Predicting fibromyalgia, a narrative review: are we better than fools and children?

Fibromyalgia syndrome (FMS) is a common and intriguing condition, manifest by chronic pain and fatigue. Although the pathogenesis of FMS is not yet completely understood, predicting the future development of FMS and chronic pain is a major challenge with great potential advantages, both from an individual as well as an epidemiological standpoint. Current knowledge indicates a genetic underpinning for FMS, and as increasing data are accumulated regarding the genetics involved, the prospect of utilizing these data for prediction becomes ever more attractive. The co-existence of FMS with multiple other functional disorders indicates that the clinical identification of such symptom constellations in a patient can alert the physician to the future development of FMS. Hypermobility syndrome is another clinical (as well as genetic) phenotype that has emerged as a risk factor for the development of FMS. Stressful events, including early life trauma, are also harbingers of the future development of FMS. Functional neuroimaging may help to elucidate the neural processes involved in central sensitization, and may ultimately also evolve into markers of predictive value. Last but not least, obesity and disturbed sleep are clinical (inter-related) features relevant for this spectrum. Future efforts will aim at integrating genetic, clinical and physiological data in the prediction of FMS and chronic pain.

Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene.

BACKGROUND: Recent evidence suggests that genetic factors might contribute to individual differences in pain sensitivity, risk for developing clinical pain conditions and efficacy of pain treatments. The purpose of the present study was to investigate the relationship of three common haplotypes of COMT gene affecting the metabolism of catecholamines on pain sensitivity in patients with fibromyalgia (FM). METHODS: One hundred and thirteen FM patients and 65 age-matched healthy volunteers participated in the study. We genotyped four single-nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4818 and rs4680 or Val158Met) and identified haplotypes previously designated as low (LPS), average (APS) and high pain sensitivity (HPS). Thermal, pressure and touch thresholds were also examined using a quantitative sensory testing protocol. RESULTS: The frequency of genetic variations associated with low COMT enzyme activity was significantly higher in FM patients than in healthy volunteers. FM patients were more sensitive to experimental pain than healthy volunteers and, in particular, FM individuals with the met/met genotype (Val158Met SNP) or the HPS-APS haplotypes showing higher sensitivity to thermal and pressure pain stimuli than patients carrying the LPS haplotype or val alleles (Val158Met SNP). No differences due to genotype or haplotypes were found on non-painful touch thresholds. CONCLUSIONS: According with previous research, our findings revealed that haplotypes of the COMT gene and genotypes of the Val158Met polymorphism play a key role on pain sensitivity in FM patients.

Pediatric fibromyalgia.

Fibromyalgia (FM) is currently defined as chronic widespread pain (CWP) with allodynia or hyperalgesia to pressure pain. It is classified as one of the large group of soft-tissue pain syndromes. Pain is the cardinal symptom of FM; however, most patients also experience additional symptoms such as debilitating fatigue, disrupted or non-restorative sleep, functional bowel disturbances, and a variety of neuropsychiatric problems, including cognitive dysfunction, anxiety and depressive symptoms. Its pathogenesis is not entirely understood, although it is currently believed to be the result of a central nervous system (CNS) malfunction that increases pain transmission and perception. FMS usually involves females, and in these patients it often makes its first appearance during menopause. But it is often diagnosed both in young as well as elderly individuals. Pediatric FMS is a frustrating condition affecting children and adolescents at a crucial stage of their physical and emotional development. Pediatric FMS is an important differential diagnosis to be considered in the evaluation of children suffering from widespread musculoskeletal pain, and must be differentiated from a spectrum of inflammatory joint disorders such as juvenile idiopathic arthritis (JIA), juvenile ankylosing spondylitis, etc. The management of pediatric FMS is centered on the issues of education, behavioral and cognitive change (with a strong emphasis on physical exercise), and a relatively minor role for pharmacological treatment with medications such as muscle relaxants, analgesics and tricyclic agents.

Sexual dysfunction is correlated with tenderness in female fibromyalgia patients.

OBJECTIVES: The purpose of the current study was to evaluate sexual dysfunction among female fibromyalgia syndrome (FMS) patients. METHODS: Fifty female subjects were recruited and were asked to complete a questionnaire regarding sexual functioning. The control group included fifty-five healthy age-matched volunteers. The participants underwent a physical examination and tender point assessment was performed using manual palpation. All participants filled out the Arizona Sexual Experience Scale, which evaluates five areas of sexual functioning: sexual drive, sexual arousal, vaginal wetting, orgasm and sexual satisfaction. RESULTS: FMS patients had significantly lower scores on all five aspects of sexual function assessed. A positive correlation was observed between the sexual drive score, signifying a decrease in sexual drive, and the number of tender points documented on examination. Similarly, a positive correlation was observed between the sexual satisfaction scale (indicating decreasing levels of sexual satisfaction) and the number of tender points documented. A positive correlation was demonstrated between the sexual arousal and orgasmatic scales and between the tender point counts, indicating a decrease in sexual arousal and in orgasmatic function in correlation with an increasing number of tender points. CONCLUSIONS: The results of the current study indicate a multi-factorial sexual dysfunction among female FMS patients. All stages of sexual functioning, evaluated were significantly disturbed in comparison with the healthy controls. Physicians treating FMS patients should be aware of, and actively inquire about, sexual dysfunction as part of a multi-disciplinary evaluation of such patients.

Holocaust survivors: the pain behind the agony. Increased prevalence of fibromyalgia among Holocaust survivors.

OBJECTIVES: To assess the frequency of fibromyalgia among a population of Holocaust survivors in Israel as well as the occurrence of post-traumatic stress disorder (PTSD) and concurrent psychiatric symptoms, including depression and anxiety among survivors. METHODS: Eighty-three survivors of the Nazi Holocaust and 65 age-matched individuals not exposed to Nazi occupation were recruited. Physical examination and manual tender point assessment was performed for the establishment of the diagnosis of fibromyalgia and information was collected regarding quality of life (SF-36), physical function and health (FIQ), psychiatric symptoms (SCL-90) and PTSD symptoms (CAPS). RESULTS: Significantly increased rates of fibromyalgia were identified among Holocaust survivors compared with controls (23.81% vs. 10.94, p<0.05). Significantly increased rates of posttraumatic symptoms and measures of mental distress were also identified among survivors. CONCLUSIONS: The results indicate a significantly increased prevalence of fibromyalgia among Holocaust survivors six decades after the end of the Second World War. This finding furthers our knowledge regarding the long-term effect of stress on the development of fibromyalgia.

A tale of two cities - the effect of low intensity conflict on prevalence and characteristics of musculoskeletal pain and somatic symptoms associated with chronic stress.

UNLABELLED: Although both acute and chronic stress leads to pain, the precise characteristics of this association have not been well defined. Sderot is an Israeli town exposed to repeated missile attacks. Ofakim, a town of similar demographic and socioeconomic characteristics, had not been targeted, as of the period of our study. We examined the occurrence and characteristics of pain and related somatic symptoms in Sderot and Ofakim. METHODS: One thousand and twenty-four individuals in Sderot and 1006 in Ofakim were interviewed regarding pain, somatic symptoms, mood, trauma-exposure, and general health status. RESULTS: Significantly higher levels of trauma-related symptoms and somatic symptoms were noted in Sderot compared with Ofakim (p<0.001). Chronic widespread pain (CWP) was more common in Sderot (11.1%) than Ofakim (8.3%; OR 1.37, p=0.038). Women were more likely (13.9% vs. 9.3%; OR 1.45, p=0.06) than men (8.9% vs. 7.3%, OR 1.24, p=0.37) to experience CWP in Sderot vs. Ofakim. Amongst males, chronic regional pain (CRP) was more common in Sderot (19.2%) than in Ofakim (14.2%; p=0.036). Pain severity in Sderot was significantly higher than in Ofakim (p<0.001). CONCLUSIONS: Similar to previous studies that have suggested that chronic stress is associated with chronic pain, this study demonstrates significantly increased rates of somatic complaints, including pain, fatigue and IBS-like symptoms, among individuals in Sderot compared with Ofakim, as well as significantly higher rates of trauma-related symptoms. Thus, a fibromyalgia-like symptoms cluster was more likely to be found in Sderot compared with Ofakim. Widespread pain was reported as being significantly more frequent by inhabitants of Sderot compared with Ofakim. These results have relevance to both the general population and for populations enduring chronic stress.

Differences in the personality profile of fibromyalgia patients and their relatives with and without fibromyalgia.

OBJECTIVES: To investigate whether Fibromyalgia (FM) patients differ from their first-degree relatives with and without FM regarding the four personality traits, based on Cloninger's TPQ questionnaire (1). METHODS: The study population was obtained from a genetic study from 2003-2007 and included 129 female FM patients, 27 female relatives with undiagnosed FM and 30 female relatives without FM. All participants completed a socio-demographic questionnaire and the Tridimensional Personality Questionnaire (TPQ) (1) that refers to four personality dimensions: 'novelty seeking', 'harm avoidance', 'reward dependence' and 'persistence'. Non-articular tenderness was evaluated by tender point count and by dolorimetry. RESULTS: FM patients and their relatives with FM had higher scores on 'harm avoidance' than relatives without FM (p<0.001, p=0.017 respectively). Furthermore, the mean point counts of FM patients were significantly higher and their tenderness thresholds were significantly lower than that of their relatives in the other two groups (p<0.001; p<0.001, respectively). CONCLUSIONS: The findings suggest that relatives with FM display personality resemblance to FM patients especially in the personality trait harm avoidance. It appears that there are factors in this personality trait that are hereditary and that may contribute to the development of FM. However, the results could not differentiate between factors from a genetic or a non-genetic origin, due to the study design. In addition, FM's place as an independent component among genetic disorders such as pain, depression and anxiety is still unclear.

Are psychological distress symptoms different in fibromyalgia patients compared to relatives with and without fibromyalgia?

OBJECTIVES: Investigating psychological distress symptoms in the context of fibromyalgia (FM) is important due to their role in pain perception, and in the development of pain related disability. Although The Symptom Check-List-90-Revised (SCL-90-R) (1) questionnaire was used to evaluate psychological distress symptoms in FM patients, it was not applied in a familial context in families of FM patients. Our aim was to identify possible differences between FM patients and their relatives with and without FM regarding psychological distress symptoms. METHODS: The participants of the current investigation included 127 diagnosed female patients with FM, and 57 of their first degree relatives, 27 of whom had previously undiagnosed FM. Psychological distress was measured using The Symptom Check-List-90-Revised (SCL-90-R), a self report symptom inventory that addresses 9 distress dimensions reflecting various types of psychopathology. RESULTS: FM patients reported significantly higher severity in 6 of the 9 distress symptoms compared to relatives without FM: somatisation, obsessive-compulsive, interpersonal sensitivity, depression, anxiety and psychoticism. Similar results were observed among relatives with FM, compared to the healthy group, except for anxiety. No differences were observed between FM patients and relatives with FM in the report of psychological distress. CONCLUSIONS: FM patients and relatives with FM expressed similar symptoms of psychological distress compared to the healthy group.

The relationship between a common catechol-O-methyltransferase (COMT) polymorphism val(158) met and fibromyalgia.

OBJECTIVES: Fibromyalgia syndrome (FM) is an idiopathic chronic pain syndrome characterised by widespread nonarticular musculoskeletal pain, generalised tender points, in the absence of inflammatory or structural musculoskeletal abnormalities, accompanied by a constellation of symptoms that include fatigue and disturbances of sleep and mood. Catechol-O-methyltransferase (COMT) is the major catecholamine-clearing pathway and involved in the mediation of pain perception in humans, and the hypothesized role of pain perception in FM. The association between Val/Met polymorphism at the COMT gene was evaluated in FM disorder. METHODS: 209 FM female patients were compared with 152 of their non-affected relatives. DNA was obtained from all family members and extracted. We used the logistic based variant of the transmission disequilibrium test to assess association (and linkage) without confounding effect of population stratification. RESULTS: We observed an association between FM and the COMT val(158) met polymorphism in a dose response effect of the COMT genotype and the number of pressure points reported. We also observed that non-affected relatives of FM patients had a reduced percentage of the COMT met allele. CONCLUSIONS: Our results are consistent with carriers of the COMT met/met genotype showing increased sensitivity to pain as one mechanism for the role of this gene in conferring risk for FM. We suggest that the reduced frequency of the met allele in the non-affected relatives acts as a 'protective' allele in this group and prevents the development of clinical FM.

A painful train of events: increased prevalence of fibromyalgia in survivors of a major train crash.

OBJECTIVES: To evaluate the prevalence of fibromyalgia in survivors of a major train crash in southern Israel, three years after the event. METHODS: Survivors were contacted by mail and telephone. Individuals consenting to participate in the study underwent physical examination, including a tender point count and dolorimetry, as well as extensive evaluation of parameters relating to quality of life, presence of widespread pain, fatigue, physical and social function, posttraumatic symptoms and symptoms related to anxiety, dissociation, depression, somatisation, etc. RESULTS: Fifteen percent of survivors participating in the study met ACR criteria for the classification of fibromyalgia. Significantly lower rates of physical and emotional functioning were found among survivors with fibromyalgia compared with those not meeting the classification criteria. Survivors with fibromyalgia rated significantly higher on scales of somatisation, obsessive-compulsive ideation, interpersonal sensitivity, depression, anger and hostility, phobic and general anxiety, paranoid ideation and psychoticism. Survivors with fibromyalgia also rated significantly higher on scales of posttraumatic symptoms including intrusion, avoidance and arousal. These individuals also rated significantly higher on the Peritraumatic Dissociative Experiences Questionnaire (PDE-Q) and the Dissociative Experiences Scale (Hebrew version) (DES-H). CONCLUSION: Fibromyalgia was found to be highly prevalent, three years after a major train crash, among individuals exposed to the combination of physical injury and extreme stress. This finding is in accordance with previous data regarding the association of fibromyalgia with both physical and emotional trauma and calls attention to studying the underlying susceptibility factors which may partake in this association.

Fibromyalgia syndrome: preventive, social and economic aspects.

There many open questions concerning the concept of primary prevention in FM. Diagnostic or classification criteria are not universally accepted, and this leads to difficulties in establishing the onset and duration of the disease. In the case of FM, primary prevention may consist of the immediate care of acute pain or treatment for affective disturbances as we do not have any specific laboratory or instrumental tests to determine risk factors of the disease. The goal of secondary prevention is early detection of the disease when patients are largely asymptomatic and intervention improves outcome. Screening allows for identification of an unrecognized disease or risk factor, which, for potential FM patients, includes analysis of tender points, Fibromyalgia Impact Questionnaire (FIQ), pain location and intensity, and fatigue and sleep complaints. Tertiary prevention inhibits further deterioration or reduces complications after the disease has developed. In FM the aim of treatment is to decrease pain and increase function via multimodal therapeutic strategies, which, in most cases, includes pharmacological and non-pharmacological interventions. Patients with FM are high consumers of health care services, and FM is associated with significant productivity-related costs. The degree of disability and the number of comorbidities are strongly associated with costs. An earlier diagnosis of FM can reduce referral costs and investigations, thus, leading to a net savings for the health care sector. However, every social assessment is closely related to the socio-economic level of the general population and to the legislation of the country in which the FM patient resides.

Autoimmune diseases and infections: controversial issues.

The etiology and pathogenesis of certain types of disease remain controversial and stand like a bridge that crosses infectious, autoimmune and autoinflammatory pathways. Infection, for example, may initiate a disease, although it is the genetic regulation in the host, the interplay between virus or bacteria persistence and autoimmunity that produces the later phases of disease, the antigenic determinants responsible for inducing autoimmune disease, and the pathogenetic effector mechanisms. Infections agents cause pericarditis, but in 85% of cases it is "idiopathic". It has also been shown that persistent Clamydia pneumoniae, Porphyromonas gingivalis, and Helicobacter pylori infections cause host immunity and promote atherogenesis. A number of infectious agents have been suggested as potential triggers for primary biliary cirrhosis. Infections and vaccinations have also been linked to the pathogenesis of fibromyalgia syndrome, a common, chronic syndrome of widespread pain. Many factors are also responsible for fever of unknown origin such as: infections, autoimmunity disease, etc. However, it is difficult to determine a direct correlation between the infections agents in such a large group of diseases. The aim of this review is to analyze some of the controversies about the role of infections in autoimmune diseases.

Fibromyalgia syndrome: definition and diagnostic aspects.

Ever since it was first defined, fibromyalgia (FM) has been considered one of the most controversial diagnoses in the field of rheumatology, to the point that not everybody accepts its existence as an independent entity. The sensitivity and specificity of the proposed diagnostic criteria are still debated by various specialists (not only rheumatologists), whose main criticism of the 1990 American College of Rheumatology criteria is that they identify subsets of particular patients that do not reflect everyday clinical reality. Furthermore, the symptoms characterising FM overlap with those of many other conditions classified in a different manner. Over the last few years, this has led to FM being considered less as a clinical entity and more as a possible manifestation of alterations in the psychoneuroendocrine system (the spectrum of affective disorders) or the stress reaction system (dysfunctional symptoms). More recently, doubts have been raised about even these classifications; and it now seems more appropriate to include FM among the central sensitisation syndromes, which identify the main pathogenetic mechanism as the cause of skeletal and extra-skeletal symptoms of FM and other previously defined "dysfunctional" syndromes.

Etiopathogenetic mechanisms of fibromyalgia syndrome.

Fibromyalgia syndrome (FMS) is a common chronic condition of widespread pain with causal mechanisms that are largely unknown. It is characterized by moderate to severe musculoskeletal pain and allodynia, but its pathogenesis appears confined to the nociceptive structures of the central nervous system. FMS is often triggered by negative environmental influences, especially if they occur in childhood. In a fetus, these environmental triggers may influence the development of the autonomic nervous system (ANS) and the hypothalamic-pituitary-adrenal axis (HPA). Increasing evidence supports the comorbidity of psychological conditions including depression, panic disorders, anxiety, and post-traumatic stress disorder (PTSD). Recent evidence suggests that genetic factors may play a role in the pathogenesis of FMS. Central sensitization has long been associated with FMS pain. It describes enhanced excitability of dorsal horn neurons, which leads to transmission of altered nociceptive information to the brain. Understanding of pathogenetic pathways in FMS has advanced beyond observing patient responses to neurophysiologically targeted therapies and basic research.

Non pharmacological treatments in fibromyalgia.

Fibromyalgia is a complex syndrome associated with significant impairment in quality of life and function and with substantial financial costs. Once the diagnosis is made, providers should aim to increase patients' function and minimize pain. Fibromyalgia patients frequently use alternative therapies, strongly indicating both their dissatisfaction with and the substantial ineffectiveness of traditional medical therapy, especially pharmacological treatments. At present, pharmacological treatments for fibromyalgia have a rather discouraging cost/benefit ratio in terms of poor symptom control and high incidence of side effects. The interdisciplinary treatment programs have been shown to improve subjective pain with greater success than monotherapy. Physical therapies, rehabilitation and alternative therapies are generally perceived to be more "natural," to have fewer adverse effects, and in some way, to be more effective. In this review, physical exercise and multimodal cognitive behavioural therapy are presented as the more accepted and beneficial forms of nonpharmacological therapy.

Symptoms and signs in fibromyalgia syndrome.

Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population. Chronic widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headaches, and mood disorders. The etiology of FM is not completely understood and the syndrome is influenced by factors such as stress, medical illness, and a variety of pain conditions. Establishing diagnosis may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. A unifying hypothesis is that FM results from sensitization of the central nervous system; this new concept could justify the variety of characteristics of the syndrome. FM symptoms can be musculoskeletal, non-musculoskeletal, or a combination of both; and many patients will also experience a host of associated symptoms or conditions. The ACR classification criteria focus only on pain and disregard other important symptoms; but three key features, pain, fatigue and sleep disturbance, are present in virtually every patient with FM. Several other associated syndromes, including circulatory, nervous, digestive, urinary and reproductive systems are probably a part of the so called central sensitivity or sensitization syndrome. A minority subgroup of patients (30-40%) has a significant psychological disturbance. Psychological factors are an important determinant of any type of pain, and psychological comorbidity is frequent in FM. Psychiatric disorders most commonly described are mood disorders, but psychiatric illness is not a necessary factor in the etiopathogenesis of FM.

Fibromyalgia syndrome: the pharmacological treatment options.

Pharmacological treatment has been gradually enriched by a variety of compounds; however, no single drug is capable of fully managing the constellation of fibromyalgia (FM) symptoms. Currently, it is not possible to draw definite conclusions concerning the best pharmacological approach to managing FM because results of randomized clinical trials present methodological limitations and therapeutic programs are too heterogeneous for adequate comparison. However, a variety of pharmacological treatments including antidepressants, nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, sedatives, muscle relaxants and antiepileptics have been used to treat FM with varying results. In this review, we will evaluate those pharmacological therapies that have produced the most significant clinical results in treating FM patients. The nature of FM suggests that an individualized, multimodal approach that includes both pharmacologic and nonpharmacologic therapies seems to be the most appropriate treatment strategy to date.

The evaluation of the fibromyalgia patients.

Fibromyalgia (FM) is a rheumatic disease characterized by musculoskeletal pain, chronic diffuse tension and/or stiffness in joints and muscles, easy fatigue, sleep and emotional disturbances, and pressure pain sensitivity in at least 11 of 18 tender points. At present, there are no instrumental tests or specific diagnostic markers for FM; in fact, many of the existing indicators are significant for research purposes only. Many differential diagnoses may be excluded by an extensive clinical examination and patient history. Considering overlap of FM with other medical conditions, the treating physicians should be vigilant: chest-X-rays and abdominal ultrasonography are the first steps of general evaluation for all the patients with suspected FM. Functional neuroimaging methods have revealed a large number of supraspinal effects in FM, a disorder mediated by mechanisms that are essentially unknown. Many treatments are used in FM patients, but evaluating their therapeutic effects in FM is difficult because the syndrome is so multifaceted. To address the identification of core outcome domains, the Initiative on IMMPACT and OMERACT workshop convened a meeting to develop consensus recommendations for chronic pain clinical trials.

EULAR evidence-based recommendations for the management of fibromyalgia syndrome.

OBJECTIVE: To develop evidence-based recommendations for the management of fibromyalgia syndrome. METHODS: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords "fibromyalgia", "treatment or management" and "trial". Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. RESULTS: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and "other pharmacological" and exercise, cognitive behavioural therapy, education, dietary interventions and "other non-pharmacological". In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. CONCLUSIONS: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.