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1.  Fibromyalgia: A Primer for the Anesthesia Community 
Purpose of the Review
The present review is intended to give an overview of fibromyalgia for the anesthesiologist. While the basics of the treatment of fibromyalgia are included, the intent is to provide context to discuss the potential implications in perioperative management.
Recent Findings
One of the most important changes in the last year is the new criteria established by the American College of Rheumatology for the diagnosis of fibromyalgia. Instead of a combination of self-report and a tender point examination, there is a new self-report questionnaire that is now used diagnose fibromyalgia. This tool incorporates aspects of widespread body pain and some of the known comorbid symptoms. A score of 0-31 is given, which allows for the disease to be viewed as a continuum of sensitivity and symptomatology, instead of as a binary diagnosis. This continuum has been termed “fibromyalgia-ness.” This article also reviews the advances in understanding of the pathophysiology and emerging therapies. Little is known about the impact of fibromyalgia in the perioperative period.
Summary
The impact of fibromyalgia on anesthesia care is not known. Years of quality research have clearly demonstrated multiple pathophysiologic changes that could impact anesthesia care and future study is needed.
doi:10.1097/ACO.0b013e32834a1091
PMCID: PMC3422621  PMID: 21799404
fibromyalgia; treatment; anesthesiology; postoperative pain; chronic post-surgical pain
2.  Fibromyalgia: Presentation and management with a focus on pharmacological treatment 
Fibromyalgia is a condition with widespread muscle pain. Prevalence studies showed that 2% to 7% of the population have fibromyalgia, which affects approximately one million Canadians. Fibromyalgia is most common in women, but it also involves men and children. As with most chronic illnesses, the causes of fibromyalgia are unknown. However, recent research supports underlying abnormalities in the central nervous system, which supports fibromyalgia as a chronic disease state and valid clinical entity. Pain is the primary symptom, often accompanied by overwhelming fatigue, sleep dysfunction and cognitive impairment. In 1990, the American College of Rheumatology developed diagnostic criteria for the diagnosis of fibromyalgia. Lifestyle changes, including pacing of activities and aerobic exercise, are very important in managing fibromyalgia symptoms. Emotional and behavioural therapy can also be helpful. Controlled trials of antidepressants, gabapentinoids, tramadol, zopiclone and sodium oxybate have shown effectiveness in fibromyalgia patients. Pregabalin and duloxetine were recently approved in the United States. Effective management of fibromyalgia is complex and requires a multidisciplinary treatment approach. Response and tolerance of different therapeutic interventions vary from patient to patient. Recent advances in the pathophysiology of fibromyalgia offer hope for new and improved therapies in the management of this disabling condition.
PMCID: PMC2799316  PMID: 19225604
Fatigue; Fibromyalgia; Pain; Treatment
3.  Fibromyalgia and Depression 
Pain Research and Treatment  2011;2012:486590.
Fibromyalgia and depression might represent two manifestations of affective spectrum disorder. They share similar pathophysiology and are largely targeted by the same drugs with dual action on serotoninergic and noradrenergic systems. Here, we review evidence for genetic and environmental factors that predispose, precipitate, and perpetuate fibromyalgia and depression and include laboratory findings on the role of depression in fibromyalgia. Further, we comment on several aspects of fibromyalgia which support the development of reactive depression, substantially more so than in other chronic pain syndromes. However, while sharing many features with depression, fibromyalgia is associated with somatic comorbidities and absolutely defined by fluctuating spontaneous widespread pain. Fibromyalgia may, therefore, be more appropriately grouped together with other functional pain disorders, while psychologically distressed subgroups grouped additionally or solely with affective spectrum disorders.
doi:10.1155/2012/486590
PMCID: PMC3236322  PMID: 22191023
4.  Effectiveness of the psychological and pharmacological treatment of catastrophization in patients with fibromyalgia: a randomized controlled trial 
Trials  2009;10:24.
Background
Fibromyalgia is a prevalent and disabling disorder characterized by widespread pain and other symptoms such as insomnia, fatigue or depression. Catastrophization is considered a key clinical symptom in fibromyalgia; however, there are no studies on the pharmacological or psychological treatment of catastrophizing. The general aim of this study is to assess the effectiveness of cognitive-behaviour therapy and recommended pharmacological treatment for fibromyalgia (pregabalin, with duloxetine added where there is a comorbid depression), compared with usual treatment at primary care level.
Method/design
Design: A multi-centre, randomized controlled trial involving three groups: the control group, consisting of usual treatment at primary care level, and two intervention groups, one consisting of cognitive-behaviour therapy, and the other consisting of the recommended pharmacological treatment for fibromyalgia.
Setting: 29 primary care health centres in the city of Zaragoza, Spain.
Sample: 180 patients, aged 18–65 years, able to understand and read Spanish, who fulfil criteria for primary fibromyalgia, with no previous psychological treatment, and no pharmacological treatment or their acceptance to discontinue it two weeks before the onset of the study.
Intervention: Psychological treatment is based on the manualized protocol developed by Prof. Escobar et al, from the University of New Jersey, for the treatment of somatoform disorders, which has been adapted by our group for the treatment of fibromyalgia. It includes 10 weekly sessions of cognitive-behaviour therapy. Pharmacological therapy consists of the recommended pharmacological treatment for fibromyalgia: pregabalin (300–600 mg/day), with duloxetine (60–120 mg/day) added where there is a comorbid depression).
Measurements: The following socio-demographic data will be collected: sex, age, marital status, education, occupation and social class. The diagnosis of psychiatric disorders will be made with the Structured Polyvalent Psychiatric Interview. Other instruments to be administered are the Pain Catastrophizing Scale, the Hamilton tests for Anxiety and for Depression, the Fibromyalgia Impact Questionnaire (FIQ), the EuroQuol-5 domains (EQ-5D), and the use of health and social services (CSRI). Assessments will be carried out at baseline, 1, 3, and 6 months.
Main variable: Pain catastrophizing.
Analysis: The analysis will be per intent to treat. We will use the general linear models of the SPSS version 15 statistical package, to analyse the effect of the treatment on the result variable (pain catastrophizing).
Discussion
It is necessary to assess the effectiveness of pharmacological and psychological treatments for pain catastrophizing in fibromyalgia. This randomized clinical trial will determine whether both treatments are effective for this important prognostic variable in patients with fibromyalgia.
Trial registration
Current Controlled Trials ISRCTN10804772
doi:10.1186/1745-6215-10-24
PMCID: PMC2689860  PMID: 19389246
5.  Disability and quality of life in patients with fibromyalgia 
Background
Patients with fibromyalgia often feel disabled in the performance of daily activities. Psychological factors seem to play a pronounced disabling role in fibromyalgia.
The objectives of the study are: Firstly, to investigate contributing factors for disability in fibromyalgia. Secondly, to study psychological distress in patients with fibromyalgia as compared to other nonspecific pain syndromes. And finally, to explore the impact of fibromyalgia on a patient's quality of life.
Methods
In this cross sectional study, explaining factors for disability were studied based on a regression analysis with gender, mental health, physical and social functioning as independent variables. For the assessment of disability in fibromyalgia the FIQ was used. The levels of psychological distress in patients with fibromyalgia, Complex Regional Pain Syndrome (CRPS) and chronic low back pain (CLBP) were compared based on scores on the Symptom Checklist (SCL90). Quality of life of patients with fibromyalgia was compared with scores (SF36) of both patients with fibromyalgia and other health conditions as derived from the literature.
Results
Disability in fibromyalgia seemed best explained by a patients mental health condition (β = -0.360 p = 0.02). The level of psychological distress was higher in patients with fibromyalgia as compared to patients with CRPS or CLBP (p < 0.01). The impact of fibromyalgia on quality of life appeared to be high as compared to the impact of other health conditions.
Conclusion
Patients with fibromyalgia report a considerable impact on their quality of life and their perceived disability level seems influenced by their mental health condition. In comparison with patients with other pain conditions psychological distress is higher.
doi:10.1186/1477-7525-6-8
PMCID: PMC2265693  PMID: 18211701
6.  Understanding why cognitive–behavioral therapy is an effective treatment for adolescents with juvenile fibromyalgia 
Recent studies have demonstrated that cognitive–behavioral therapy (CBT) is an effective treatment for children and adolescents with juvenile fibromyalgia. Unfortunately, the specific psychological changes that occur during treatment that explain why CBT works are not well understood. Historically, the increased use of specific coping strategies learned during CBT was thought to be the primary reason for why CBT was effective. However, evidence to support the notion that increases in adaptive coping directly lead to patient improvement is minimal. Instead, a growing number of studies in adults suggest that CBT results in more global changes of psychological perceptions of the pain itself (cognitive appraisals) and one’s ability to manage the pain. This report discusses the role of coping and aspects of cognitive appraisal as potential psychological changes that explain CBT-related improvements for youths with juvenile fibromyalgia.
doi:10.2217/IJR.13.3
PMCID: PMC3885254  PMID: 24416078
adaptive coping; catastrophic thinking; chronic pain; cognitive appraisal; cognitive–behavioral therapy; coping self-efficacy; juvenile fibromyalgia
7.  Structural alterations in brainstem of fibromyalgia syndrome patients correlate with sensitivity to mechanical pressure☆ 
NeuroImage : Clinical  2013;3:163-170.
Fibromyalgia syndrome is a chronic pain disorder characterised by widespread pain and tenderness in muscles and deep tissues. Current theories regarding the pathophysiological origins of fibromyalgia syndrome point towards central sensitisation and a decreased capacity of descending nociceptive controls. Morphological alterations to subcortical brain regions may contribute to such pathophysiological mechanisms, and to pain and other symptoms seen in fibromyalgia. Therefore, we evaluated geometric differences in subcortical structures in fibromyalgia patients relative to healthy people using a novel method of shape analysis. Sixteen female fibromyalgia patients and 15 age and sex matched, healthy control subjects underwent high-resolution T1-weighted magnetic resonance image scanning. Data was analysed using shape analysis of 15 subcortical regions and standard voxel-based morphometry analysis.
Fibromyalgia syndrome patients, relative to healthy control participants, exhibited alterations to the shape of the left lateral aspect of the lower brainstem (medulla). The mean total volume of the brainstem was also found to be significantly reduced in the patient group compared to healthy control subjects, and this brainstem volume reduction in patient group significantly correlated with clinical manual tender point scale scores. Voxel-based morphometry analysis revealed that patients also demonstrated decreased local grey matter volumes in the brainstem (pons) and left precuneus, and increased grey matter volumes in bilateral primary somatosensory cortices.
Results suggest that the volume reduction and associated geometric shape alterations seen in the brainstem of the patient group may contribute to sensitivity to pressure pain in fibromyalgia syndrome. This finding may be due to structure-related deficiencies in regions subserving descending nociceptive control.
Highlights
•Fibromyalgia syndrome patients exhibited shape alterations in the brainstem.•The mean brainstem volume was also significantly reduced in FMS patients.•This volume reduction correlated with clinical manual tender point scores.•Structural alterations in the brainstem may contribute to clinical symptoms of FMS.
doi:10.1016/j.nicl.2013.07.011
PMCID: PMC3791285  PMID: 24179860
8.  New and emerging therapeutic agents for the treatment of fibromyalgia: an update 
Journal of pain research  2010;3:89-103.
Fibromyalgia (FM) is a chronic widespread pain condition that is estimated to affect 5 million US adults. Several molecular pathophysiologies are thought to contribute to the symptoms of FM, complicating the development of effective clinical management techniques. It is now known that abnormalities in both nociceptive and central pain processing systems are necessary (but perhaps not sufficient) to condition the onset and maintenance of FM, producing associated neuropsychologic symptoms such as pronounced fatigue, sleep abnormalities, cognitive difficulties, stress sensitivity, anxiety, and depression. Current treatment strategies are focused primarily on correcting the pathophysiologic mechanisms underlying these nervous system abnormalities. Clinical studies demonstrate the safety and efficacy of three drugs recently approved for the treatment of FM: pregabalin (an alpha-2-delta ligand), and duloxetine and milnacipran (serotonin/norepinephrine reuptake inhibitors). This review describes these pharmaceuticals in detail and discusses their current roles in FM management.
PMCID: PMC3004640  PMID: 21197313
fibromyalgia; treatment; pharmacotherapy; pregabalin; duloxetine; milnacipran
9.  Effects of a one week multidisciplinary inpatient self-management programme for patients with fibromyalgia: a randomised controlled trial 
Background
Self-management programmes (SMP) are recommended for patients with fibromyalgia. The purpose of this study was to evaluate effects of a one week multidisciplinary inpatient self-management programme on psychological distress, skills as a consumer of health services, self-efficacy, and functional and symptomatic consequences of fibromyalgia (FM).
Methods
A randomised controlled two-armed, assessor-blinded trial with three-week follow-up to evaluate SMP. Primary outcomes were the General Health Questionnaire (GHQ-20) and the Effective Musculoskeletal Consumer Scale (EC-17), while secondary outcomes included the Fibromyalgia Impact Questionnaire (FIQ) and Self-efficacy scales for pain, function and symptoms (ASES).
Results
150 patients with FM were randomised to one week one SMP (n = 75) or to a waiting list control group (n = 75). Of these, 58 participants in the treatment group and 60 in the control group completed the study. At three weeks’ follow up there was a significant difference in EC-17 (0-100) in favour of the treatment group (mean difference 4.26, 95 CI 0.8 to 7.7, p = 0.02). There were no differences between the groups for any of the other outcomes.
Conclusion
This study shows that in patients with FM the SMP had no effect on psychological distress, functional and symptomatic consequences and self-efficacy, except for a small short-term effect on skills and behaviour that are important for managing and participating in health care (EC-17). Clinical Trials.gov Id: NCT01035125.
Trial registration
Clinical Trials.gov Id: NCT01035125
doi:10.1186/1471-2474-13-189
PMCID: PMC3551734  PMID: 23013162
Self-management programme; RCT; Fibromyalgia
10.  Pathophysiology of Fibromyalgia 
The American journal of medicine  2009;122(12 Suppl):S22.
This article reviews the biologic, genetic, and environmental factors that may contribute to the pathophysiology of fibromyalgia. As an affective spectrum disorder, fibromyalgia may share these causal factors with a number of related and co-occurring pain conditions such as irritable bowel syndrome or temporomandibular disorder. There is strong evidence that cardinal pain symptoms of fibromyalgia may be due to alterations in central processing of sensory input, along with aberrations in the endogenous inhibition of pain, Genetic research has shown familial aggregation of fibromyalgia and other related disorders such as major depressive disorder. Exposure to physical or psychosocial stressors, as well as abnormal biologic responses in the autonomic nervous system and neuroendocrine responses, may also contribute to dysfunctional pain processing. As fibromyalgia research continues to progress, it is expected that the pathophysiology of this disorder will be further elucidated, leading to more rational and targeted strategies for the treatment of fibromyalgia patients.
doi:10.1016/j.amjmed.2009.09.008
PMCID: PMC2821819  PMID: 19962493
Fibromyalgia; affective spectrum disorders; pathophysiology; neuroendocrine system; autonomic nervous system; genetics; environmental stressors
11.  Exercise Therapy for Fibromyalgia 
Current Pain and Headache Reports  2011;15(5):358-367.
Fibromyalgia syndrome, a chronic condition typically characterized by widespread pain, nonrestorative sleep, fatigue, cognitive dysfunction, and other somatic symptoms, negatively impacts physical and emotional function and reduces quality of life. Exercise is commonly recommended in the management of people with fibromyalgia, and interest in examining exercise benefits for those with the syndrome has grown substantially over the past 25 years. Research supports aerobic and strength training to improve physical fitness and function, reduce fibromyalgia symptoms, and improve quality of life. However, other forms of exercise (e.g., tai chi, yoga, Nordic walking, vibration techniques) and lifestyle physical activity also have been investigated to determine their effects. This paper highlights findings from recent randomized controlled trials and reviews of exercise for people with fibromyalgia, and includes information regarding factors that influence response and adherence to exercise to assist clinicians with exercise and physical activity prescription decision-making to optimize health and well-being.
doi:10.1007/s11916-011-0214-2
PMCID: PMC3165132  PMID: 21725900
Fibromyalgia; Nonpharmacologic therapy; Pain management; Exercise; Aerobics; Strengthening; Aquatics; Flexibility; Pilates; Vibration; Tai chi; Nordic walking; Physical activity; Randomized control trial; Review article; Cognitive behavioral therapy; Pain; Fatigue; Exercise progression; Exercise prescription; Adults; Yoga
12.  Antidepressants in the treatment of fibromyalgia 
Fibromyalgia syndrome is a chronic disease of widespread and debilitating pain whose cause is unknown and whose risk factors are poorly understood. It is often comorbid with rheumatoid and other pain disorders as well as psychiatric disorders such as anxiety and depression. Although they are not officially approved for this indication, antiepileptics and antidepressants are often used to treat fibromyalgia. The tricyclic antidepressants (TCAs), particularly amitriptyline, are among the most common treatment strategies. Because of the poor tolerability of the tricyclics, the newer antidepressants have been widely tested in fibromyalgia. The selective serotonin reuptake inhibitors (SSRIs) and the reversible monoamine oxidase inhibitors do not seem to be particularly helpful. The serotonin and norepinephrine reuptake inhibitors (SNRIs), duloxetine and milnacipran, on the other hand, have been shown in placebo-controlled trials to offer significant relief to patients suffering from fibromyalgia. Although no direct comparative studies have been performed, these compounds appear to be as effective as the TCAs but much better tolerated. The effectiveness of the SNRIs as well as other dual acting antidepressants, such as mirtazapine, but not the SSRIs, implies that a dysfunction of both serotonin and norepinephrine neurotransmission probably exists in fibromyalgia. The effectiveness of antidepressants appears to be independent of their effect on comorbid depression.
PMCID: PMC2671948  PMID: 19412502
fibromyalgia syndrome; FMS; pain; depression; antidepressants; norephinephrine; serotonin
13.  Fibromyalgia and Myofascial Pain Syndrome-A Dilemma 
Indian Journal of Anaesthesia  2009;53(5):575-581.
Summary
Pain and fatigue associated to the musculoskeletal system are among the leading causes of patients to visit their physicians and nearly one-third of such patients suffer from fibromyalgia. Fibromyalgia syndrome (FMS) is a chronic debilitating disorder characterized by widespread pain with tenderness in specific areas, leading to fatigue, headache and sleep disorder. Myofascial Pain Syndrome (MPS), is also a localized musculoskeletal pain producing condition whose diagnostic and management criteria differ from FMS but still considered by many only a subtype of FMS. Till date no exact cause has been held responsible for these painful conditions, therefore treatment of these disorders is always a challenge. The therapies are not precise but multimodal including pharmacological and alternative approaches. This article describes the existing knowledge pertaining to these conditions in regard of causative factors diagnosis and management.
PMCID: PMC2900090  PMID: 20640108
Myofascial pain; Fibromyalgia; Taut bands; Trigger points
14.  Newer treatments for fibromyalgia syndrome 
Fibromyalgia syndrome is a common chronic pain disorder of unknown etiology. The lack of understanding of the pathophysiology of fibromyalgia has made this condition frustrating for patients and clinicians alike. The most common symptoms of this disorder are chronic widespread pain, fatigue, sleep disturbances, difficulty with memory, and morning stiffness. Emerging evidence points towards augmented pain processing within the central nervous system (CNS) as having a primary role in the pathophysiology of this disorder. Currently the two drugs that are approved by the United States Food and Drug Administration (FDA) for the management of fibromyalgia are pregabalin and duloxetine. Newer data suggests that milnacipran, a dual norepinephrine and serotonin reuptake inhibitor, may be promising for the treatment of fibromyalgia. A double-blind, placebo-controlled trial of milnacipran in 125 fibromyalgia patients showed significant improvements relative to placebo. Milnacipran given either once or twice daily at doses up to 200 mg/day was generally well tolerated and yielded significant improvements relative to placebo on measures of pain, patient’s global impression of change in their disease state, physical function, and fatigue. Future studies are needed to validate the efficacy of milnacipran in fibromyalgia.
PMCID: PMC2643113  PMID: 19337439
fibromyalgia; pain; pharmacological; treatment
15.  Fibromyalgia: From treatment to rehabilitation 
Fibromyalgia is a clinical syndrome of chronic widespread pain and reduced pain thresholds to palpation. The pathophysiology remains unknown, but there is increasing evidence that peripheral and central sensitization cause an amplification of sensory impulses that may alter pain perception in fibromyalgia patients. Interventions to treat fibromyalgia should aim at different targets simultaneously in order to reduce peripheral and central sensitization. There are both pharmacologic and non-pharmacologic approaches with evidence for effectiveness in the treatment of fibromyalgia and its associated symptoms. Evidence from randomized trials and meta-analyses shows that partial and short-term improvements in fibromyalgia symptoms can be achieved with low doses of antidepressants and with physical activity such as aerobic and strengthening exercises. A multidimensional approach which emphasizes education and integration of exercise and cognitive behavior therapy improves quality of life and reduces pain, fatigue and depressive symptoms when measured on a short term basis. More recently, trials have shown the neuromodulators gabapentin and pregabalin to be effective in reducing pain and improving quality of sleep in fibromyalgia. In addition, small trials of noninvasive brain stimulation have also shown benefits in reducing pain in fibromyalgia. It is essential to keep in mind that some important clinical conditions can mimic and overlap with fibromyalgia and should always be ruled out by a complete history, physical examination and appropriate laboratory testing.
doi:10.1016/j.eujps.2009.08.011
PMCID: PMC2907544  PMID: 20657807
Fibromyalgia syndrome; Chronic Pain; Disability; Treatment; Rehabilitation
16.  Duloxetine for the treatment of fibromyalgia 
This article presents a brief review of the physiologic abnormalities seen in fibromyalgia, current theories of widespread pain, and treatment options, including emerging therapeutics, with a focus on the use of duloxetine to manage fibromyalgia symptoms. Major clinical trials that examine the efficacy and effectiveness of duloxetine to date are reviewed, and safety issues are discussed.
doi:10.1586/eci.10.64
PMCID: PMC3056054  PMID: 20828282
duloxetine; fibromyalgia; pain; serotonin and norepinephrine inhibitors; SNRI
17.  Fibromyalgia Syndrome: Etiology, Pathogenesis, Diagnosis, and Treatment 
Pain Research and Treatment  2012;2012:426130.
Fibromyalgia syndrome is mainly characterized by pain, fatigue, and sleep disruption. The etiology of fibromyalgia is still unclear: if central sensitization is considered to be the main mechanism involved, then many other factors, genetic, immunological, and hormonal, may play an important role. The diagnosis is typically clinical (there are no laboratory abnormalities) and the physician must concentrate on pain and on its features. Additional symptoms (e.g., Raynaud's phenomenon, irritable bowel disease, and heat and cold intolerance) can be associated with this condition. A careful differential diagnosis is mandatory: fibromyalgia is not a diagnosis of exclusion. Since 1990, diagnosis has been principally based on the two major diagnostic criteria defined by the ACR. Recently, new criteria have been proposed. The main goals of the treatment are to alleviate pain, increase restorative sleep, and improve physical function. A multidisciplinary approach is optimal. While most nonsteroidal anti-inflammatory drugs and opioids have limited benefit, an important role is played by antidepressants and neuromodulating antiepileptics: currently duloxetine (NNT for a 30% pain reduction 7.2), milnacipran (NNT 19), and pregabalin (NNT 8.6) are the only drugs approved by the US Food and Drug Administration for the treatment of fibromyalgia. In addition, nonpharmacological treatments should be associated with drug therapy.
doi:10.1155/2012/426130
PMCID: PMC3503476  PMID: 23213512
18.  Sodium oxybate therapy provides multidimensional improvement in fibromyalgia: results of an international phase 3 trial 
Annals of the Rheumatic Diseases  2012;71(6):935-942.
Background
Fibromyalgia is characterised by chronic musculoskeletal pain and multiple symptoms including fatigue, multidimensional function impairment, sleep disturbance and tenderness. Along with pain and fatigue, non-restorative sleep is a core symptom of fibromyalgia. Sodium oxybate (SXB) is thought to reduce non-restorative sleep abnormalities. This study evaluated effects of SXB on fibromyalgia-related pain and other symptoms.
Methods
573 patients with fibromyalgia according to 1990 American College of Rheumatology criteria were enrolled at 108 centres in eight countries. Subjects were randomly assigned to placebo, SXB 4.5 g/night or SXB 6 g/night. The primary efficacy endpoint was the proportion of subjects with ≥30% reduction in pain visual analogue scale from baseline to treatment end. Other efficacy assessments included function, sleep quality, effect of sleep on function, fatigue, tenderness, health-related quality of life and subject's impression of change in overall wellbeing.
Results
Significant improvements in pain, sleep and other symptoms associated with fibromyalgia were seen in SXB treated subjects compared with placebo. The proportion of subjects with ≥30% pain reduction was 42.0% for SXB4.5 g/night (p=0.002) and 51.4% for SXB6 g/night (p<0.001) versus 26.8% for placebo. Quality of sleep (Jenkins sleep scale) improved by 20% for SXB4.5 g/night (p≤0.001) and 25% for SXB6 g/night (p≤0.001) versus 0.5% for placebo. Adverse events with an incidence ≥5% and twice placebo were nausea, dizziness, vomiting, insomnia, anxiety, somnolence, fatigue, muscle spasms and peripheral oedema.
Conclusion
These results, combined with findings from previous phase 2 and 3 studies, provide supportive evidence that SXB therapy affordsimportant benefits across multiple symptoms in subjects with fibromyalgia.
doi:10.1136/annrheumdis-2011-200418
PMCID: PMC3371223  PMID: 22294641
19.  Beyond pain in fibromyalgia: insights into the symptom of fatigue 
Fatigue is a disabling, multifaceted symptom that is highly prevalent and stubbornly persistent. Although fatigue is a frequent complaint among patients with fibromyalgia, it has not received the same attention as pain. Reasons for this include lack of standardized nomenclature to communicate about fatigue, lack of evidence-based guidelines for fatigue assessment, and a deficiency in effective treatment strategies. Fatigue does not occur in isolation; rather, it is present concurrently in varying severity with other fibromyalgia symptoms such as chronic widespread pain, unrefreshing sleep, anxiety, depression, cognitive difficulties, and so on. Survey-based and preliminary mechanistic studies indicate that multiple symptoms feed into fatigue and it may be associated with a variety of physiological mechanisms. Therefore, fatigue assessment in clinical and research settings must consider this multi-dimensionality. While no clinical trial to date has specifically targeted fatigue, randomized controlled trials, systematic reviews, and meta-analyses indicate that treatment modalities studied in the context of other fibromyalgia symptoms could also improve fatigue. The Outcome Measures in Rheumatology (OMERACT) Fibromyalgia Working Group and the Patient Reported Outcomes Measurement Information System (PROMIS) have been instrumental in propelling the study of fatigue in fibromyalgia to the forefront. The ongoing efforts by PROMIS to develop a brief fibromyalgia-specific fatigue measure for use in clinical and research settings will help define fatigue, allow for better assessment, and advance our understanding of fatigue.
doi:10.1186/ar4395
PMCID: PMC3978642  PMID: 24289848
20.  General symptom reporting in female fibromyalgia patients and referents: a population-based case-referent study 
BMC Public Health  2009;9:402.
Background
Fibromyalgia is characterized by widespread musculoskeletal pain and palpation tenderness. In addition to these classic symptoms, fibromyalgia patients tend to report a number of other complaints. What these other complaints are and how often they are reported as compared with related referents from the general population is not very well known. We therefore hypothesized that subjects with fibromyalgia report more of a wide range of symptoms as compared with referents of the same sex and age from the general population.
Methods
138 women with diagnosed fibromyalgia in primary health care and 401 referents from the general population matched to the cases by sex, age and residential area responded to a postal questionnaire where information on marital status, education, occupational status, income level, immigrant status, smoking habits physical activity, height and weight history and the prevalence of 42 defined symptoms was sought.
Results
The cases had lower educational and income levels, were more often unemployed, on sick leave or on disability pension and were more often first generation immigrants than the referents. They were also heavier, shorter and more often had a history of excessive food intake and excessive weight loss. When these differences were taken into account, cases reported not only significantly more presumed fibromyalgia symptoms but also significantly more of general symptoms than the referents. The distribution of symptoms was similar in subjects with fibromyalgia and referents, indicating a generally higher symptom reporting level among the former.
Conclusion
Subjects with fibromyalgia had a high prevalence of reported general symptoms than referents. Some of these differences may be a consequence of the disorder while others may reflect etiological processes.
doi:10.1186/1471-2458-9-402
PMCID: PMC2776598  PMID: 19878599
21.  New treatment options in the management of fibromyalgia: role of pregabalin 
Fibromyalgia (FM) is a common, chronic pain disorder with unknown etiology, characterized by widespread musculoskeletal pain and tenderness, and accompanied by several other symptoms such as sleep disturbance, fatigue, and mood disorders. Pregabalin is the first drug approved for the treatment of FM. Pregabalin has analgesic, anticonvulsant, and anxiolytic activity and has earlier demonstrated efficacy in the management of neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, and as adjuvant therapy for adult patients with partial onset seizures. Pregabalin, a lipophilic gamma-aminobutyric acid (GABA) analog, is α2δ-1 ligand that binds to, and modulates, voltage-gated calcium channels. This modulation is characterized by a reduction of the excessive neurotransmitter release that is observed in certain neurological and psychotic disorders. Several randomized, double-blind, placebo-controlled studies have demonstrated that pregabalin has been effective in pain management, improving sleep quality and fatigue, as well as in several domains of health related quality of life. Because of mild to moderate adverse effects it can be considered a well-tolerated therapy for FM.
PMCID: PMC2646648  PMID: 19337459
fibromyalgia; pregabalin; GABA analog; fibromyalgia treatment
22.  Evaluation of the efficacy of memantine in the treatment of fibromyalgia: study protocol for a doubled-blind randomized controlled trial with six-month follow-up 
Trials  2013;14:3.
Background
Fibromyalgia is a prevalent chronic rheumatic disease of great clinical importance. Recent studies have found raised levels of glutamate in the insula, hippocampus and posterior cingulate cortex regions of the brains of fibromyalgia (FM) patients. This finding has led researchers to speculate about the usefulness of glutamate-blocking drugs such as memantine in the treatment of fibromyalgia. The hypothesis of this study is that the administration of memantine will reduce the glutamate levels, and futhermore, will decrease the perceived pain. The aim of this study is to evaluate the efficacy of memantine in the treatment of pain (pain perception). A secondary objective is to evaluate the efficacy of memantine in the treatment of other clinical symptoms of FM, and to evaluate the efficacy of memantine in reducing brain levels of glutamate, and its effects on the central nervous system as a whole.
Method/Design
A double-blind parallel randomized controlled trial. Participants, Seventy patients diagnosed with FM will be recruited from primary health care centers in Zaragoza, Spain. Intervention. The subjects will be randomized in two groups: A) A treatment group (n = 35), which will receive 20 mg of memantine daily; B) A control group (n = 35), to which will be administered a placebo. There will be a six-month follow-up period (including a titration period of one month). Outcomes. The main efficacy variable of this study is pain (pain perception). The secondary efficacy variables are clinical symptoms (pain threshold, cognitive function, health status, anxiety, depression, clinical impression and quality of life) and glutamate levels in different regions of the brain, which will be assessed by magnetic resonance spectroscopy. Randomization and blinding. Randomization has been computer-generated, and the random allocation sequence will be implemented by telephone. Subjects of the study and the research assistants will be blinded to group assignment.
Discussion
There is a need for the development of innovative and more effective treatments for fibromyalgia. This clinical trial will determine whether memantine can be an effective pharmacological treatment for fibromyalgia patients.
Trial registration
Current Controlled Trials http://ISRCTN45127327 EUDRACT 2011-006244-73
doi:10.1186/1745-6215-14-3
PMCID: PMC3598995  PMID: 23286311
Fibromyalgia; Memantine; Chronic pain; Magnetic resonance spectroscopy; Randomized controlled trial
23.  The Science of Fibromyalgia 
Mayo Clinic Proceedings  2011;86(9):907-911.
Fibromyalgia (FM) is a common chronic widespread pain disorder. Our understanding of FM has increased substantially in recent years with extensive research suggesting a neurogenic origin for the most prominent symptom of FM, chronic widespread pain. Neurochemical imbalances in the central nervous system are associated with central amplification of pain perception characterized by allodynia (a heightened sensitivity to stimuli that are not normally painful) and hyperalgesia (an increased response to painful stimuli). Despite this increased awareness and understanding, FM remains undiagnosed in an estimated 75% of people with the disorder. Clinicians could more effectively diagnose and manage FM if they better understood its underlying mechanisms. Fibromyalgia is a disorder of pain processing. Evidence suggests that both the ascending and descending pain pathways operate abnormally, resulting in central amplification of pain signals, analogous to the “volume control setting” being turned up too high. Patients with FM also exhibit changes in the levels of neurotransmitters that cause augmented central nervous system pain processing; levels of several neurotransmitters that facilitate pain transmission are elevated in the cerebrospinal fluid and brain, and levels of several neurotransmitters known to inhibit pain transmission are decreased. Pharmacological agents that act centrally in ascending and/or descending pain processing pathways, such as medications with approved indications for FM, are effective in many patients with FM as well as other conditions involving central pain amplification. Research is ongoing to determine the role of analogous central nervous system factors in the other cardinal symptoms of FM, such as fatigue, nonrestorative sleep, and cognitive dysfunction.
doi:10.4065/mcp.2011.0206
PMCID: PMC3258006  PMID: 21878603
24.  Fibromyalgia: When Distress Becomes (Un)sympathetic Pain 
Pain Research and Treatment  2011;2012:981565.
Fibromyalgia is a painful stress-related disorder. A key issue in fibromyalgia research is to investigate how distress could be converted into pain. The sympathetic nervous system is the main element of the stress response system. In animal models, physical trauma, infection, or distressing noise can induce abnormal connections between the sympathetic nervous system and the nociceptive system. Dorsal root ganglia sodium channels facilitate this type of sympathetic pain. Similar mechanisms may operate in fibromyalgia. Signs of sympathetic hyperactivity have been described in this condition. Genetic factors and/or distressful lifestyle may lead to this state of sympathetic hyperactivity. Trauma and infection are recognized fibromyalgia triggers. Women who suffer from fibromyalgia have catecholamine-evoked pain. Sympathetic dysfunction may also explain nonpain-related fibromyalgia symptoms. In conclusion, in fibromyalgia, distress could be converted into pain through forced hyperactivity of the sympathetic component of the stress response system.
doi:10.1155/2012/981565
PMCID: PMC3200207  PMID: 22110948
25.  Role and rationale for the use of milnacipran in the management of fibromyalgia 
Fibromyalgia (FM) is a complex syndrome characterized by chronic widespread musculoskeletal pain which is often accompanied by multiple other symptoms, including fatigue, sleep disturbances, decreased physical functioning, and dyscognition. Due to these multiple symptoms, as well as high rates of comorbidity with other related disorders, patients with FM often report a reduced quality of life. Although the pathophysiology of FM is not completely understood, patients with FM experience pain differently from the general population, most likely due to dysfunctional pain processing in the central nervous system leading to both hyperalgesia and allodynia. In many patients with FM, this aberrant pain processing, or central sensitization, appears to involve decreased pain inhibition within the spinal tract, which is mediated by descending pathways that utilize serotonin, norepinephrine, and other neurotransmitters. The reduced serotonin and norepinephrine levels observed in patients with FM suggest that medications which increase the levels of these neurotransmitters, such as serotonin and norepinephrine reuptake inhibitors (SNRIs), may have clinically beneficial effects in FM and other chronic pain conditions. Milnacipran is an SNRI that has been approved for the management of FM. In clinical trials, treatment with milnacipran for up to 1 year has been found to improve the pain and other symptoms of FM. Because FM is characterized by multiple symptoms that all contribute to the decreased quality of life and ability to function, the milnacipran pivotal trials implemented responder analyses. These utilized a single composite endpoint to identify the proportion of patients who reported simultaneous and clinically significant improvements in pain, global disease status, and physical function. Other domains assessed during the milnacipran trials include fatigue, multidimensional functioning, mood, sleep quality, and patient-reported dyscognition. This review article provides information intended to help clinicians make informed decisions about the use of milnacipran in the clinical management of patients with FM. It draws primarily on results from 2 of the pivotal clinical trials that formed the basis of approval of milnacipran in the United States by the Food and Drug Administration.
PMCID: PMC2877602  PMID: 20520784
fibromyalgia; milnacipran; pain; serotonin and norepinephrine reuptake inhibitors; SNRI

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