antidepressants: a meta-analysis Journal of the American Medical Association 2009 301 2 198 209 2-s2.0-58249090925 19141768 10.1001/jama.2008.944

177 Staud R Treatment of fibromyalgia and its symptoms Expert Opinion on Pharmacotherapy 2007 8 11 1629 1642 2-s2.0-34548099816 17685881 10.1517/14656566.8.11.1629

178 Beliles K Stoudemire A Psychopharmacologic treatment of depression in the medically III Psychosomatics 1998 39 3 S2 S19 2-s2.0-0031744947 9664784 10.1016/S0033-3182(98)71339-8

179 Goldenberg DL Pharmacological treatment of fibromyalgia and other chronic musculoskeletal pain Best Practice and Research 2007 21 3 499 511 2-s2.0-34250885099 17602996 10.1016/j.berh.2007.02.012

180 Hayden JA Van Tulder MW Tomlinson G Systematic review: strategies for using exercise therapy to improve outcomes in chronic low back pain Annals of Internal Medicine 2005 142 9 776 785 2-s2.0-17844378696 15867410 10.7326/0003-4819-142-9-200505030-00014

181 Häkkinen A Kautiainen H Hannonen P Ylinen J Strength training and stretching versus stretching only in the treatment of patients with chronic neck pain: a randomized one-year follow-up study Clinical Rehabilitation 2008 22 7 592 600 2-s2.0-55249125681 18586810 10.1177/0269215507087486

182 Jones KD Sherman CA Mist SD Carson JW Bennett RM Li F A randomized controlled trial of 8-form Tai chi improves symptoms and functional mobility in fibromyalgia patients Clinical Rheumatology 2012 31 8 1205 1214 22581278 10.1007/s10067-012-1996-2 PMC5571653

183 Wang C Schmid CH Rones R A randomized trial of tai chi for fibromyalgia The New England Journal of Medicine 2010 363 8 743 754 2-s2.0-77955871815 20818876 10.1056/NEJMoa0912611 PMC3023168

184 Li F Harmer P Fitzgerald K Tai chi and postural stability in patients with Parkinson's disease The New England Journal of Medicine 2012 366 511 519 22316445 10.1056/NEJMoa1107911 PMC3285459

185 Hydrotherapy Association of Chartered Physiotherapists, Guidance on good practice in hydrotherapy, Chartered Society of Physiotherapy, September 2006

186 Verhagen AP Cardoso JR Bierma-Zeinstra SM Aquatic exercise & balneotherapy in musculoskeletal conditions Best Practice & Research Clinical Rheumatology 2012 26 335 343 22867930 10.1016/j.berh.2012.05.008

187 Sukenik S Flusser D Abu-Shakra M The role of Spa therapy in various rheumatic diseases Rheumatic Disease Clinics of North America 1999 25 4 883 897 2-s2.0-0032700259 10573764 10.1016/s0889-857x(05)70108-3

188 Bender T Karagülle Z Bálint GP Gutenbrunner C Bálint PV Sukenik S Hydrotherapy, balneotherapy, and spa treatment in pain management Rheumatology International 2005 25 3 220 224 2-s2.0-17744383758 15257412 10.1007/s00296-004-0487-4

189 Fioravanti A Cantarini L Guidelli GM Galeazzi M Mechanisms of action of spa therapies in rheumatic diseases: what scientific evidence is there? Rheumatology International 2011 31 1 1 8 2-s2.0-78751571320 21120502 10.1007/s00296-010-1628-6

190 Melzack R Wall PD Pain mechanisms: a new theory Science 1965 150 3699 971 979 2-s2.0-0013851199 5320816 10.1126/science.150.3699.971

191 McVeigh JG McGaughey H Hall M Kane P The effectiveness of hydrotherapy in the management of fibromyalgia syndrome: a systematic review Rheumatology International 2008 29 2 119 130 2-s2.0-55949089638 18751709 10.1007/s00296-008-0674-9

192 Vlaeyen JWS Teeken-Gruben NJG Goossens MEJB Cognitive-educational treatment of fibromyalgia: a randomized clinical trial. I Clinical effects Journal of Rheumatology 1996 23 7 1237 1245 2-s2.0-0029680677 8823699

193 Turk DC Cognitive-behavioral approach to the Treatment of chronic pain patients Regional Anesthesia and Pain Medicine 2003 28 6 573 579 2-s2.0-0345357733 14634950 10.1016/s1098-7339(03)00392-4

194 Thieme K Gracely RH Are psychological treatments effective for fibromyalgia pain? Current Rheumatology Reports 2009 11 6 443 450 2-s2.0-72549086502 19922735 10.1007/s11926-009-0065-6

195 Munguía-Izquierdo D Legaz-Arrese A Exercise in warm water decreases pain and improves cognitive function in middle-aged women with fibromyalgia Clinical and Experimental Rheumatology 2007 25 6 823 830 2-s2.0-38649108220 18173915

196 Tomas-Carus P Gusi N Häkkinen A Häkkinen K Leal A Ortega-Alonso A Eight months of physical training in warm water improves physical and mental health in women with fibromyalgia: a randomized controlled trial Journal of Rehabilitation Medicine 2008 40 4 248 252 2-s2.0-42649132796 18382819 10.2340/16501977-0168

197 Gusi N Tomas-Carus P Cost-utility of an 8-month aquatic training for women with fibromyalgia: a randomized controlled trial Arthritis Research and Therapy 2008 10 1, article R24 2-s2.0-41149111100 10.1186/ar2377 PMC2374450 18294367

198 André-Obadia N Peyron R Mertens P Mauguière F Laurent B Garcia-Larrea L Transcranial magnetic stimulation for pain control. Double-blind study of different frequencies against placebo, and correlation with motor cortex stimulation efficacy Clinical Neurophysiology 2006 117 7 1536 1544 2-s2.0-33745414759 16753335 10.1016/j.clinph.2006.03.025

199 Graff-Guerrero A González-Olvera J Fresán A Gómez-Martín D Méndez-Núñez JC Pellicer F Repetitive transcranial magnetic stimulation of dorsolateral prefrontal cortex increases tolerance to human experimental pain Cognitive Brain Research 2005 25 1 153 160 2-s2.0-24644481457 15935625 10.1016/j.cogbrainres.2005.05.002

200 Nahmias F Debes C de Andrade DC Mhalla A Bouhassira D Diffuse analgesic effects of unilateral repetitive transcranial magnetic stimulation (rTMS) in healthy volunteers Pain 2009 147 1–3 224 232 2-s2.0-70449642372 19822394 10.1016/j.pain.2009.09.016

201 Summers J Johnson S Pridmore S Oberoi G Changes to cold detection and pain thresholds following low and high frequency transcranial magnetic stimulation of the motor cortex Neuroscience Letters 2004 368 2 197 200 2-s2.0-4444277058 15351448 10.1016/j.neulet.2004.07.008

202 Valmunen T Pertovaara A Taiminen T Virtanen A Parkkola R Jääskeläinen SK Modulation of facial sensitivity by navigated rTMS in healthy subjects Pain 2009 142 1-2 149 158 2-s2.0-60149083949 19201092 10.1016/j.pain.2008.12.031

203 Fregni F Freedman S Pascual-Leone A Recent advances in the treatment of chronic pain with non-invasive brain stimulation techniques Lancet Neurology 2007 6 2 188 191 2-s2.0-33846213970 17239806 10.1016/S1474-4422(07)70032-7

204 Lefaucheur JP The use ofrepetitive transcranial magnetic stimulation (rTMS) inchronic neuropathic pain Neurophysiologie Clinique 2006 36 3 117 124 2-s2.0-33750034400 17046606 10.1016/j.neucli.2006.08.002

205 Khedr EM Kotb H Kamel NF Ahmed MA Sadek R Rothwell JC Longlasting antalgic effects of daily sessions of repetitive transcranial magnetic stimulation in central and peripheral neuropathic pain Journal of Neurology, Neurosurgery and Psychiatry 2005 76 6 833 838 2-s2.0-20444397455 10.1136/jnnp.2004.055806 PMC1739662 15897507

206 Defrin R Grunhaus L Zamir D Zeilig G The effect of a series of repetitive transcranial magnetic stimulations of the motor cortex on central pain after spinal cord injury Archives of Physical Medicine and Rehabilitation 2007 88 12 1574 1580 2-s2.0-36349004061 18047871 10.1016/j.apmr.2007.07.025

207 Katayama Y Yaniamoto T Kobayashi K Oshima H Fukaya C Deep brain and motor cortex stimulation for post-stroke movement disorders and post-stroke pain Acta Neurochirurgica, Supplementum 2003 87 121 123 2-s2.0-0142213318 10.1007/978-3-7091-6081-7_25 14518537

208 Nuti C Peyron R Garcia-Larrea L Motor cortex stimulation for refractory neuropathic pain: four year outcome and predictors of efficacy Pain 2005 118 1-2 43 52 2-s2.0-27644491501 16214292 10.1016/j.pain.2005.07.020

209 Tsubokawa T Katayama Y Yamamoto T Hirayama T Koyama S Chronic motor cortex stimulation for the treatment of central pain Acta Neurochirurgica, Supplement 1991 52 137 139 2-s2.0-0026286784 10.1007/978-3-7091-9160-6_37 1792954

210 Mhalla A Baudic S De Andrade DC Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia Pain 2011 152 7 1478 1485 2-s2.0-79958731773 21397400 10.1016/j.pain.2011.01.034

211 Park DC Glass JM Minear M Crofford LJ Cognitive function in fibromyalgia patients Arthritis & Rheumatism 2001 44 2125 2133 11592377 10.1002/1529-0131(200109)44:9<2125::AID-ART365>3.0.CO;2-1