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Predicting fibromyalgia, a narrative review: Are we better than fools and children?
Abstract
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.
... Tendo em vista a ampla gama de sintomas, fica clara a complexa fisiopatologia da FM e também que é improvável que ela tenha uma etiologia única. Nesse cenário, o fator genético parece ter um importante papel já que se sabe que algumas condições de dor crônica possuem origem multifatorial (Mogil, 2012;Ablin & Buskila, 2014) e que pacientes com FM, em especial, demonstram um padrão de agregação familiar, indicando que há uma predisposição genética nesses indivíduos (Clauw, 2014;Ablin & Buskila, 2015). Pacientes com FM têm uma probabilidade maior de possuírem parentes em primeiro grau com FM ou outras condições de dor crônica do que pessoas que não possuem essa condição (Arnold et al., 2004). ...
... Estudos de grandes coortes, realizados com gêmeos, sugerem que a probabilidade de um indivíduo desenvolver FM ou outras condições de dor crônica é cerca de 50% atribuída a fatores genéticos (Reichborn-Kjennerud et al., 2002;Kato et al., 2009;Markkula et al., 2009). Sabe-se também que diversos fatores genéticos são determinantes da maneira pela qual a dor é transmitida e processada pelo sistema nervoso (Ablin & Buskila, 2014). O presente artigo tem por objetivo realizar uma revisão narrativa da literatura sobre os aspectos genéticos da FM em seu desenvolvimento e gravidade dos sintomas. ...
... Genes implicados na via monoaminérgica têm sido amplamente investigados, tendo em vista o que já se avançou na compreensão da fisiopatologia da FM, especialmente no que diz respeito ao conceito da SC no processamento e transmissão da dor. Por isso, polimorfismos em genes relacionados a neurotransmissores e outros componentes que participam dessa via, agindo na modulação da dor como serotonina, norepinefrina, dopamina, entre outros, são frequentemente encontrados em estudos de associação genética com a FM (Lee et al., 2012;Ablin & Buskila, 2014;Zorina-Lichtenwalter et al., 2016). Porém, outros genes-alvo têm surgido, relacionados às vias responsáveis pelos mecanismos dos mais diversos sintomas que podem acometer esses pacientes, como inflamação, vascularização, estresse oxidativo, ciclo celular, entre outros (Karakus et al., 2012;Yigit et al., 2013;Inanir et al., 2015;da Silveira Alves et al., 2020;Estévez-López et al., 2021b). ...
A fibromialgia é uma desordem reumática que tem como principal sintoma a dor crônica generalizada acompanhada de um conjunto de sintomas como distúrbio do sono, depressão e fadiga crônica, entre outros. Sua fisiopatologia é complexa, de origem multifatorial, incluindo a influência de fatores genéticos. Já foi demonstrado que indivíduos com fibromialgia apresentam um padrão de agregação familiar e que a probabilidade de um indivíduo desenvolver essa condição é cerca de 50% atribuída a fatores genéticos. Neste sentido, o presente artigo tem por objetivo realizar uma revisão narrativa da literatura sobre os aspectos genéticos da fibromialgia em seu desenvolvimento e gravidade dos sintomas. Para tal foram feitas buscas nas bases de dados PubMed e Scopus, com a utilização de descritores específicos: “fibromyalgia” e “polymorphism”. Polimorfismos que influenciam na modulação da dor, como os que ocorrem em genes da via monoaminérgica ou do metabolismo das catecolaminas, são encontrados com frequência em estudos de associação com a fibromialgia. Porém, outros genes-alvo têm surgido, relacionados às vias responsáveis pelos mecanismos dos mais diversos sintomas que podem acometer esses pacientes, como neuroplasticidade, neurotransmissão, inflamação, vascularização, estresse oxidativo, ciclo celular, entre outros.
... Yoga, with its holistic approach, may be well-adapted to meet these criteria, and has shown promise in reducing pain and functional outcomes in both low back and FM pain. 1,[7][8][9][10][11][12][13][14] Most patients with FM also suffer from significant disturbances initiating or maintaining sleep, 15 and robust relationships are observed between pain severity and sleep disturbance in FM patients, 16 suggesting this to be an important aim for treatment strategy success. ...
... 9,32,33 These studies have shown a modest effect on reducing pain and disability, pain catastrophizing and acceptance, as well as cortisol, proinflammatory cytokines, and endorphin levels. 1,[7][8][9][10][11][12][13][14][34][35][36] Further analysis revealed the degree of benefit to be unequally distributed among participants, with some participants reporting more marked pain reduction. Specifically, pain reduction was inversely correlated with a greater amount of home practice, and most pronounced in those reporting greater than 25 mins of home practice on average. ...
... 11,38 Patients with sleep disturbance are more likely to develop chronic pain, and degree of sleep disturbance predicts severity of FM symptoms. 12,13 Epidemiologic surveys consistently report that the vast majority of patients with FM suffer from significant disturbances initiating or maintaining sleep, 15 and robust relationships are observed between pain severity and sleep disturbance in FM patients. 16 Our study indicated beneficial effects of yoga practice on sleep quality and subjective fatigue in patients with FM, similar to earlier studies. ...
Background
Fibromyalgia (FM) is a chronic widespread pain disorder characterized by negative affect, sleep disturbance, and fatigue. This uncontrolled pilot study investigated the efficacy of daily yoga-based exercise to improve FM symptoms and explored baseline phenotypic characteristics associated with the greatest benefit.
Methods
FM patients (n=46, with 36 completers) reported psychosocial functioning and a range of FM symptoms using validated instruments before and after participation in Satyananda yoga, which included weekly in-person pain-tailored group classes for 6 weeks and daily home yoga video practice.
Results
Changes in FM symptoms from pre- to post-yoga were variable amongst participants. Group means for pain decreased, as reported by average daily diary and Brief Pain Inventory, with greater home practice minutes associated with a greater decrease in pain. Average daily ratings of sleep and fatigue improved. Pain catastrophizing was decreased overall, with greater change correlated to a decrease in FM symptoms. We did not observe any group mean changes in actigraphy sleep efficiency, Patient-Reported Outcomes Measurement Information System-anxiety and the Revised Fibromyalgia Impact Questionnaire. Multilevel Modeling analysis revealed a significant interaction between anxiety and catastrophizing for end-study sleep efficiency, fatigue, and pain, such that patients with higher baseline catastrophizing and lower baseline anxiety reported less pain and fatigue, and higher sleep efficiency after the sixth week of yoga practice.
Conclusion
This pilot study suggests that yoga may reduce pain and catastrophizing, as well as improve sleep, but these changes were modest across study participants. Greater uptake of home yoga practice as well as a phenotype of higher baseline catastrophizing combined with lower baseline anxiety were associated with greater impact. Future randomized, controlled trials comparing different types of yoga or exercise will allow determination of the most effective treatments for FM and allow closer targeting to the patients who will benefit most from them.
... burden of FM is well recognized, resulting from reductions in patient function, productivity, and quality of life, as well as high health care resource utilization. [4][5][6][7][8] The 1990 American College of Rheumatology (ACR) classification criteria have long provided guidance for the diagnosis of FM based on the primary criteria of widespread pain and a manual tender-point exam for demonstrating the presence of tenderness at a minimum of 11 of 18 specified points. These criteria were updated in 2010 by adding a symptom-severity assessment and eliminating the tenderpoint exam. ...
... 5 A recent narrative review of biologic markers further highlighted the need for such identification, since while several markers can be considered suggestive of FM, none has unequivocally been shown to be a clinically useful predictor of developing this condition. 6 Another relevant approach is to identify variables associated with an FM diagnosis, which can be used to inform health care providers of patients in the clinical setting who have a high likelihood of FM, thus reducing the diagnostic delay and facilitating earlier treatment initiation. To identify such variables, it may be necessary to go beyond the demographic and clinical characteristics that have been evaluated based on their ready availability in databases that are frequently used for these types of analyses. ...
Background
Diagnosis of fibromyalgia (FM) is often challenging. Identifying factors associated with an FM diagnosis may guide health care providers in implementing appropriate diagnostic and management strategies.
Methods
This retrospective study used the de-identified Humedica electronic medical record (EMR) database to identify variables associated with an FM diagnosis. Cases (n=4,296) were subjects ≥18 years old with ≥2 International Classification of Diseases, Ninth Revision (ICD-9) codes for FM (729.1) ≥30 days apart during 2012, associated with an integrated delivery network, with ≥1 encounter with a health care provider in 2011 and 2012. Controls without FM (no-FM; n=583,665) did not have the ICD-9 codes for FM. Demographic, clinical, and health care resource utilization variables were extracted from structured EMR data. Univariate analysis identified variables showing significant differences between the cohorts based on odds ratios (ORs).
Results
Consistent with FM epidemiology, FM subjects were predominantly female (78.7% vs 64.5%; P<0.0001) and slightly older (mean age 53.3 vs 52.7 years; P=0.0318). Relative to the no-FM cohort, the FM cohort was characterized by a higher prevalence of nearly all evaluated comorbidities; the ORs suggested a higher likelihood of an FM diagnosis (P<0.0001), especially for musculoskeletal and neuropathic pain conditions (OR 3.1 for each condition). Variables potentially associated with an FM diagnosis included higher levels of use of specific health care resources including emergency-room visits, outpatient visits, hospitalizations, and medications. Units used per subject for emergency-room visits, outpatient visits, hospitalizations, and medications were also significantly higher in the FM cohort (P<0.0001), confirming resource utilization as an important variable associated with an FM diagnosis.
Conclusion
Significant differences between the FM and no-FM cohorts were observed for nearly all the demographic, clinical, and health care resource variables, suggesting an association with FM diagnosis. These results also support use of EMR data for identifying variables associated with FM, which may help in the diagnosis and management of this condition.
... Various risk factors contribute to the onset of fibromyalgia as well. The clear predominance in favour of the female sex is well-known, along with associations with potential triggers such as early psychological trauma or joint hypermobility (Ablin & Buskila, 2014;Yunus, 2001). ...
Background
Geographic origin may represent a variable capable of influencing health status. This study aims to investigate the presence of differences of disease severity in Italian patients with fibromyalgia from different macro‐regions.
Methods
This retrospective, cross‐sectional study involved patients included in the Italian Fibromyalgia Registry. Three geographical macro‐regions were identified, comprising patients from Northern Italy, Central Italy and Southern Italy. Clinical differences (evaluated through PolySymptomatic Distress Scale [PSD], revised Fibromyalgia Impact Questionnaire [FIQR] and modified Fibromyalgia Assessment Status [FASmod]) among the geographical macro‐regions were studied using one‐way analysis of variance (ANOVA) and the Scheffé's test.
Results
A total of 6095 patients (5719 females and 376 males) were included, with 1957 from Northern Italy, 2979 from Central Italy and 1159 from Southern Italy. All studied clinical indices showed a trend indicative of greater disease severity in Southern Italy, followed by Northern Italy and then Central Italy (mean values for PSD: 19.97 ± 6.20 in Northern Italy, 18.61 ± 7.12 in Central Italy, 23.01 ± 5.66 in Souther Italy). These differences were statistically significant for the overall scores of all studied indices, evaluated with ANOVA (all p < 0.001) and in the head to head comparisons, evaluted with Scheffé's test.
Conclusions
Geographic background is significantly associated with variations in the severity of fibromyalgia in Italian patients.
Significance Statement
This is the first study to demonstrate geographical origin‐dependent intra‐national differences in the severity of fibromyalgia. The results confirm the necessity of considering fibromyalgia within the context of the biopsychosocial model and of implementing healthcare policies targeted towards the most underserved regions.
... Cedraschi et al. [36] identify that there are probably numerous distressing events that can have this effect, and many narratives talk of a cascade of disruptive events, suggesting an increasing loss of control. Ablin and Buskila [37] discuss the impact of stressful events, such as early life trauma. Sallinen, Kukkurainen, and Peltokallio [38] reported that the onset of FM was perceived as the result of suffering from violence but that this violence is often still hidden behind a wall of silence. ...
Fibromyalgia patients experience difficulties in their daily lives that are difficult to identify and recognize due to the stigma associated with the disease. Nurses can help identify them to establish biopsychosocial coping and treatment. The main aim of this study was to explore Spanish nurses’ perceptions of the illness experiences of their fibromyalgia patients. Qualitative content analysis from the etic perspective was used. Eight nurses met in focus groups to report their perceptions of the illness experiences of FM patients after led group-based problem-solving therapy in fibromyalgia patients. Four themes emerged: (1) the presence of a “specific trigger” (stressful event) for FM symptoms; (2) fulfilling expected gender roles; (3) a lack of support from the family; (4) abuse. Nurses recognize the mind–body connection after the impact of stress on patients’ bodies. The expected gender roles interfere with patients’ recovery because they feel frustration and guilt about not being able to fulfil them. Managing emotions and improving communication in fibromyalgia is recommended. Clinicians might also consider issues such as abuse and the absence of social–family support for the comprehensive evaluation and effective management of fibromyalgia.
... Constatou ainda que um volume de doentes igualmente significativo praticava homeopatia, tomava suplementos dietéticos, ou fazia acupunctura ou meditação, como yoga ou tai chi (Langhorst, Hauser, et al., 2014). Os tratamentos SPA, desde há muito conhecidos e praticados em vastas zonas do globo, com uma rica história cultural, são igualmente reconhecidos como parte integrante dos recursos terapêuticos para doentes com fibromialgia (Ablin & Buskila, 2014;Ablin, Häuser, & Buskila, 2013). No mesmo sentido, a balneoterapia e a hidroterapia assumem valor potencial no tratamento suplementar dos principais sintomas (Naumann & Sadaghiani, 2014). ...
... neurological, genitourinary, throat problems and gastrointestinal. Each of these domains were predominantly driven by pain-based risk factors (via inspection of the frequency of Read codes used), with three of these risk factors (headaches, cystitis and abdominal pain) being also widely associated with pain syndromes [1,12,67]. Single site musculoskeletal pain appears to be capable of triggering widespread pain [26,36,52,64], however our data also suggests that pain triggers may not be limited to just musculoskeletal pain. It may be that pain pathways of the CWP patient develop early, consequently early interventions focused on the management of pain and the consequences of pain may help prevent the development of CWP. ...
A significant proportion of children/adolescents report Chronic Widespread Pain (CWP), but little is known about clinically relevant CWP or what factors lead to onset in this population. Objectives were to report the primary care consultation prevalence of CWP, and investigate risk factors associated with onset. A validated algorithm for identifying CWP status from primary care electronic healthcare records, was applied to a child/adolescent population (aged 8 to 18 years). The algorithm records patients who have recurrent pain consultations (axial skeleton and upper or lower limbs), or those with a non-specific generalised pain disorder (e.g. fibromyalgia). Prevalence was described, and a nested case-control study established to identify risk factors associated with CWP onset using logistic regression producing Odds Ratios (OR) and 95% Confidence Intervals (95%CI). 271 children/adolescents were identified with CWP, resulting in a five-year consultation prevalence of 3.19%. Risk factors significantly associated with CWP onset were; mental health (e.g. anxiety/neurosis consultations), neurological (e.g. headaches), genitourinary (e.g. cystitis), gastrointestinal (e.g. abdominal pain) and throat problems (e.g. sore throats). Children/adolescents with one or two risk factors (OR 2.15, 95% CI 1.6 to 2.9) or three or more risk factors (OR 9.17, 95% CI 5.9 to 14.3) were at significantly increased odds of CWP onset compared to those with none. Findings show a significant proportion of the child/adolescent primary care population have CWP. The majority of risk factors involved pain-related conditions, suggesting potential pathways of pain development. Further work is now needed to better understand the development of CWP in children and adolescents.
... 1. Cierta vulnerabilidad genética (Ablin & Buskila, 2014;Crofford, 2013;Saldívar et al., 2010 A pesar de los avances tecnológicos, las nuevas investigaciones y la existencia de un gran número de publicaciones con respecto a su proceso etiopatogénico, todavía no se establece un consenso con respecto a la enfermedad (Simon, 2014;Saldívar et al., 2010;Aroca et al., 2010;Restrepo et al., 2009), cuestionándose incluso el que pueda ser una enfermedad en sí misma o si es, en realidad, un conjunto de síntomas (es decir, un síndrome) correspondiente a enfermedades reumatológicas, neurológicas o inmunológicas (Peñacoba, 2009;Viana, 2009). ...
RESUMEN Introducción: El componente psicológico continúa generando suspicacia a la hora de realizarse un diagnóstico. Una muestra de eso es la fibromialgia, proceso reumático crónico que afecta el aparato locomotor y las partes blandas del cuerpo, que se caracteriza por un estado doloroso persistente sin etiología conocida. Esto obliga al profesional de la salud a trabajar a nivel de diagnóstico diferencial y descarte, deteriorándose severamente la calidad de vida de las personas que la padecen. Objetivo: Sistematizar la información obtenida sobre resultados de investigación sobre factores psicológicos que forman parte del proceso salud-enfermedad en Fibromialgia. Método: Se realiza una revisión bibliográfica de investigaciones realizadas en el área entre los años 2003 y 2014 y publicadas online en idioma español. Resultados: Se comprobó una prevalencia de la función evaluativa-diagnostica y en un considerable menor porcentaje la de intervención. Conclusiones: se constata la inexistencia de una comprensión psicológica integrativa, evidenciando la necesidad de seguir explorando los diversos componentes que dan forma a la compleja FM, enfermedad que requiere de una comprensión mucho más integral para ahondar en el desarrollo, mantención y abordaje de su expresión sintomática. ABSTRACT Introduction: When undergoing a diagnosis, it is well known that psychological factors have a negative effect on a patient's perceptions of their diagnosis, especially if the diagnosis is fibromyalgia. This disorder is characterized by issues to the musculoskeletal system accompanied by pain, fatigue, mood swings, sleep and memory disorders. Because the origin of fibromyalgia is still unclear, the physician is forced to make a diagnosis based on trial and error, thus deteriorating fibromyalgia patients' life quality severely. Objective: To systematize research results on psychological factors involved in the fibromyalgia health-illness process. Method: A literature review of the topic was done based on online papers published in Spanish between 2003 and 2014. Results: The reviews showed a higher preference for evaluation-diagnosis over an intervention approach. Conclusion: The absence of an integrative psychological understanding was found, demonstrating the need to further explore the various components that shape the complex disease of FM. It requires a much more comprehensive understanding to deepen the development to address patients' symptoms.
... The need to identify FM predictors was further emphasized in a recent narrative review of predictive FM studies. 21 The review discussed the association of FM with potential biological markers and clinical characteristics, but also highlighted the complexity of determining the importance of these variables as predictors, suggesting that additional studies or new approaches may be needed. ...
Background: Diagnosis of fibromyalgia (FM), a chronic musculoskeletal condition characterized by widespread pain and a constellation of symptoms, remains challenging and is often delayed. Methods: Random forest modeling of electronic medical records was used to identify variables that may facilitate earlier FM identification and diagnosis. Subjects aged ≥18 years with two or more listings of the International Classification of Diseases, Ninth Revision, (ICD-9) code for FM (ICD-9 729.1) ≥30 days apart during the 2012 calendar year were defined as cases among subjects associated with an integrated delivery network and who had one or more health care provider encounter in the Humedica database in calendar years 2011 and 2012. Controls were without the FM ICD-9 codes. Seventy-two demographic, clinical, and health care resource utilization variables were entered into a random forest model with downsampling to account for cohort imbalances (<1% subjects had FM). Importance of the top ten variables was ranked based on normalization to 100% for the variable with the largest loss in predicting performance by its omission from the model. Since random forest is a complex prediction method, a set of simple rules was derived to help understand what factors drive individual predictions. Results: The ten variables identified by the model were: number of visits where laboratory/non-imaging diagnostic tests were ordered; number of outpatient visits excluding office visits; age; number of office visits; number of opioid prescriptions; number of medications prescribed; number of pain medications excluding opioids; number of medications administered/ordered; number of emergency room visits; and number of musculoskeletal conditions. A receiver operating characteristic curve confirmed the model's predictive accuracy using an independent test set (area under the curve, 0.810). To enhance interpretability, nine rules were developed that could be used with good predictive probability of an FM diagnosis and to identify no-FM subjects. Conclusion: Random forest modeling may help to quantify the predictive probability of an FM diagnosis. Rules can be developed to simplify interpretability. Further validation of these models may facilitate earlier diagnosis and enhance management.
... Movement in these patients may represent hypermobility, a potentially damaging extension beyond the normal range of motion. Hypermobility may be a risk factor for developing pain (Ablin and Buskila 2014) or exacerbating pain (Hasenbring et al. 2012). In the case of physical pain, patients exhibit hypermobility when they overextend a limb. ...
There may be important similarities between chronic emotional pain and chronic physical pain. Both forms of chronic pain may promote negative beliefs about the self and the future. Chronic emotional pain and chronic physical pain both serve to disrupt patients’ focus from their actions and goals. Techniques used for the treatment of physical pain may be translated into the treatment of emotional pain. Four core strategies are reviewed including: (1) reducing catastrophic interpretations, (2) increasing tolerance by promoting acceptance, (3) cultivating positive expectations, and (4) remaining flexible in movements and attitudes. Patients can learn to tolerate limitations while pursuing their goals. Clinicians can help patients to reduce emotional pain by making a series of small changes in their thoughts and behavior.
... The need to identify FM predictors was further emphasized in a recent narrative review of predictive FM studies. 21 The review discussed the association of FM with potential biological markers and clinical characteristics, but also highlighted the complexity of determining the importance of these variables as predictors, suggesting that additional studies or new approaches may be needed. ...
Background
Diagnosis of fibromyalgia (FM), a chronic musculoskeletal condition characterized by widespread pain and a constellation of symptoms, remains challenging and is often delayed.
Methods
Random forest modeling of electronic medical records was used to identify variables that may facilitate earlier FM identification and diagnosis. Subjects aged ≥18 years with two or more listings of the International Classification of Diseases, Ninth Revision, (ICD-9) code for FM (ICD-9 729.1) ≥30 days apart during the 2012 calendar year were defined as cases among subjects associated with an integrated delivery network and who had one or more health care provider encounter in the Humedica database in calendar years 2011 and 2012. Controls were without the FM ICD-9 codes. Seventy-two demographic, clinical, and health care resource utilization variables were entered into a random forest model with downsampling to account for cohort imbalances (<1% subjects had FM). Importance of the top ten variables was ranked based on normalization to 100% for the variable with the largest loss in predicting performance by its omission from the model. Since random forest is a complex prediction method, a set of simple rules was derived to help understand what factors drive individual predictions.
Results
The ten variables identified by the model were: number of visits where laboratory/non-imaging diagnostic tests were ordered; number of outpatient visits excluding office visits; age; number of office visits; number of opioid prescriptions; number of medications prescribed; number of pain medications excluding opioids; number of medications administered/ordered; number of emergency room visits; and number of musculoskeletal conditions. A receiver operating characteristic curve confirmed the model’s predictive accuracy using an independent test set (area under the curve, 0.810). To enhance interpretability, nine rules were developed that could be used with good predictive probability of an FM diagnosis and to identify no-FM subjects.
Conclusion
Random forest modeling may help to quantify the predictive probability of an FM diagnosis. Rules can be developed to simplify interpretability. Further validation of these models may facilitate earlier diagnosis and enhance management.
Rheumatic diseases (RD) are often diagnosed in childhood. Sleep disorders are commonly associated with RD in children. It is stressed that sleep disorders found in this type of clinical pathology cannot be exceptionally considered as an epiphenomenon typical to any form of chronic disease; rather, sleep disorders should be regarded as a part of the clinical manifestations of RD. An important role in the origins of this association is played by specific inflammatory mediators involved in the pathogenesis of various RD, which simultaneously affect the structure of sleep and contribute to sleep disorders. There are both nonspecific and characteristic variants of sleep disorders detected in some leading clinical forms of RD in children, in particular in juvenile rheumatoid (idiopathic) arthritis, systemic lupus erythematosus, systemic scleroderma, seronegative spondyloarthropathies, fibromyalgia. There is a relationship between the severity of sleep disorders, the activity of RD, the degree of emotional disorders and pain symptoms in children. Approaches to the correction of sleep disorders in children in the context of the treatment of RD are substantiated.
FM is a chronic pain disorder which manifests with chronic widespread pain, accompanied by fatigue and mood and sleep disorders. The current concept views FM as the consequence of central nervous system malfunction resulting in amplification of pain transmission and interpretation. Our understanding of fibromyalgia has made significant advances over the past decade, still despite extensive research this disease’s clear etiology and pathophysiology is yet to be discovered. Current knowledge indicates several triggers and possible etiologies to the development of FM. Past research has demonstrated a role for polymorphisms of genes with clear familial aggregation and genetic underpinning in the etiopathogenesis of FM. Furthermore, the role of stressful events has been well established in the literature, depicting either mechanical stress as injury or psychological stress including early life trauma as trigger and predisposition for future development of FM. Not only recent studies exhibited development of FM in the workplace in correlation with stress, low work performance, and even posttraumatic stress disorder (PTSD). Moreover, it is known that other various external stimuli such as infections or vaccinations may contribute to the development of the FM syndrome.
Frequent headache and juvenile fibromyalgia (JFM) are common conditions observed in childhood and adolescents. They can present in isolation or as comorbid conditions. There is no scientific literature investigating this association in adolescents or childhood. There is evidence in adults that headache, particularly migraine, can be a potential risk factor for developing fibromyalgia (FMS) and that migraine can be also a comorbid and perpetuating factor of FMS. Comorbidity between these two conditions can lead to increased levels of sensitization of the central nervous system and limit therapeutic approaches. Additionally, the presence of comorbid FMS and migraine is associated with worse clinical presentation and higher psychological disturbances. Early identification of risk factors for development of this comorbid association seems to be a challenge for pediatric clinicians.
Aim:
To identify the main biological, psychological and sociological problems and potential solutions for patients diagnosed with fibromyalgia by use of Group Problem-Solving Therapy.
Background:
Group Problem-Solving Therapy is a technique for identifying and solving problems, increasing assertiveness, self-esteem and eliminating negative thoughts.
Design:
Qualitative phenomenological interpretive design: Group Problem-Solving Therapy sessions conducted with patients suffering fibromyalgia were studied; participants recruited via the Rheumatology Department at a general hospital and associations in Catalonia, Spain with sessions conducted in nearby university setting.
Methods:
The study included 44 people diagnosed with fibromyalgia (43 female, 1 male) from 6 Group Problem-Solving Therapy sessions. Data collected from March-June 2013. A total of 24 sessions were audio recorded, all with prior informed consent. Data were transcribed and then analysed in accordance with established methods of inductive thematic analysis, via a process of reduction to manage and classify data.
Findings:
Five themes were identified: (1) Current problems are often related to historic trauma; (2) There are no 'one size fits all' solutions; (3) Fibromyalgia is life-changing; (4) Fibromyalgia is widely misunderstood; (5) Significant impacts on physical, psychological and social are described.
Conclusion:
The majority of patients' problems were associated with their previous history and the onset of fibromyalgia; which may be related to trauma in adolescence, early adulthood or later. The solutions provided during the groups appeared to be accepted by the participants. These findings can improve the self-management of fibromyalgia patients by helping to enhance adaptive behaviours and incorporating the female gender approach. This article is protected by copyright. All rights reserved.
Sleep is an important regulator of growth, metabolism, tissue repair, cell division, endocrine segregation, and immunologic functions. Therefore, many medical disorders are affected by sleep dysfunctions and impact upon sleep quality.
During the first two decades, sleep duration, sleep timing, and sleep characteristics are of utmost importance to an adequate children development being crucial for physical, mental, emotional, and behavioral equilibrium.
A number of medical conditions may give rise to sleep disturbances: asthma and allergies, hematologic diseases, metabolic disorders and obesity, gastrointestinal disorders, including colic and gastroesophageal reflux, chronic pain syndromes, cystic fibrosis, and other orphan genetic diseases.
Central sensitization (CS), simply defined as an amplified response of the central nervous system to peripheral input, is a concept of great importance in clinical medicine. It has helped to explain aspects of the pathophysiology of common diseases, e.g. fibromyalgia syndrome (FMS), irritable bowel syndrome, vulvodynia, headaches, chronic pelvic pain and other overlapping conditions (collectively called central sensitivity syndromes, or CSS). It also applies to pain of complex regional pain syndrome, osteoarthritis (OA), rheumatoid arthritis (RA) and post-operative pain. The pathology-pain gap in CSS is readily explained by CS. Many FMS and other CSS patients have peripheral pathology, e.g. nociceptive areas in the muscles, arthritis, small fiber neuropathy and inflammation. Pro-inflammatory cytokines are elevated in some patients. Identification of CS in patients with structural pathology, e.g. OA and RA, has helped to explain why not all patients benefit from nonsteroidal anti-inflammatory drugs or joint replacement surgery, and require therapy directed at CS. Glial cells are important in pain processing. Remarkable advances have been achieved in neuroimaging, including visualization of grey matter and white matter, not only during provoked pain but also pain at rest. Based on CS mechanisms, targeted individual therapy may now be possible. Appropriate nosology is important particularly for effective patient care. Dichotomy of neurochemical-structural ("functional") and structural ("organic") pathology should be abandoned; many patients have both. Psychobiology is also biology. Patient-blaming terms like somatization, somatizer and catastrophizing should be avoided. For therapy, both pharmacological and non- pharmacological approaches are important, including recognition of subgroups and person/patient-centered care.
Neural mechanisms mediating the transition from acute to chronic pain remain largely unknown. In a longitudinal brain imaging study, we followed up patients with a single sub-acute back pain (SBP) episode for more than 1year as their pain recovered (SBPr), or persisted (SBPp) representing a transition to chronic pain. We discovered brain white matter structural abnormalities (n=24 SBP patients; SBPp=12 and SBPr=12), as measured by diffusion tensor imaging (DTI), at entry into the study in SBPp in comparison to SBPr. These white matter fractional anisotropy (FA) differences accurately predicted pain persistence over the next year, which was validated in a second cohort (n=22 SBP patients; SBPp=11 and SBPr=11), and showed no further alterations over a 1-year period. Tractography analysis indicated that abnormal regional FA was linked to differential structural connectivity to medial vs lateral prefrontal cortex. Local FA was correlated with functional connectivity between medial prefrontal cortex and nucleus accumbens in SBPr. As we have earlier shown that the latter functional connectivity accurately predicts transition to chronic pain, we can conclude that brain structural differences, most likely existing before the back pain-inciting event and independent of the back pain, predispose subjects to pain chronification.
To characterise levels of objectively measured sedentary time and physical activity in women with fibromyalgia.
Cross-sectional study.
Local Association of Fibromyalgia (Granada, Spain).
The study comprised 94 women with diagnosed fibromyalgia who did not have other severe somatic or psychiatric disorders, or other diseases that prevent physical loading, able to ambulate and to communicate and capable and willing to provide informed consent.
Sedentary time and physical activity were measured by accelerometry and expressed as time spent in sedentary behaviours, average physical activity intensity (counts/minute) and amount of time (minutes/day) spent in moderate intensity and in moderate-to-vigorous-intensity physical activity (MVPA).
The proportion of women meeting the physical activity recommendations of 30 min/day of MVPA on 5 or more days a week was 60.6%. Women spent, on average, 71% of their waking time (approximately 10 h/day) in sedentary behaviours. Both sedentary behaviour and physical activity levels were similar across age groups, waist circumference and percentage body fat categories, years since clinical diagnosis, marital status, educational level and occupational status, regardless of the severity of the disease (all p>0.1). Time spent on moderate-intensity physical activity and MVPA was, however, lower in those with greater body mass index (BMI) (-6.6 min and -7 min, respectively, per BMI category increase, <25, 25-30, >30 kg/m(2); p values for trend were 0.056 and 0.051, respectively). Women spent, on average, 10 min less on MVPA (p<0.001) and 22 min less on sedentary behaviours during weekends compared with weekdays (p=0.051).
These data provide an objective measure of the amount of time spent on sedentary activities and on physical activity in women with fibromyalgia.
Export Date: 21 June 2013, Source: Scopus, Art. No.: e002722
Fibromyalgia (FM) is a chronic disorder characterized by widespread, persistent pain. Prospective and retrospective studies have demonstrated substantial health-care costs associated with FM in a number of countries. This study evaluated and compared health-resource use (HRU) and associated costs related to FM in routine clinical practice across the US, France, and Germany.
Two separate, cross-sectional, observational studies of subjects with FM were conducted: one in the US and one in France and Germany. HRU related to prescription medication, physician office visits, diagnostic tests, and hospitalizations was abstracted from chart review; patient out-of-pocket costs and lost productivity were collected via subject self-report. Costs were assigned to HRU based on standard algorithms. Direct and indirect costs were evaluated and compared by simple linear regression.
A total of 442 subjects (203 US, 70 France, 169 Germany) with FM were analyzed. The mean (standard deviation) age in the US, France, and Germany was 47.9 (10.9), 51.2 (9.5), and 49.2 (9.8), respectively (P = 0.085). Most subjects were female (95% US, 83% France, 80% Germany) (P < 0.001). Adjusted annual direct costs per subject for FM were significantly higher in the US (481, P < 0.001) or Germany (6431) than in France (10,001), but represented a significant proportion of total costs in all countries.
The significant HRU and costs associated with FM in the US, France, and Germany documented in this study highlight the substantial global economic burden of FM. Indirect costs represented a significant proportion of the total costs, particularly in Europe. Comparisons between the three countries show differences in HRU, with significantly higher direct costs in the US compared with France and Germany.
The mechanism of brain reorganization in pain chronification is unknown. In a longitudinal brain imaging study, subacute back pain (SBP) patients were followed over the course of 1 year. When pain persisted (SBPp, in contrast to recovering SBP and healthy controls), brain gray matter density decreased. Initially greater functional connectivity of nucleus accumbens with prefrontal cortex predicted pain persistence, implying that corticostriatal circuitry is causally involved in the transition from acute to chronic pain.
Sleep problems are common among patients with fibromyalgia (FM). However, it is not known whether poor sleep is a contributing factor in FM or a consequence of the illness. The aim of the current study was to prospectively investigate the association between self-reported sleep problems and risk of FM among adult women.
We longitudinally studied 12,350 women who did not have FM, musculoskeletal pain, or physical impairments at baseline (1984-1986). A generalized linear model was used to calculate the adjusted relative risk (RR) of FM at followup in 1995-1997.
Incident FM was reported by 327 women at followup. A dose-dependent association was found between sleep problems and risk of FM (P for trend<0.001), with an adjusted RR of 3.43 (95% confidence interval [95% CI] 2.26-5.19) among women who reported having sleep problems often or always, compared to women who never experienced sleep problems. Age-stratified analysis showed that women age≥45 years who reported having sleep problems often or always had an adjusted RR of 5.41 (95% CI 2.65-11.05), whereas the corresponding RR for women ages 20-44 years who reported having sleep problems often or always was 2.98 (95% CI 1.76-5.05).
These prospective data indicate a strong dose-dependent association between sleep problems and risk of FM. The association is somewhat, although not significantly, stronger in middle-aged and older women than in younger women.
Pain sensitivity varies substantially among humans. A significant part of the human population develops chronic pain conditions that are characterized by heightened pain sensitivity. We identified three genetic variants (haplotypes) of the gene encoding catecholamine-O-methyltransferase (COMT) that we designated as low pain sensitivity (LPS), average pain sensitivity (APS) and high pain sensitivity (HPS). We show that these haplotypes encompass 96% of the human population, and five combinations of these haplotypes are strongly associated (P=0.0004) with variation in the sensitivity to experimental pain. The presence of even a single LPS haplotype diminishes, by as much as 2.3 times, the risk of developing myogenous temporomandibular joint disorder (TMD), a common musculoskeletal pain condition. The LPS haplotype produces much higher levels of COMT enzymatic activity when compared with the APS or HPS haplotypes. Inhibition of COMT in the rat results in a profound increase in pain sensitivity. Thus, COMT activity substantially influences pain sensitivity, and the three major haplotypes determine COMT activity in humans that inversely correlates with pain sensitivity and the risk of developing TMD.
Fibromyalgia is a chronic disorder of uncertain etiology, characterized by widespread pain, muscle tenderness, and decreased pain threshold to pressure and other stimuli. Obesity is a well-known aggravating factor for certain rheumatologic conditions, such as knee osteoarthritis. Emerging evidences are exploring the link between obesity and other rheumatic diseases, such as fibromyalgia. Epidemiological data show that fibromyalgia patients have higher prevalence of obesity (40%) and overweight (30%) in multiple studies compared with healthy patients. Several mechanisms have been proposed to explain "the hidden link", but at this time is not possible to ascertain whether obesity is cause or consequence of fibromyalgia. Among mechanisms proposed, there are the following: impaired physical activity, cognitive and sleep disturbances, psychiatric comorbidity and depression, dysfunction of thyroid gland, dysfunction of the GH/IGF-1 axis, impairment of the endogenous opioid system. In this article, we review the scientific evidence supporting a possible link between obesity and fibromyalgia, how obesity influences fibromyalgia symptoms and how fibromyalgia severity can be improved by weight loss. In addition, we analyze the possible mechanisms by which fibromyalgia and obesity interrelate.
Background:
Variation in the serotonin transporter (5-HTT) gene (SLC6A4) has been shown to influence a wide range of affective processes. Low 5-HTT gene-expression has also been suggested to increase the risk of chronic pain. Conditioned pain modulation (CPM)--i.e. 'pain inhibits pain'--is impaired in chronic pain states and, reciprocally, aberrations of CPM may predict the development of chronic pain. Therefore we hypothesized that a common variation in the SLC6A4 is associated with inter-individual variation in CPM. Forty-five healthy subjects recruited on the basis of tri-allelic 5-HTTLPR genotype, with inferred high or low 5-HTT-expression, were included in a double-blind study. A submaximal-effort tourniquet test was used to provide a standardized degree of conditioning ischemic pain. Individualized noxious heat and pressure pain thresholds (PPTs) were used as subjective test-modalities and the nociceptive flexion reflex (NFR) was used to provide an objective neurophysiological window into spinal processing.
Results:
The low, as compared to the high, 5-HTT-expressing group exhibited significantly reduced CPM-mediated pain inhibition for PPTs (p = 0.02) and heat-pain (p = 0.02). The CPM-mediated inhibition of the NFR, gauged by increases in NFR-threshold, did not differ significantly between groups (p = 0.75). Inhibition of PPTs and heat-pain were correlated (Spearman's rho = 0.35, p = 0.02), whereas the NFR-threshold increase was not significantly correlated with degree of inhibition of these subjectively reported modalities.
Conclusions:
Our results demonstrate the involvement of the tri-allelic 5-HTTLPR genotype in explaining clinically relevant inter-individual differences in pain perception and regulation. Our results also illustrate that shifts in NFR-thresholds do not necessarily correlate to the modulation of experienced pain. We discuss various possible mechanisms underlying these findings and suggest a role of regulation of 5-HT receptors along the neuraxis as a function of differential 5-HTT-expression.
AIM: The main aim of this study was to assess if the perception of thermal pain thresholds is associated with genetically inferred levels of expression of the 5-HT transporter (5-HTT). Additionally, the perception of the so-called thermal grill illusion (TGI) was assessed. Forty-four healthy individuals (27 females, 17 males) were selected a-priori based on their 5-HTTLPR/rs25531 ('tri-allelic 5-HTTLPR') genotype, with inferred high or low 5-HTT expression. Thresholds for heat- and cold-pain were determined along with the sensory and affective dimensions of the TGI. RESULTS: Thresholds to heat- and cold-pain correlated strongly (rho = -0.58, p
Migraine is a common episodic neurological disorder, typically presenting with recurrent attacks of severe headache and autonomic dysfunction. Apart from rare monogenic subtypes, no genetic or molecular markers for migraine have been convincingly established. We identified the minor allele of rs1835740 on chromosome 8q22.1 to be associated with migraine (P = 5.38 × 10⁻⁹, odds ratio = 1.23, 95% CI 1.150-1.324) in a genome-wide association study of 2,731 migraine cases ascertained from three European headache clinics and 10,747 population-matched controls. The association was replicated in 3,202 cases and 40,062 controls for an overall meta-analysis P value of 1.69 × 10⁻¹¹ (odds ratio = 1.18, 95% CI 1.127-1.244). rs1835740 is located between MTDH (astrocyte elevated gene 1, also known as AEG-1) and PGCP (encoding plasma glutamate carboxypeptidase). In an expression quantitative trait study in lymphoblastoid cell lines, transcript levels of the MTDH were found to have a significant correlation to rs1835740 (P = 3.96 × 10⁻⁵, permuted threshold for genome-wide significance 7.7 × 10⁻⁵. To our knowledge, our data establish rs1835740 as the first genetic risk factor for migraine.
To systematically assess the potential association of fibromyalgia syndrome (FMS) with emotional, physical, and sexual abuse.
The databases EMBase, Google Scholar, Medline, and PsycINFO (through April 2010) and the reference sections of original studies were searched for eligible studies. Eligible studies were cohort or case--control studies that assessed at least one type of emotional, physical, or sexual abuse in childhood or adulthood in patients with FMS and in controls. Two authors independently extracted descriptive, quality, and outcome data from included studies. Methodologic quality was assessed by the Newcastle-Ottawa Quality Assessment Scale. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were pooled across studies by using the random-effects model. Heterogeneity was assessed by I(2) statistics.
The search identified 18 eligible case-control studies with 13,095 subjects. There were significant associations between FMS and self-reported physical abuse in childhood (OR 2.49 [95% CI 1.81-3.42], I(2) = 0%; 9 studies) and adulthood (OR 3.07 [95% CI 1.01-9.39], I(2) = 79%; 3 studies), and sexual abuse in childhood (OR 1.94 [95% CI 1.36-2.75], I(2) = 20%; 10 studies) and adulthood (OR 2.24 [95% CI 1.07-4.70], I(2) = 64%; 4 studies). Study quality was mostly poor. Low study quality was associated with higher effect sizes for sexual abuse in childhood, but not with other effect sizes.
The association of FMS with physical and sexual abuse could be confirmed, but is confounded by study quality.
Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.
Genetic risk factors for pain sensitivity may also play a role in susceptibility to chronic pain disorders, in which subjects have low pain thresholds. The aim of this study was to determine if proposed functional single nucleotide polymorphisms (SNPs) in the GTP cyclohydrolase (GCH1) and mu opioid receptor (OPRM1) genes previously associated with pain sensitivity affect susceptibility to chronic widespread pain (CWP). Pain data was collected using body manikins via questionnaire at three time-points over a four year period from subjects aged 25-65 in the North-West of England as part of a population based cohort study, EPIFUND. CWP was defined at each time point using standard criteria. Three SNPs forming a proposed "pain-protective" haplotype in GCH1 (rs10483639, rs3783641 and rs8007267) and two SNPs in OPRM1 (rs1777971 (A118G) and rs563649) were genotyped in cases with persistent CWP (CWP present at >or=2 time-points) and controls who were pain-free at all time-points. The expectation-maximisation algorithm was used to estimate haplotype frequencies. The frequency of the "pain-protective" (CAT - C allele of rs10483639, A allele of rs3783641 and T allele of rs8007267) haplotype was compared to the frequency of the other haplotypes between cases and controls using the chi2 test. Allele frequencies and carriage of the minor allele was compared between cases and controls using chi2 tests for the OPRM1 SNPs. The frequency of the proposed GCH1 "pain-protective" haplotype (CAT) did not significantly differ between cases and controls and no significant associations were observed between the OPRM1 SNPs and CWP. In conclusion, there was no evidence of association between proposed functional SNPs, previously reported to influence pain sensitivity, in GCH1 and OPRM1 with CWP. Further evidence of null association in large independent cohorts is required to truly exclude these SNPs as genetic risk factors for CWP.
Nociceptors with peripheral and central projections express temperature sensitive transient receptor potential (TRP) ion channels, also called thermoTRP's. Chemosensitivity of thermoTRP's to certain natural compounds eliciting pain or exhibiting thermal properties has proven to be a good tool in characterizing these receptors. Capsaicin, a pungent chemical in hot peppers, has assisted in the cloning of the first thermoTRP, TRPV1. This discovery initiated the search for other receptors encoding the response to a wide range of temperatures encountered by the body. Of these, TRPV1 and TRPV2 encode unique modalities of thermal pain when exposed to noxious heat. The ability of TRPA1 to encode noxious cold is presently being debated. The role of TRPV1 in peripheral inflammatory pain and central sensitization during chronic pain is well known. In addition to endogenous agonists, a wide variety of chemical agonists and antagonists have been discovered to activate and inhibit TRPV1. Efforts are underway to determine conditions under which agonist-mediated desensitization of TRPV1 or inhibition by antagonists can produce analgesia. Also, identification of specific second messenger molecules that regulate phosphorylation of TRPV1 has been the focus of intense research, to exploit a broader approach to pain treatment. The search for a role of TRPV2 in pain remains dormant due to the lack of suitable experimental models. However, progress into TRPA1's role in pain has received much attention recently. Another thermoTRP, TRPM8, encoding for the cool sensation and also expressed in nociceptors, has recently been shown to reduce pain via a central mechanism, thus opening a novel strategy for achieving analgesia. The role of other thermoTRP's (TRPV3 and TRPV4) encoding for detection of warm temperatures and expressed in nociceptors cannot be excluded. This review will discuss current knowledge on the role of nociceptor thermoTRPs in pain and therapy and describes the activator and inhibitor molecules known to interact with them and modulate their activity.
The μ-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There
are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic
variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence
of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations
in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5′-UTR
of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants.
Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic
variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.
Though it is clear that genomic variability plays an integral role in accounting for pain sensitivity, controversy exists over which genes are involved. While recent data suggest a "protective" (i.e., less pain) haplotype in the GTP cyclohydrolase (GCH1) gene, other research has failed to confirm this association. Possibly, the effects of single nucleotide polymorphisms (SNPs) vary depending on the pain task. The current investigation analyzed the association of five previously identified GCH1 SNPs with ratings of pain induced by topical high concentration (10%) capsaicin applied to the skin of 39 healthy human volunteers. Each of the GCH1 polymorphisms was associated with lower pain ratings. When combined, three of the five accounted for a surprisingly high 35% of the inter-individual variance in pain ratings. We conclude that SNPs of the GCH1 gene may profoundly affect the ratings of pain induced by capsaicin.
To test the hypothesis that joint hypermobility may play a part in the pathogenesis of pain in fibromyalgia, schoolchildren were examined for the coexistence of joint hypermobility and fibromyalgia.
The study group consisted of 338 children (179 boys, 159 girls; mean age 11.5 years, range 9-15 years) from one public school in Beer-Sheva, Israel. In the assessment of joint hypermobility, the criteria devised by Carter and Bird were used. Any child who met at least three of five criteria was considered to have joint hypermobility. Children were considered to have fibromyalgia if they fulfilled the 1990 American College of Rheumatology criteria for the diagnosis of fibromyalgia, namely, widespread pain in combination with tenderness of 11 or more of the 18 specific tender point sites. The blind assessments of joint hypermobility (by AG) and fibromyalgia (by DB) were carried out independently.
Of the 338 children 43 (13%) were found to have joint hypermobility and 21 (6%) fibromyalgia; 17 (81%) of the 21 with fibromyalgia had joint hypermobility and 17 (40%) of the 43 with joint hypermobility had fibromyalgia. Using chi 2 statistical analysis, joint hypermobility and fibromyalgia were found to be highly associated.
This study suggests that there is a strong association between joint hypermobility and fibromyalgia in schoolchildren. It is possible that joint hypermobility may play a part in the pathogenesis of pain in fibromyalgia. More studies are needed to establish the clinical significance of this observation.
To investigate the hypothesis that fibromyalgia represents one end of a spectrum in which there is a more general association between musculoskeletal pain and tender points.
The subjects studied were 177 individuals selected from a population based screening survey for musculoskeletal pain. All subjects completed a pain mannikin and were examined for the presence of tender points at the nine American College of Rheumatology bilateral sites.
There were moderately strong associations (odds ratios range 1.3-3.1) between the reported presence of pain in a body segment and the presence of a tender point within that segment. Further, there was evidence of a trend of increasing number of tender points with increasing number of painful segments. The reporting of non-specific pain, aching, or stiffness, was also associated with high tender point counts.
This study illustrates that the association between tender points and pain is not restricted to the clinically defined subgroup with chronic widespread pain. Given that widespread pain and tender points have previously been linked with distress, this might reflect lesser degrees, or earlier phases of the somatisation of distress.
Fibromyalgia, a condition characterized by chronic widespread pain, tenderness and fatigue, markedly impairs the quality of life of affected patients. Knowledge of its pathogenesis might help us to prevent or treat the disease, but our understanding of the underlying mechanisms is currently limited.
We examined the prospective association between occupational stress and incidence of newly diagnosed fibromyalgia.
Fibromyalgia is a syndrome characterized by the presence of chronic widespread pain, representing sensitization of the central nervous system. The pthophysiology of fibromyalgia is a complex and remains in evolution, encompassing diverse issues such as disturbed patterns of sleep, alter processing and decreased conditioned pain modulation at the spinal level, as well as increased connectivity between various pain - processing areas of the brain. This evolution is continuously uncovering potential novel therapeutic targets. Treatment of fibromyalgia is a multi - faceted endeavor, inevitably combining pharmacological as well as non - pharmacological approaches. 2δ ligands and selective nor-epinephrine - serotonin reuptake inhibitors are the current mainstays of pharmacological treatment. Novel re-uptake inhibitors targeting both nor -epinephrine and dopamine are potential additions to this armamentarium as are substance P antagonists, Opiod antagonism is another intriguing possibility. Canabinoid agonists hold promise in the treatment of fibromyalgia although current evidence is incomplete. Sodium Oxybate is a unique sleep - promoting medication while drugs those promot arousals such as modafilnil are also under investigation. In the current review, current and emerging therapeutic options for the syndrome of fibromyalgia are covered.
Although perceived as a rare condition, joint hypermobility syndrome is common. Its prevalence in rheumatology clinics is extremely high. Early estimates suggest that it may be the most common of all rheumatologic conditions. The problem lies in the general lack of awareness of the syndrome, its means of recognition, and the resultant failure to diagnose it correctly when present. It is a worldwide problem. This article provides an overview of hypermobility and hypermobility syndrome, stressing its multisystemic nature and the negative impact that it may have on quality of life, with particular reference to gastrointestinal involvement.
Objective:
Familial aggregation of fibromyalgia has been increasingly recognized. The goal of this study was to conduct a genome-wide linkage scan to identify susceptibility loci for fibromyalgia.
Methods:
We genotyped members of 116 families from the Fibromyalgia Family Study and performed a model-free genome-wide linkage analysis of fibromyalgia with 341 microsatellite markers, using the Haseman-Elston regression approach.
Results:
The estimated sibling recurrence risk ratio (λs ) for fibromyalgia was 13.6 (95% confidence interval 10.0-18.5), based on a reported population prevalence of 2%. Genome-wide suggestive evidence of linkage was observed at markers D17S2196 (empirical P [Pe ]=0.00030) and D17S1294 (Pe=0.00035) on chromosome 17p11.2-q11.2.
Conclusion:
The estimated sibling recurrence risk ratio (λs ) observed in this study suggests a strong genetic component of fibromyalgia. This is the first report of genome-wide suggestive linkage of fibromyalgia to the chromosome 17p11.2-q11.2 region. Further investigation of these multicase families from the Fibromyalgia Family Study is warranted to identify potential causal risk variants for fibromyalgia.
The objective of this study is to test the hypothesis that the number of functional somatic syndromes (FSSs) predicts new, additional FSSs.
In a recent case-control study of interstitial cystitis/painful bladder syndrome (IC/PBS), we used symptom-based consensus definitions to identify these FSSs: fibromyalgia (FM), chronic fatigue syndrome (CFS), irritable bowel syndrome (IBS), chronic pelvic pain, migraine, sicca syndrome and panic disorder. Those present before the incidence year were called antecedent FSSs; those with onset during the incidence year were called incident FSSs. In each of two groups, 312 IC/PBS cases and 313 controls, rates of incident FSSs were compared among those with 0, 1, 2, or ≥3 antecedent FSSs. Confounding was assessed using logistic regression analyses that included the individual antecedent FSSs, published correlates of these FSSs, and demographic variables.
The incidence of a new FSS increased with the number of antecedent FSSs, as did that of incident FM, CFS and IBS studied separately. These findings were not confounded by other variables. The presence of multiple antecedent FSSs generally had the highest odds ratio for new, different, incident FSSs.
This study revealed that the number of antecedent FSSs was among the strongest risk factors for other FSSs, especially incident FM, CFS and IBS. This suggests that the FSSs are linked through a polysyndromic phenotype. If each FSS is heterogeneous, to seek a pathogenesis common to all FSSs, individuals with multiple FSSs should be sought; to seek a pathogenesis unique to a specific FSS, mature persons who have only that FSS should be studied.
Objective
To estimate and compare the prevalence of fibromyalgia by 2 different methods in Olmsted County, Minnesota.Methods
The first method was a retrospective review of medical records of potential cases of fibromyalgia in Olmsted County using the Rochester Epidemiology Project (from January 1, 2005, to December 31, 2009) to estimate the prevalence of diagnosed fibromyalgia in clinical practice. The second method was a random survey of adults in Olmsted County using the fibromyalgia research survey criteria to estimate the percentage of responders who met the fibromyalgia research survey criteria.ResultsOf the 3,410 potential patients identified by the first method, 1,115 had a fibromyalgia diagnosis documented in the medical record by a health care provider. The age- and sex-adjusted prevalence of diagnosed fibromyalgia by this method was 1.1%. By the second method, of the 2,994 people who received the survey by mail, 830 (27.6%) responded and 44 (5.3%) met the fibromyalgia research survey criteria. The age- and sex-adjusted prevalence of fibromyalgia in the general population of Olmsted County by this method was estimated at 6.4%.Conclusion
To the best of our knowledge, this is the first report of the rate at which fibromyalgia is being diagnosed in a community. This is also the first report of prevalence as assessed by the fibromyalgia research survey criteria. Our results suggest that patients, particularly men, who meet the fibromyalgia research survey criteria are unlikely to have been given a diagnosis of fibromyalgia.
Unlabelled:
Fibromyalgia represents the tip of the iceberg of chronic pain in the general population. We have attempted to estimate the prevalence of fibromyalgia in the Israeli population, using the London Fibromyalgia Epidemiology Study Screening Questionnaire (LFESSQ), an instrument previously utilised in several European countries.
Methods:
The LFESSQ-4 screens for widespread pain, and the LFESSQ-6 for widespread pain and chronic fatigue. The LFESSQ was administered via telephone to a sample of 1019 individuals. To estimate the positive predictive value (PPV) of LFESSQ-4 and LFESSQ-6, this questionnaire was submitted to a sample of rheumatology outpatients (n=76), who were examined to confirm or exclude fibromyalgia according to the 1990 criteria. The prevalence of fibromyalgia in the general population was estimated by applying the PPV to community subjects.
Results:
In the community survey, 5.1% and 3.9% of individuals screened positive for the LFESSQ-4 and LFESSQ-6, respectively. The point prevalence of FMS in the Israeli general population was 2.6% (95%CI 1.7-3.4) when using LFESSQ-4 and 2.0% (95%CI 1.3-2.7) when using the LFESSQ-6 criteria.
Conclusions:
The prevalence of the fibromyalgia syndrome in the Israeli population is considerable and constitutes a significant health care issue. The prevalence is similar to that observed in other western populations. Based on this tool, over 25% of fibromyalgia cases appear to be among males, a proportion higher than generally appreciated.
clinical features of fibrositis syndrome / alpha NREM [nonrapid eye movement] sleep and fibrositis / psychological distress and fibrositis syndrome / noxious environmental stimuli and fibrositis / primary sleep pathologies and fibrositis / rheumatic disease and fibrositis / altered central nervous system metabolism and fibrositis syndrome (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Objective
Chronic widespread pain, the clinical hallmark of the fibromyalgia syndrome, is associated with other physical and psychological symptoms both in patients studied in a clinical setting and in those identified in the community. The present study was undertaken to examine the hypothesis that psychological and physical indicators of the process of somatization predict the development of new chronic widespread pain.Methods
In this population-based prospective study, 1,658 adults ages 18–65 years completed a detailed pain questionnaire, which included a pain drawing. They also completed the following psychosocial instruments: General Health Questionnaire, Somatic Symptom Checklist, Fatigue Questionnaire, and Illness Attitude Scales. Individuals were followed up at 12 months, at which time 1,480 (93% of subjects still living at their baseline address) provided data on pain status, using the same instruments.ResultsAt baseline, 825 subjects were classified as pain free and 833 as having pain not satisfying criteria for chronic widespread pain. Of those, 18 (2%) and 63 (8%), respectively, were classified as having chronic widespread pain at followup. After adjustment for age and sex, there were strong relationships between baseline test scores and subsequent risk of chronic widespread pain (odds ratio for the Somatic Symptom Checklist 3.3; odds ratio for the Illness Behavior subscale of the Illness Attitude Scales 9.0). All 95% confidence intervals excluded unity. These associations were independent of baseline pain status.Conclusion
Subjects who are free of chronic widespread pain are at increased future risk of its development if they display other aspects of the process of somatization. Data from this population-based prospective study lend powerful support to the hypothesis that chronic widespread pain can be one manifestation of the somatization of distress.
Obesity is a risk factor for fibromyalgia in adults, but whether a similar relationship exists in children is uncertain. This study examined whether obesity is associated with reporting of musculoskeletal pain, including chronic regional pain (CRP) and chronic widespread pain (CWP), in adolescents, in a population-based setting. A pain questionnaire was administered to offspring of the Avon Longitudinal Study of Parents and Children at age 17, asking about site, duration, and pain intensity, from which participants with different types of musculoskeletal pain were identified. Relationships between obesity and pain were examined by calculating odds ratios stratified by gender and adjusted for socioeconomic status as reflected by level of maternal education. A total of 3376 participants (1424 boys) with complete data were identified, mean age 17.8; 44.7% of participants reported any pain within the last month lasting 1day or longer; 16.3% reported lower back pain, 9.6% shoulder pain, 9.4% upper back pain, 8.9% neck pain, 8.7% knee pain, 6.8% ankle/foot pain, 4.7% CRP, and 4.3% CWP; 7.0% of participants were obese. Obesity was associated with increased odds of any pain (odds ratio [OR] 1.33, P=.04), CRP (OR 2.04, P=.005), and knee pain (OR 1.87, P=.001), but not CWP (OR 1.10, P=.5). Compared with non obese participants, those with any pain, knee pain, and CRP reported more severe average pain (P<.01). Obese adolescents were more likely to report musculoskeletal pain, including knee pain and CRP. Moreover, obese adolescents with knee pain and CRP had relatively high pain scores, suggesting a more severe phenotype with worse prognosis.
Objective
To characterize the patterns of alpha electroencephalographic sleep and their associations with pain and sleep in patients with fibromyalgia.Methods
Pain and sleep symptoms of 40 female patients with fibromyalgia and 43 healthy control subjects were studied before and after overnight polysomnography. Blinded analyses of alpha activity in non–rapid eye movement (non-REM) sleep were performed using time domain, frequency domain, and visual analysis techniques.ResultsThree distinct patterns of alpha sleep activity were detected in fibromyalgia: phasic alpha (simultaneous with delta activity) in 50% of patients, tonic alpha (continuous throughout non-REM sleep) in 20% of patients, and low alpha activity in the remaining 30% of patients. Low alpha activity was exhibited by 83.7% of control subjects (P < 0.01). All fibromyalgia patients who displayed phasic alpha sleep, activity reported worsening of pain after sleep, compared with 58.3% of patients with low alpha activity (P < 0.01) and 25.0% of patients with tonic alpha activity (P < 0.01). Postsleep increase in the number of tender points occurred in 90.0% of patients with phasic alpha activity, 41.7% of patients with low alpha activity, and 25.0% of patients with tonic alpha activity (P < 0.01). Self ratings of poor sleep were reported by all patients with phasic alpha activity, 58.3% of patients with low alpha activity (P < 0.01), and 12.5% of patients with tonic alpha activity (P < 0.01). Patients with phasic alpha activity reported longer duration of pain than patients in other subgroups (P < 0.01). Additionally, patients with phasic alpha sleep activity exhibited less total sleep time than patients in other subgroups (P < 0.05), as well as lower sleep efficiency (P < 0.05) and less slow wave sleep (P < 0.05) than patients with a tonic alpha sleep pattern.Conclusion
Alpha intrusion during sleep can be of different patterns. Phasic alpha sleep activity was the pattern that correlated better with clinical manifestations of fibromyalgia.
Fibromyalgia (FM) represents a complex disorder that is characterized by widespread pain and tenderness and is frequently accompanied by additional somatic and cognitive/affective symptoms. Genetic risk factors are known to contribute to the etiology of the syndrome. The aim of this study was to examine >350 genes for association with FM, using a large-scale candidate gene approach.
The study group comprised 496 patients with FM (cases) and 348 individuals with no chronic pain (controls). Genotyping was performed using a dedicated gene array chip, the Pain Research Panel, which assays variants characterizing >350 genes known to be involved in the biologic pathways relevant to nociception, inflammation, and mood. Association testing was performed using logistic regression.
Significant differences in allele frequencies between cases and controls were observed for 3 genes: GABRB3 (rs4906902; P = 3.65 × 10(-6)), TAAR1 (rs8192619; P = 1.11 × 10(-5)), and GBP1 (rs7911; P = 1.06 × 10(-4)). These 3 genes and 7 other genes with suggestive evidence for association were examined in a second, independent cohort of patients with FM and control subjects who were genotyped using the Perlegen 600K platform. Evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4.
Variation in these 4 replicated genes may serve as a basis for development of new diagnostic approaches, and the products of these genes may contribute to the pathophysiology of FM and represent potential targets for therapeutic action.
Individuals with fibromyalgia generally experience chronic widespread pain, which can be accompanied by further symptoms including fatigue, sleep disturbances, cognitive dysfunction, anxiety and depressive episodes. As the recognition and diagnosis of fibromyalgia has improved, the availability of therapeutic options for patients has increased. Furthermore, research into the neurobiological mechanisms that contribute to the chronic pain and concomitant symptoms experienced by patients with fibromyalgia has advanced our understanding of this debilitating disorder. In this Review, we aim to provide an overview of existing pathophysiological concepts. The roles of biological and psychological stress, genetic factors, and pain and sensory processing in the pathophysiology of fibromyalgia and related conditions are discussed. In addition, pharmacological treatments, including monoamine modulators, calcium channel modulators and γ-aminobutyric acid modulators, as well as nonpharmacological treatment options are considered.
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.
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.
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.
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.
The aim of the current study was to investigate whether genetic variation in genes across the serotoninergic system is associated with chronic widespread pain (CWP) and the number of pain sites reported.
A discovery cohort, with pain data at 3 time points, was used to investigate genetic associations with 2 phenotypes: 1) CWP (at ≥ 2 time points; n = 164) compared with pain-free controls (at 3 time points; n = 172), and 2) the maximum number of pain sites reported at any 1 of the 3 time points (range of sites 0-29; n = 989). A cohort of 2,285 men for whom a DNA sample and pain data were available (including 203 CWP cases and 929 controls) was used for validation. Pairwise tagging (r(2) > 0.8) single-nucleotide polymorphisms (SNPs) were genotyped. Logistic and zero-inflated negative binomial regression analyses were used to test for SNP associations with CWP and the number of pain sites, respectively.
SNPs in HTR2A were associated with both pain phenotypes in the discovery cohort, and a number of these SNP associations were replicated in the validation cohort, some of which were attenuated after adjustment for depression. There was an increased likelihood of having CWP in subjects with 1 or 2 copies of the T allele of rs12584920 (odds ratio [OR] 1.64, 95% confidence interval [95% CI] 1.01-2.60 [P = 0.03] in the discovery cohort, and OR 1.46, 95% CI 1.07-2.00 [P = 0.018] in the validation cohort). A similar association was observed between rs17289394 and the maximum number of pain sites reported in both cohorts. Results from a meta-analysis of the data from the 2 cohorts further strengthened these findings.
The findings of this study support the role of HTR2A in the genetic predisposition to musculoskeletal pain.
Temporomandibular joint and muscle disorders (TMJD) are ill-defined, painful debilitating disorders. This study was undertaken to identify the spectrum of clinical manifestations based on self-report from affected patients.
A total of 1511 TMJD-affected individuals were recruited through the web-based registry of patients maintained by The TMJ Association, Ltd, a patient advocacy organization, and participated in the survey as well as 57 of their nonaffected friends. Results were also compared with US population for questions in common with the National Health and Nutrition Examination Survey.
The TMJD-affected individuals were on average 41 years of age and predominantly female (90%). Nearly 60% of both men and women reported recent pain of moderate-to-severe intensity with a quarter of them indicating interference or termination of work-related activities. In the case-control comparison, a higher frequency of headaches, allergies, depression, fatigue, degenerative arthritis, fibromyalgia, autoimmune disorders, sleep apnea, and gastrointestinal complaints were prevalent among those affected with TMJD. Many of the associated comorbid conditions were over 6 times more likely to occur after TMJD was diagnosed. Among a wide array of treatments used (46 listed), the most effective relief for most affected individuals (91%) was the use of thermal therapies--hot/cold packs to the jaw area or hot baths. Nearly 40% of individuals affected with TMJD patients reported one or more surgical procedures and nearly all were treated with one or many different medications. Results of these treatments were generally equivocal. Although potentially limited to the most severe TMJD affected individuals, the survey results provide a comprehensive dataset describing the clinical manifestations of TMJD.
The data provide evidence that TMJD represent a spectrum of disorders with varying pathophysiologies, clinical manifestations, and associated comorbid conditions. The findings underscore the complex nature of TMJD, the need for more extensive interdisciplinary basic and clinical research, and the development of outcome-based strategies to more effectively diagnose, prevent, and treat these chronic, debilitating conditions.
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.
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).
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.
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.
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.
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.
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).
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.
The aim of this study was to explore whether the candidate gene polymorphisms contribute to fibromyalgia susceptibility. The authors conducted a meta-analysis on associations between serotonin transporter (5-HTT) gene-linked polymorphic region (5-HTTLPR) S/L allele, catechol-O-methltransferase (COMT) val158Met, and serotonin 2A (5-HT2A) receptor 102T/C polymorphisms and fibromyalgia susceptibility as determined using the following: (1) allele contrast, (2) recessive, (3) dominant models, and (4) contrast of homozygotes. We also performed a systematic review with available data of the candidate genes. A total of 21 separate comparisons were considered in this systematic review and meta-analysis. Seventeen candidate genes and over 35 different polymorphisms were identified in studies on fibromyalgia susceptibility. Meta-analysis of the 5-HTTLPR S/L allele and COMT val158Met failed to reveal any association with fibromyalgia. However, meta-analysis of the C allele, CC + CT genotype, and CC versus TT genotype of the 5-HT2A receptor 102T/C polymorphism showed significant association with fibromyalgia. The overall OR of the association between the C allele and fibromyalgia was 1.333 (95% CI = 1.053-1.688, P = 0.017). The ORs for the CC + CT genotype, and CC versus TT genotype showed the same pattern as that observed for the C allele (OR = 1.541, 95% CI = 1.032-2.303, P = 0.035; OR = 1.838, 95% CI = 1.151-2.936, P = 0.011). This meta-analysis demonstrates that the 5-HT2A receptor 102T/C polymorphism confers susceptibility to fibromyalgia. In contrast, no association was found between the 5-HTTLPR S/L allele, COMT val158Met, and susceptibility to fibromyalgia.
Although the serotonin (5-hydroxytryptamine (5-HT)) 2A receptor has been reported to be associated with pain, no relationship has been found between single nucleotide polymorphisms in the 5-HT2A receptor gene and analgesic requirements. To clarify the mechanism of individual differences in analgesic requirements, we investigated the relationship between the 5-HT2A 102T/C gene polymorphism and analgesic requirements in 135 patients who underwent major open abdominal surgery and were managed with continuous epidural analgesia with opioids after surgery. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism. We found that the 102T/C polymorphism had significant main effects with regard to analgesic requirements. In addition, significant interaction effects were found between the 102T/C polymorphism and sex in terms of analgesic requirements. Among female subjects, patients with the T/T genotype of the 102T/C polymorphism had more analgesic requirements than those with the other genotypes. This finding suggests that the linkage disequilibrium block, which includes the 102T/C polymorphism of the 5-HT2A receptor gene, is involved in individual differences in analgesic requirements in women.
More than 1 in 10 adults in the general population experience chronic widespread body pain (CWP), which lies at one end of a continuous spectrum of pain ranging in both severity and duration. Neuroendocrine factors can modify the effect of known psychological and psychosocial risk factors for progression along the spectrum of pain and development of CWP, and genetic variants that affect neuroendocrine and neural processing potentially affect susceptibility to chronic pain development. We have examined variants across genes encoding the beta2-adrenergic receptor (ADRB2) and catecholamine-O-methyltransferase (COMT) - key neuroendocrine signalling factors - in a large population-based sample to determine whether these may be involved in pain progression and CWP development. A nested association study was conducted using individuals from the 1958 British Birth Cohort Study who had been assessed for pain status. Genotypes were available for nine single nucleotide polymorphisms (SNPs) across ADRB2 and 11 SNPs across COMT. ADRB2 SNPs rs12654778 and rs1042713 were associated either with CWP alone (p=0.02 for both) or with position along pain spectrum (pain status; p=0.04). Common functional ADRB2 haplotype combinations were also associated with pain status (p(model)=0.002) and, further, with both extent and duration of pain (p(model)=0.003 and p(model)=0.002, respectively). There were no associations of either CWP or pain status with COMT genotypes or haplotypes. These results are the first to suggest that functional ADRB2 variants are involved in regulating pain status at a population level. A role for COMT in chronic pain development was not identified, though could not be excluded.
This article attempts to demonstrate insight into understanding the evolving spectrum of functional somatic syndromes. It will become evident that in understanding these highly complex disorders, neither the Cartesian dichotomy regarding body-mind distinction nor the pure reductionist approach to disease (which attempts to explain clinical phenomena on the basis of underlying structural derangement) can be strictly adhered to. Only use of a truly integrative framework of thinking can allow us to both recognize and accept the overlapping basic similarity between these conditions and, in turn, teach us about nearly any medical condition characterized by pain or sensory symptoms.
The transient receptor potential (TRP) superfamily of ion channels are a large and diverse group that have received increased attention in recent years. The sub-family of thermo-TRPs which are regulated by temperature, among other physical and chemical stimuli, are of particular interest for the development of potential pain therapeutics.
We review the advances in the field in recent years, focusing on a rationale for pain therapy and potential challenges associated with these targets.
Vanilloid-type TRP 1 (TRPV1) is the most well studied and advanced member of the family, with selective agonists and antagonists already in clinical use or development, respectively. Among other thermo-TRPs (including TRPV2 - 4, Ankyrin type TRP 1 (TRPA1) and melastatin type TRP 8 (TRPM8)), TRPA1 and TRPM8 are emerging as promising novel pain targets.
Chronic diffuse myalgia, localized areas of tenderness, fatigue, and unrefreshing sleep are related to a physiologic arousal disorder within sleep, that is, the alpha EEG NREM sleep anomaly. This sleep physiologic disorder, nonrestorative sleep, and symptoms of fibrositis syndrome are shown to occur with psychologic, environmental, and physiologic distress conditions. Pathogenic mechanisms that link nonrestorative sleep physiology to pain and fatigue may involve metabolic dysfunction of the brain with sleep-related alteration in immunologic and neurotransmitter functions (serotonin, substance P, endorphins). These sleep-related mechanisms have important implications for the understanding and treatment of fibrositis/fibromyalgia syndrome.
Based on a possible involvement of serotonergic dysfunction in the pathophysiology of fibromyalgia (FM) and on preliminary reports of a possible genetically driven vulnerability for this disorder we investigated the silent T102C polymorphism of the 5-HT2A-receptor gene in 168 FM patients and 115 healthy controls. Our results showed a significantly different genotype distribution in FM patients with a decrease in T/T and an increase in both T/C and C/C genotypes as compared to the control population (Fisher's Exact test, two-sided, P = 0.008). However, the increase in allele-C102 frequency felt short of significance (P = 0.07). Correlation of genotypes to clinical parameters revealed no influences on age of onset, duration of disease or psychopathological symptoms, measured with the Beck Depression Inventory and the symptom checklist SCL-90-R. In contrast to that the pain score, being a self reported information on pain severity, was significantly higher in patients of the T/T genotype (Mann-Whitney U test, P = 0.028). This suggests that the T102-allele might be involved in the complex circuits of nociception. However, the T102C polymorphism is not directly involved in the aetiology of FM but might be in linkage dysequilibrium with the true functional variant, which has to be unravelled.
To analyze the genotypes of the promoter region of the serotonin transporter gene (5-HTT) in patients with fibromyalgia (FM).
Genomic DNA from 62 patients meeting the American College of Rheumatology 1990 criteria for FM and 110 healthy controls was analyzed by polymerase chain reaction. Additionally, the psychopathologic state of 52 of the FM patients was evaluated using the Beck Depression Inventory (BDI) and the Symptom Checklist-90-Revised (SCL-90-R).
The 5-HTTLPR genotypes in FM patients versus controls were distributed as follows: L/L 27% versus 34%, L/S 42% versus 50%, and S/S 31% versus 16%. FM patients with the S/S genotype had higher mean scores on the BDI and the SCL-90-R compared with those in the L/L and L/S groups.
A higher frequency of the S/S genotype of 5-HTT was found in FM patients compared with healthy controls. The S/S subgroup exhibited higher mean levels of depression and psychological distress. These results support the notion of altered serotonin metabolism in at least a subgroup of patients with FM.
Cross-sectional studies have consistently shown a relationship between chronic widespread pain, the clinical hallmark of fibromyalgia, and psychological distress. These studies cannot distinguish the direction of any causal relationship. Recent population based studies have reported that such pain is predictive of future distress. However, chronic pain is often associated with physical and psychological co-morbid features which may confound this relationship. The aim of this study was to examine the hypothesis that chronic widespread pain increases the risk of future distress after adjusting for the effects of possible confounding factors. A population based survey of 1953 individuals identified subjects' psychological status and whether they satisfied criteria for chronic widespread pain. At baseline co-morbid features of chronic widespread pain, including reporting other somatic symptoms, abnormal illness behaviour, health anxiety, fatigue and low levels of self-care, were measured. All subjects were followed up after 12 months to determine levels of psychological distress. Subjects with chronic widespread pain at baseline were much more likely to be distressed at follow up (OR=4.0, 95% CI (2.5,6.3)). As levels of distress at follow up may simply reflect those at baseline the association was adjusted for baseline levels of distress. Chronic widespread pain was, however, still associated with future distress although the relationship was slightly attenuated (odds ratio, OR=3.0, 95% CI (1.8,5.1)). To examine our main hypothesis a final analysis was undertaken adjusting this association for those co-morbid features assessed at baseline. Following these adjustments chronic widespread pain was no longer significantly associated with future distress (OR=1.5, 95% CI (0.8,2.9)). Chronic widespread pain was associated with increased levels of psychological distress at follow up. However, a more rigorous analysis indicated that the association between baseline pain status with future distress was explained by concomitant features of chronic pain rather than pain per se. These findings indicate that it is those persons with chronic widespread pain in the presence of other physical and psychosocial factors who will become distressed.
To use functional magnetic resonance imaging (fMRI) to evaluate the pattern of cerebral activation during the application of painful pressure and determine whether this pattern is augmented in patients with fibromyalgia (FM) compared with controls.
Pressure was applied to the left thumbnail beds of 16 right-handed patients with FM and 16 right-handed matched controls. Each FM patient underwent fMRI while moderately painful pressure was being applied. The functional activation patterns in FM patients were compared with those in controls, who were tested under 2 conditions: the "stimulus pressure control" condition, during which they received an amount of pressure similar to that delivered to patients, and the "subjective pain control" condition, during which the intensity of stimulation was increased to deliver a subjective level of pain similar to that experienced by patients.
Stimulation with adequate pressure to cause similar pain in both groups resulted in 19 regions of increased regional cerebral blood flow in healthy controls and 12 significant regions in patients. Increased fMRI signal occurred in 7 regions common to both groups, and decreased signal was observed in 1 common region. In contrast, stimulation of controls with the same amount of pressure that caused pain in patients resulted in only 2 regions of increased signal, neither of which coincided with a region of activation in patients. Statistical comparison of the patient and control groups receiving similar stimulus pressures revealed 13 regions of greater activation in the patient group. In contrast, similar stimulus pressures produced only 1 region of greater activation in the control group.
The fact that comparable subjectively painful conditions resulted in activation patterns that were similar in patients and controls, whereas similar pressures resulted in no common regions of activation and greater effects in patients, supports the hypothesis that FM is characterized by cortical or subcortical augmentation of pain processing.