Beyond pain in fibromyalgia: insights into the symptom of fatigue

  • Ann Vincent1, 2Email author,

    Affiliated with

    • Roberto P Benzo3,

      Affiliated with

      • Mary O Whipple2,

        Affiliated with

        • Samantha J McAllister2,

          Affiliated with

          • Patricia J Erwin4 and

            Affiliated with

            • Leorey N Saligan5

              Affiliated with

              Arthritis Research & Therapy201315:221

              DOI: 10.1186/ar4395

              Published: 29 November 2013

              Abstract

              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.

              Fatigue in fibromyalgia: common problem, multiple causes

              Fibromyalgia is a chronic, multi-symptom complex with no effective treatment. It affects 2% of the United States population and significantly impacts both healthcare costs and utilization of healthcare resources [1, 2]. In addition to unrefreshing sleep, cognitive difficulties and affective symptoms, chronic widespread pain and fatigue are its cardinal symptoms [3, 4]. For patients with fibromyalgia and their treating clinicians, fatigue is a complicated, multifactorial, and vexing symptom that is highly prevalent (76%) and stubbornly persistent, as evidenced by longitudinal studies over 5 years [57].

              Despite its disabling effects, fatigue has not received the same research attention in fibromyalgia as has pain, for a variety of reasons. First, there is no established nomenclature with which to describe the multiple types and manifestations of fatigue. Patients with fibromyalgia may experience fatigue physically (lack of energy, physical exhaustion), emotionally (lack of motivation), cognitively (inability to think or concentrate), or via the symptom’s impact on virtually any aspect of living, such as the ability to work, meet family needs, or engage in social activities [8]. Patients may experience these different types of fatigue simultaneously, but clinicians rarely sort this through during the typical office visit, and the complaint is often chronicled simply as 'fatigue’. Second, clinical experience indicates that patients usually do not feel comfortable making an appointment for 'just’ fatigue. They need a medical condition or an acceptable symptom (as institutionally and culturally dictated), such as pain, despite the fact that fatigue is reported as a bothersome symptom in up to 80% of patients with chronic conditions and is a common complaint in both primary and specialty clinics [911]. Third, the lack of understanding of the mechanisms of fatigue contributes to poor assessment and treatment strategies, and may make providers wary of broaching the topic in a clinical encounter.

              Fortunately, two recent initiatives, the Outcome Measures in Rheumatology (OMERACT) [1215] and the Patient Reported Outcomes Measurement Information System (PROMIS) [16], are helping to move the study of fatigue in fibromyalgia forward. OMERACT organized focus groups and Delphi studies of both patients with fibromyalgia and physician experts that have resulted in important recommendations for assessment and treatment of fatigue. First among these was the ranking of fatigue, pain, sleep, quality of life, mood, and cognition as the most relevant symptoms in fibromyalgia, and second, the recommendation that fatigue be assessed in all clinical trials of fibromyalgia. PROMIS, an initiative of the National Institutes of Health, developed item response theory-based banks to assess symptoms such as fatigue, pain, and sleep, as well as quality of life measures. The goal of this initiative was to 1) create measures that are valid, reliable, and generalizable for clinical outcomes that are important to patients, 2) reliably assess patient response to interventions, and 3) inform treatment modifications. The PROMIS Fatigue Item Bank (PROMIS-FIB) contains 95 items that evaluate the spectrum of fatigue from mild subjective feelings of tiredness to an overwhelming, debilitating, and sustained sense of exhaustion that interferes with activities of daily living, family, and social roles [17]. The assessment categories are divided into the experience (frequency, duration, and intensity) and impact of fatigue on physical, mental, and social activities. Work is currently underway to assess the psychometric properties of the PROMIS-FIB and develop a brief fibromyalgia-specific measure for clinical and research purposes.

              The objectives of this narrative review are to 1) provide a general overview of the current knowledge of fatigue in the context of fibromyalgia, 2) suggest a rationale for assessment of fatigue, and 3) describe non-pharmacological and pharmacological management modalities studied in the context of fibromyalgia that also improve fatigue. While this is not a systematic review, this critical narrative review may guide clinical decisions when faced with a fatigued patient with fibromyalgia.

              Search strategy

              The search was performed using Ovid MEDLINE, Ovid EMBASE, and EBSCO CINAHL (Cumulative Index of Nursing and Allied Health Literature), covering 2000 through May 2013. The search strategy used controlled vocabulary (subject headings) and text words in the title and/or abstract - fibromyalgia, fatigue and synonyms related to fatigue (for example, weakness, tiredness, exhaustion, stiffness, depression). The results were limited to English, publication format (review, meeting abstract) and study designs (trials, cohort studies, systematic reviews), yielding a total of 644 unique publications.

              Fatigue characteristics: qualitative research

              Results of qualitative studies provide insights into the encumbrance that fatigue inflicts on patients with fibromyalgia and the concomitant problem of articulating to their doctors what is wrong. Patients with fibromyalgia describe fatigue as 'an inescapable or overwhelming feeling of profound physical tiredness’, 'weakness in the muscles’, 'an uncontrollable, unpredictable constant state of never being rested’, 'a ghastly sensation of being totally drained of every fiber of energy’, 'not proportional to effort exerted’, 'not relieved by rest’, 'having to do things more slowly’, and 'an invisible foe that creeps upon them unannounced and without warning’ [8, 18, 19]. Patients also report that fatigue is interwoven, influenced, and intensified by pain, and is sometimes more severe than pain [18]. Although fatigue is reported by both men and women with fibromyalgia, one study demonstrated that men had less fatigue compared to women and a second study reported that men tend to focus more on pain and women on fatigue [8, 20].

              Fatigue correlates: insights into etiology

              The key symptoms of fibromyalgia - pain, fatigue, unrefreshing sleep, dyscognition, and depressed mood - do not occur in isolation. Rather, they often present concurrently, in varying severity, and are intertwined with and influence each other (Figure 1). Indeed, studies demonstrate that chronic persistent pain (both from abnormal central sensitization and maintenance of nociceptive pain from peripheral pain generators), poor sleep quality (subjective report and objective measures), depressed mood, anxiety, or combinations of these are associated with fatigue [2123] (Table 1). In addition to common fibromyalgia symptoms, clinical characteristics (for example, body mass index), health behaviors (for example, physical activity levels), and psychological variables (for example, negative affect, catastrophizing, affect regulation), also demonstrate strong associations with fatigue [2227] (Table 1). In addition to cross-sectional associations, diurnal rhythmicity and lag relationships have also been demonstrated between fatigue and other fibromyalgia symptoms (particularly pain, stiffness, and affect), suggesting that one variable can influence or predict the others [28, 29]. Appreciating these associations is important in fatigue assessment because daily assessment of fatigue may uncover lag relationships with other symptoms, providing avenues for intervention. Collectively, these studies indicate that many symptoms feed into fatigue and the implication of this finding, for both clinical practice and research, is that fatigue assessment must consider this multi-dimensionality. This is not unlike pain in fibromyalgia, which is increasingly demonstrated to be multidimensional, with contributions from central pain, peripheral musculoskeletal pain generators, and neuropathic pain, among other pathways [30].
              http://static-content.springer.com/image/art%3A10.1186%2Far4395/MediaObjects/13075_2013_4046_Fig1_HTML.jpg
              Figure 1

              Association of fatigue and other fibromyalgia symptoms.

              Table 1

              Correlates of fatigue

              Correlate

              Design and sample

              Direction

              Pain

              4 cross-sectional [5, 3133]

              Positive

              6 longitudinal (5 months, 30 days, 10 days, 6 days) [21, 22, 28, 29, 3436]

              Sleep duration

              1 longitudinal (30 days) [34]

              Negative

              Sleep quality

              2 longitudinal (6 days, 3 days) [21, 37]

              Negative

              Sleep disturbance

              1 cross-sectional [5]

              Positive

              1 longitudinal (30 days) [29, 35]

              Anxiety and depression

              5 cross-sectional [5, 31, 3840]

              Positive

              4 longitudinal (5 months, 30 days, 6 days) [21, 22, 29, 34, 35]

              Tenderness

              2 cross-sectional [5, 38]

              Positive

              Stiffness

              1 cross-sectional [33]

              Positive

              1 longitudinal (10 days) [28]

              Disability

              2 cross-sectional [5, 33]

              Positive

              Cognitive complaints

              1 cross-sectional [41]

              Positive

              Gastrointestinal distress

              1 cross-sectional [5]

              Positive

              Negative events

              1 longitudinal (30 days) [35]

              Positive

              Positive events

              1 longitudinal (30 days) [35]

              Negative same day, positive following day

              Positive affect

              1 cross-sectional [42]

              Negative

              1 longitudinal (30 days) [29]

              Negative affect

              1 longitudinal (30 days) [29]

              Positive

              Internal locus of control

              1 cross-sectional [43]

              Negative

              External locus of control

              1 cross-sectional [43]

              Negative

              Emotional distress

              1 longitudinal (30 days) [36]

              Positive

              Fibromyalgia severity

              2 cross-sectional [5, 44]

              Positive

              The association of objective tests assessing the hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis, and corticotropin releasing factor in the cerebrospinal fluid with fatigue have been negative or inconclusive [38, 45, 46]. However, preliminary studies indicate that histological characteristics of skeletal muscle, such as muscle fiber distribution and capillary density, may be correlated with post-exertional malaise [47]. More recently, genomic studies have sought to identify possible physiologic pathways to explain the symptoms experienced by patients with fibromyalgia. Gene expression studies suggest the significant role of the catechol-O-methyltransferase, cytokine, adrenergic, dopamine, glucocorticoid and mineralocorticoid receptors, iron channel receptors and serotonin transporter in developing and maintaining the symptom complex [48, 49]. However, most of the early studies were conducted using pre-selected gene single nucleotide polymorphisms, which may introduce selection bias in assuming the disease etiology of fibromyalgia. One recent study investigating whole genome expression in patients with fibromyalgia with fatigue found an upregulation of centromere protein K (CENPK) and heat shock protein 90 kDa alpha (cytosolic, class A member 1 (HSP90AA1)) genes in fibromyalgia subjects when compared with age-, gender-, and race-matched healthy controls [50]. These genes are associated with glucocorticoid receptor signaling and the protein ubiquitination pathway (GIN1, GRAMD1C, ZNF880, NFYB, CENPK, CA1, and TNS1) [51]. Impairment of the ubiquitination pathways has been demonstrated to be associated with neurodegenerative diseases (for example, Alzheimer’s and Parkinson’s disease) and depression [52]. Additionally, interferon signaling and interferon regulatory pathways (associated with spinal nociception) distinguished between the pain groups, and dendritic cell maturation (associated with mood) delineated between the catastrophizing groups [50]. Collectively, these studies suggest that multiple physiological mechanisms may be associated with the symptom of fatigue.

              Fatigue assessment

              In the absence of objective biomarkers, assessment of fatigue is guided solely by patient-reported symptoms. Presently, there are no algorithms with which to systematically assess and treat fatigue. As noted, assessment must consider fatigue’s multidimensional manifestations. In clinical practice, therefore, evaluation of fatigue must account for both the experience of fatigue, as well as its functional impact, and place these in the context of other symptoms and co-morbidities specific to the particular patient.

              The assessment begins with a thorough history and physical examination (to identify reversible causes of fatigue), and a systematic symptom-centered assessment pertaining not only to fatigue but also to pain, sleep, autonomic symptoms, causes of unrefreshing sleep (for example, obstructive sleep apnea, restless leg syndrome), psychiatric disorders, such as depression and anxiety, and inquiry into health behaviors, daily practices, such as physical activity, and dietary habits (Figure 2). Table 2 illustrates common fibromyalgia symptoms, sample assessment tools, conditions to consider and suggestions for objective tests to evaluate abnormal symptoms.
              http://static-content.springer.com/image/art%3A10.1186%2Far4395/MediaObjects/13075_2013_4046_Fig2_HTML.jpg
              Figure 2

              A sample systematic symptom-centered assessment of fatigue. POTS, postural orthostatic tachycardia syndrome; tbl 2, Table 2.

              Table 2

              Symptom assessment in the clinical setting

              Symptom

              Sample assessment tools

              Conditions to consider

              Objective tests

              Activity intolerance

              BPI pain interference [53]

              Deconditioning

              6 minute walk test

               

              MFI reduced activity [54]

              Obesity

              Cardiopulmonary exercise test

                 

              30-second chair-stand test

               

              SF-36 role emotional, role physical [55, 56]

              Neuromuscular disorder

              Body mass index

              Affective

              GAD-7 [57]

              Anxiety disorder

               
               

              PHQ-9 [58]

              Generalized anxiety disorder

               
               

              HADS [59]

              Depression

               
               

              CES-D [60]

              Dysthymia

               
                

              Somatoform disorder

               

              Autonomic

              ASP-31 [61]

              Orthostatic intolerance

              Thermoregulatory sweat test

                

              Autonomic neuropathies

              Autonomic reflex screen

                

              Postural orthostatic tachycardia syndrome

               

              Pain

              BPI [53]

              Regional pain syndromes

              Imaging

               

              Pain VAS

              Neuropathy

              Electromyography

                

              Inflammatory arthritis

              Laboratory testing for inflammation

                

              Degenerative arthritis

              Muscle biopsy

                

              Headaches

              Quantitative sensory testing

                

              Myopathy

               

              Unrefreshing sleep

              MOS-Sleep [62]

              Insomnia

              Overnight oximetry

               

              Berlin Sleep Questionnaire

              Obstructive sleep apnea

              Polysomnography

               

              Restless legs screen

              Restless legs syndrome

              Actigraphy

                

              Periodic limb movement disorder

               
                

              Narcolepsy

               
                

              Sleep phase disorder

               

              ASP-31, Autonomic Symptom Profile-31; BPI, Brief Pain Inventory; CES-D, Center for Epidemiologic Studies Depression Scale; GAD-7, Generalized Anxiety Disorder questionnaire; HADS, Hospital Anxiety and Depression Scale; MFI, Multidimensional Fatigue Inventory; MOS-Sleep, Medical Outcomes Study Sleep Scale; PHQ-9, Patient Health Questionnaire; SF-36, Medical Outcomes Study Short Form-36; VAS, Visual Analogue Scale.

              In the research setting, in the absence of an objective measure, fatigue in fibromyalgia can only be assessed with validated, self-report questionnaires. Although the OMERACT Fibromyalgia Working Group recommends the assessment of fatigue in all clinical trials of fibromyalgia, no measure specific to fibromyalgia fatigue has been developed to date [12]. Fatigue assessment in clinical trials has utilized single item measures (visual analog scale - fatigue), multidimensional fatigue measures (for example, Multidimensional Fatigue Inventory and Multidimensional Assessment of Fatigue), or single items from composite measures, such as the Fibromyalgia Impact Questionnaire - Revised and the Medical Outcomes Study Short Form-36 [54, 55, 6366] (Table 3). Notably, most of these questionnaires were created for the assessment of fatigue in other chronic disorders such as cancer and rheumatologic conditions and have yet to be validated for fibromyalgia, with the exception of the single-item fatigue visual analog scale [63].
              Table 3

              Sample list of questionnaires that have been used in the assessment of fatigue in clinical trials

              Measure

              Dimensions of fatigue

              Scaling and number of items

              Features

              Chalder Fatigue Questionnaire [67, 68]

              Physical and mental

              11 items

              2-3 minute administration time

              4-point Likert scale

              Higher = worse

              Recall period for the past month

              Checklist Individual Strength (CIS) [69]

              Subjective experience, concentration, motivation, and physical activity

              20 items

              4-5 minute administration time

              7-point Likert scale

              Higher = worse

              Designed for chronic fatigue syndrome, but also used with fibromyalgia and healthy populations

              Recall period for past 2 weeks

              Fatigue Severity Scale (FSS) [70]

              Physical, social, and cognitive

              9 items

              2-3 minute administration time

              7-point Likert scale

              Higher = worse

              Recall period for the past week

              Medical Outcome Study Short Form-36 (SF-36) Vitality Subscale [55, 56]

              Energy and vitality

              4 items

              1-2 minute administration time

              6-point (version 1) or 5-point (version 2) Likert scale

              Higher scores = better

              Recall period for the past 4 weeks

              Multidimensional Assessment of Fatigue (MAF) [64]

              Severity, stress, degree of interference with activities of daily living, timing, and global

              16 items

              5-8 minute administration time

              10-point rating scales for 1–14, 15 and 16 have 4 ordinal responses

              Higher scores = worse

              Designed for rheumatoid arthritis, but also used in fibromyalgia

              Recall period for the past week

              Multidimensional Fatigue Inventory (MFI) [54]

              Global experience and somatic, cognitive, affective, and behavioral symptoms

              20 items

              4-5 minute administration time

              5-point Likert scale

              Higher scores = worse

              Recall period is stated as 'lately’

              Visual Analogue Scale (VAS)

              Any dimension required, typically severity or intensity

              1 item

              <1 minute administration time

                

              100 mm horizontal line anchored by two statements

              Recall period typically 1 week, varies

              Debate also remains concerning the aspects of fatigue that must be assessed and whether measurement of fatigue requires subsets of questions targeting its separate manifestations (for example, global, somatic, affective, cognitive, and behavioral). Ongoing work from PROMIS and other groups will bring clarity to these issues. Until then, when selecting a fatigue questionnaire, researchers must consider its purpose. If the questionnaire is to be used as a screening tool, a shorter, single-item measure may be appropriate, or if the need is to evaluate an intervention, a multidimensional scale may be more appropriate.

              Fatigue management

              Our current understanding of the pathophysiology of fatigue suggests that its management in patients with fibromyalgia is most successful if developed by a multidisciplinary team with the patient as an equal participant. The treatment program should be individualized, and likely will incorporate combinations of behavioral, pharmacological, and rehabilitative interventions. Management is not aimed at the etiology of fatigue; rather, the focus is on symptoms, contributing factors, and treatment of comorbidities. Clinical experience suggests that a step-wise approach integrating different modalities with periodic assessment is ideal. This approach should be continued until clinically meaningful symptom improvement is achieved.

              Non-pharmacologic and behavioral modalities

              Care should always begin with patient education on the nature of fatigue and fibromyalgia, setting pragmatic goals for symptom reduction, and improvement of function. Patient education can include strategies such as pacing, energy conservation, increasing lifestyle physical activity, getting regular exercise, rest-activity balance, balanced diet, lifestyle moderation, stress management, time management, and sleep hygiene. As previously mentioned, daily symptom logs can help identify activities that exacerbate fatigue and other fibromyalgia symptoms. They can also guide individualization of non-pharmacological modalities. A selected listing of pharmacological and non-pharmacological clinical trials conducted in fibromyalgia where fatigue was also assessed is given in Tables 4, 5 and 6. In all of these studies, fatigue was only assessed as a secondary outcome (pain was primary). Even so, clinically meaningful changes in fatigue were demonstrated in some of these efficacy studies. This indicates that treatment modalities studied in the context of fibromyalgia could also be utilized to improve fatigue.
              Table 4

              Non-pharmacological strategies

              Intervention

              Design and sample

              Scales used

              Effect on fatigue

              Conventional therapies

                 

              Cognitive behavioral therapy

              One RCT comparing multidisciplinary treatment to treatment augmented with CBT (n = 83) of women with FM [71]

              FIQ fatigue

              Cannot draw conclusion

              Exercise - aerobic exercise

              1 single-arm study of women with FM, CFS, and CFIDS (n = 7) [72]

              VAS fatigue

              Cannot draw conclusion in single arm study, 2 meta-analyses found improvement, MCID cannot be determined

              2 meta-analyses of 28 RCTs (n = 2,494) [73] and 34 RCTs (n = 2,276) [74]

              Exercise - strength training

              1 RCT (n = 26) of postmenopausal women with FM [75]

              VAS fatigue

              Clinically meaningful improvement in 2 RCTs, cannot draw conclusion in 1 RCT

              1 double-arm study of aerobic versus strength training (n = 30) of women with FM [76]

              1 RCT (n = 21) of premenopausal women with FM [77]

              Multicomponent/multidisciplinary treatmenta

              2 single-arm studies (n = 305) of patients with FM [78, 79], 4 RCTs (n = 513) of patients with FM [8083], 1 RCT (n = 855) in patients with FM, OA, and RA [84]

              FIQ fatigue

              Clinically meaningful improvement in 4 RCTs, no clinically meaningful improvement in 3 RCTs

              1 meta-analysis of 9 RCTs (n = 1119) [85]

              VAS fatigue

              Meta-analysis found no evidence for efficacy in long-term follow-up

              Complementary and alternative medicine

                 

              Acupuncture

              1 meta-analysis of 7 RCTs (median treatment time 9 sessions, n = 385) [86]

               

              No improvement

              Meditative movement therapies

              1 meta-analysis of 7 RCTs (n = 362) [87]

               

              Improvement overall, in subgroup analysis, only yoga improved fatigue

              aMultidisciplinary treatments varied between studies but typically included education, exercise, psychotherapy (that is, cognitive behavioral therapy (CBT), dialectical behavior therapy (DBT), and so on), and occupational and physical therapies. CF, chronic fatigue; CFIDS, chronic fatigue and immune dysfunction syndrome; FIQ, Fibromyalgia Impact Questionnaire; FM, fibromyalgia; MCID, minimal clinically important difference; OA, osteoarthritis; RA, rheumatoid arthritis; RCT, randomized controlled trial; VAS, Visual Analogue Scale.

              Table 5

              Food and Drug Administration-approved pharmacological strategies

              Intervention

              Design and sample

              Scales used

              Mechanism of action

              Effect on fatigue

              Duloxetine

              3 double blind, placebo-controlled RCTs of patients with FM (n = 899) [8890]

              MFI

              Blocks reuptake of serotonin and norepinephrine within the central nervous system

              Clinically meaningful improvement in 2 of the RCTs, no clinically meaningful improvement in the other

              FIQ fatigue

              Milnacipran

              6 double-blind, placebo-controlled RCTs of patients with FM (n = 4,243) [9196]

              MFI

              Blocks reuptake of serotonin and norepinephrine within the central nervous system

              No clinically meaningful improvement in 4 RCTs using MFI, cannot draw conclusion in 2 RCTs, and clinically meaningful improvement in 1 RCT (VAS fatigue)

              1 double-blind, dose finding trial (n = 468) [97]

              VAS fatigue

              Pregabalin

              3 double-blind, placebo-controlled RCTs of patients with FM (n = 2,328) [98100]

              MAF

              Interacts with the alpha-2-delta subunit of l-type voltage-regulated calcium channels

              No clinically meaningful improvement in 2 RCTs, cannot draw conclusion in 1 RCT

              FIQ, Fibromyalgia Impact Questionnaire; FM, fibromyalgia; MAF, Multidimensional Assessment of Fatigue; MFI, Multidimensional Fatigue Inventory; RCT, randomized controlled trial; VAS, Visual Analogue Scale.

              Table 6

              Supplementary table of non-pharmacological, pharmacological, and dietary supplements and botanicals

              Intervention

              Design and sample

              Scales used

              Effect on fatigue

              Non-pharmacological

                 

              Balneotherapy

              3 RCTs (n = 128) of women with FM [101103]

              VAS fatigue

              Clinically meaningful improvement

              Cognitive behavioral therapy

              1 RCT comparing multidisciplinary treatment to treatment augmented with CBT (n = 83) of women with FM [71]

              FIQ fatigue

              Cannot draw conclusion

              Electroconvulsive therapy

              1 pilot study (n = 13) of patients with FM and concomitant depression [104]

              FIQ fatigue

              Clinically meaningful improvement

              Low-energy laser therapy

              1 single-blind, placebo-controlled trial (n = 40) of women with FM [105]

              Likert scale rating fatigue as mild, moderate, severe or extreme

              Cannot draw conclusion in 1 RCT, clinically meaningful improvement in 1 RCT

              1 RCT (n = 75) of patients with FM [106]

              FIQ fatigue

              Mindfulness

              1 open pilot study (n = 40) of women with FM [107]

              Not identified

              Cannot draw conclusion

              Noninvasive cortical electrostimulation

              1 placebo-controlled RCT (n = 77) of patients with FM [108]

              FIQ fatigue

              Clinically meaningful improvement

              Pulsed ultrasound and interferential current

              1 double-blind, placebo-controlled RCT (n = 17) of patients with FM [109]

              VAS fatigue

              Clinically meaningful improvement

              Qigong

              1 single-arm pilot study (n = 10) in women with FM [110]

              Not identified

              Cannot draw conclusion

              Sensory motor rhythm treatment

              1 RCT (n = 36) patients with FM [111]

              VAS fatigue

              Clinically meaningful improvement

              TENS

              1 RCT (n = 28) women with FM where TENS was used as an adjuvant to aerobic and stretching exercise [112]

              FIQ fatigue

              Clinically meaningful improvement

              Transcranial magnetic stimulation

              2 double-blind, placebo-controlled RCTs (n = 70) of patients with FM [113, 114]

              FIQ fatigue

              Clinically meaningful improvement

              Vegetarian diet

              1 observational study (n = 30) of patients with FM [115] and 1 open RCT (n = 78) of patients with FM [116]

              FIQ fatigue

              Clinically meaningful improvement in 1 RCT, cannot draw conclusion in open RCT

              VAS fatigue

              Whole-body vibration exercise

              1 pilot study (n = 36) of women with FM [117]

              FIQ fatigue

              Clinically meaningful improvement

              Written emotional expression

              1 RCT (n = 92) of patients with FM [118]

              Vitality subscale of SF-36

              Cannot draw conclusion

              Yoga

              1 pilot RCT (n = 53) of women with FM [119]

              FIQ fatigue

              Clinically meaningful improvement

              Pharmacological

                 

              Amitriptyline

              2 placebo-controlled RCTs of patients with FM (n = 127) [106, 120]

              FIQ fatigue

              1 RCT found clinically meaningful improvement, 1 RCT found no clinically meaningful improvement, cannot draw conclusion in 1 open-label RCT

              1 open RCT (n = 78) of patients with FM [116]

              VAS fatigue

              2 meta-analyses found improvement, but MCID cannot be determined

              2 meta-analyses of 10 RCTs (n = 615) [121] and 13 RCTs [122] in patients with FM

              Armodafinil

              1 single-blind, placebo-controlled, RCT of patients with FM and fatigue (n = 60) [123]

              BFI

              Cannot draw conclusion

              Cyclobenzaprine

              1 meta-analysis of 5 RCTs (n = 312) in patients with FM [124]

               

              No improvement

              Esreboxetine

              2 double-blind, placebo-controlled, multicenter RCTs (n = 1,389) [125, 126]

              MAF

              No clinically meaningful improvement

              Fluoxetine

              1 double-blind, placebo-controlled RCT of patients with FM (n = 60) [127]

              FIQ fatigue

              Clinically meaningful improvement

              Gamma-hydroxybutyrate/sodium oxybate

              1 open-label pilot study (n = 11) of patient with FM [128]

              VAS fatigue

              Clinically meaningful improvement in 2 RCTs, cannot draw conclusion in 1 RCT and retrospective review

              FIQ fatigue

              3 double-blind, placebo-controlled RCTs of patients with FM (n = 876) [129131], 1 retrospective review of patients with CFS and FM treated in a neurology practice (n = 118) [132]

              Retrospective review

              Mirtazapine

              1 single-arm, open-label trial of patients with FM (n = 29) [133]

              VAS fatigue

              Cannot draw conclusion

              Pramipexole

              1 double-blind, placebo-controlled RCT (n = 60) [134]

              VAS fatigue

              Clinically meaningful improvement

              Pyridostigmine

              1 double-blind, placebo-controlled RCT of patients with FM (n = 165) [135]

              FIQ fatigue

              Clinically meaningful improvement

              Quetiapine

              1 open-label study (n = 35) of patients with FM who had not responded to previous FM treatments [136]

              FIQ fatigue

              Clinically meaningful improvement

              Raloxifene

              1 double-blind, placebo-controlled RCT (n = 100) of post-menopausal women with FM [137]

              VAS fatigue

              Clinically meaningful improvement

              Tropisetron

              1 pilot study of intravenous tropisteron in patients with FM (n = 42) [138]

              4 point rating of fatigue (0 = absent, 1 = hardly, 2 = moderate, 3 = considerable)

              Cannot draw conclusion

              Dietary supplements and botanicals

                 

              Acetyl l-carnitine

              1 double-blind, placebo-controlled RCT (n = 102) of patients with FM [139]

              VAS fatigue

              Clinically meaningful improvement

              Coenzyme Q

              1 double-blind, placebo-controlled RCT (n = 20) [140]

              FIQ fatigue

              Cannot draw conclusion

              Dehydroepiandosterone

              1 double-blind, crossover RCT in post-menopausal women with FM (n = 52) [141]

              VAS fatigue

              No clinically meaningful improvement

              Ginseng

              1 double-blind, placebo-controlled RCT (n = 52) [120]

              VAS fatigue

              No clinically meaningful improvement

              IV nutrient therapy

              1 pilot study (n = 7) of patients with FM [142]

              5 point numeric scale (5 = high energy, 0 = low energy)

              Cannot draw conclusion

              Melatonin

              1 open-label, pilot study (n = 21) of patients with FM [143]

              VAS fatigue

              Clinically meaningful improvement

              S-Adenosylmethionine

              2 double-blind, placebo-controlled RCT (n = 78) [144, 145]

              VAS fatigue

              No clinically meaningful improvement

              BFI, Brief Fatigue Inventory; CBT, cognitive behavioral therapy; CFS, chronic fatigue syndrome; FIQ, Fibromyalgia Impact Questionnaire; FM, fibromyalgia; MAF, Multidimensional Assessment of Fatigue; MCID, minimal clinically important difference; RCT, randomized controlled trial; SF-36, Medical Outcomes Study Short Form-36; TENS, transcutaneous electrical nerve stimulation; VAS, Visual Analogue Scale.

              Non-pharmacological symptom management modalities, such as graded aerobic exercise, have demonstrated beneficial effects on physical capacity and fibromyalgia symptoms, including fatigue [73, 74] (Table 4). Combining aerobic exercise with resistance and strength training may offer additional benefits [146, 147]. Cognitive behavioral-based therapies (particularly for comorbid depression, anxiety, and pain), meditative movement therapies (for example, tai chi, yoga, qigong) and education sessions led by occupational therapists to enable patients to identify individual lifestyle factors that exacerbate fatigue and develop appropriate fatigue management and energy conservation techniques have good efficacy data [51, 148150]. As with medications that require an adequate dose and duration for clinical efficacy, non-pharmacological modalities will only be effective if they are adequately dosed over the period of time that is required for physical, cognitive, and psychological rehabilitation. In most cases this may require several months and a step-wise, graded approach. Patients should be educated upfront to optimize success and compliance with the management strategy. Complementary and alternative therapies, such as acupuncture and homeopathy, have not demonstrated benefit in clinical studies, although patients commonly utilize these modalities, citing clinical benefit [151]. Carefully designed future trials will shed light on their use.

              Pharmacologic modalities

              Trials of serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, tricyclics, and alpha-2 delta ligands that impact multiple fibromyalgia symptoms suggest that these medications could also improve the symptom of fatigue (Tables 5 and 6). The choice of medication depends on the patient’s comorbid symptoms and use of a single medication to address multiple symptoms may be beneficial to minimize side effects. For example, in a fatigued patient with fibromyalgia with comorbid depression, serotonin-norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, or tricyclics that have a differential effect on mood may be the pharmacological agent of choice. On the other hand, an alpha-2-delta ligand or a tricyclic may be more appropriate for a patient with comorbid unrefreshing sleep. If insomnia and unrefreshing sleep are the most bothersome symptoms for the patient, then targeting this symptom domain alone may improve both sleep and fatigue. Central nervous system stimulants may be most appropriate for patients with fatigue and comorbid narcolepsy. Though this class of medications is widely adopted in clinical practices to help patients with function, there are not enough data to support this practice [52, 123, 152]. Despite the demonstrated efficacy of some of these pharmacological agents, the clinician should be mindful that not all patients with fibromyalgia can tolerate medications. Medication sensitivity and medication intolerance is a major patient concern. Judicious use of lower doses of medication with frequent assessment for efficacy and side effects may help some patients [153].

              Botanicals and dietary supplements

              Botanicals, such as ginseng, and dietary supplements, such as coenzyme Q10, s-adenosyl methionine and acetyl-l-carnitine, have been posited to relieve fatigue [120, 140, 144, 145] (Table 6). Although these agents are largely devoid of the side effect profile of pharmacologic agents, only preliminary efficacy data are available.

              Conclusion

              Fatigue is a complex symptom that is differentially experienced by individual patients with fibromyalgia depending on their genetic, biological, and psychosocial makeup, self-efficacy and emotional regulatory capacity, and presence of comorbidities. The profile of fatigue in fibromyalgia is similar to that in many chronic conditions, although the presence of fibromyalgia with other rheumatological conditions seems to intensify fatigue [154, 155]. A commonly observed theme in the literature is the co-occurrence of fatigue with other centrally mediated symptoms such as pain, unrefreshing sleep, affective symptoms, and the influence of psychosocial variables. This may imply that the same central mechanisms that drive pain, mood, and sleep also drive fatigue. Given that these symptoms (for example, pain, fatigue, sleep) occur concurrently, we tend to assume that they manifest at the same level. This may not be an accurate way to view fatigue. It may be that fatigue is a higher order construct, or meta-construct that is fed by other, more discrete symptoms. Only further inquiry will address these questions.

              At the clinical level, given our current limitations, fatigue management is best facilitated by conducting a nuanced fatigue assessment in routine clinical encounters to include a thoughtful history and investigation for treatable causes of fatigue, and screening for fatigue and other common comorbid fibromyalgia symptoms such as pain, anxiety, depression, sleep, and stress. Fatigue assessment and management can also be enhanced by encouraging patients to keep symptom logs to gain insights into lag relationships among symptoms, educating patients about the nature of fatigue, and setting realistic goals for symptom management (that is, focus on decreasing the impact of symptoms and improve function rather than symptom alleviation alone).

              From a research perspective, a disease-specific fatigue measure for fibromyalgia is needed to move the field forward. Additionally, studies to understand mechanisms (for example, biological, physiological, or psychological) and management of fatigue are also needed. As the study of fatigue in fibromyalgia advances, multidisciplinary collaborations that are patient-centered and facilitate patient engagement will guide treatment options to provide relief.

              Abbreviations

              CENPK: 

              Centromere protein K

              OMERACT: 

              Outcome Measures in Rheumatology

              PROMIS: 

              Patient Reported Outcomes Measurement Information System

              PROMIS-FIB: 

              PROMIS Fatigue Item Bank

              Declarations

              Acknowledgements

              This study was supported in part by the Center for Translational Science Activities (CTSA) at Mayo Clinic. This center is funded in part by a grant from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH) (RR024150). Its contents are solely the responsibility of the authors and do not necessarily represent the official view of CTSA, NCRR, or NIH.

              Authors’ Affiliations

              (1)
              Fibromyalgia and Chronic Fatigue Clinic, Mayo Clinic
              (2)
              Division of General Internal Medicine, Mayo Clinic
              (3)
              Division of Pulmonary and Critical Care Medicine, Mayo Clinic
              (4)
              Library Public Services, Mayo Clinic
              (5)
              Division of Intramural Research, National Institute of Nurs Res

              References

              1. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L: The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995, 38:19–28.PubMedView Article
              2. Chandran AB, Schaefer C, Ryan K, Baik R, McNett M, Zlateva G: The comparative economic burden of mild, moderate, and severe fibromyalgia: results from a retrospective chart review and cross-sectional survey of working-age US adults. J Manag Care Pharm 2012, 18:415–426.PubMed
              3. Arnold LM, Clauw DJ, McCarberg BH: Improving the recognition and diagnosis of fibromyalgia. Mayo Clin Proc 2011, 86:457–464.PubMedPubMed CentralView Article
              4. Mease PJ, Arnold LM, Crofford LJ, Williams DA, Russell IJ, Humphrey L, Abetz L, Martin SA: Identifying the clinical domains of fibromyalgia: contributions from clinician and patient Delphi exercises. Arthritis Rheum 2008, 59:952–960.PubMedView Article
              5. Wolfe F, Hawley DJ, Wilson K: The prevalence and meaning of fatigue in rheumatic disease. J Rheumatol 1996, 23:1407–1417.PubMed
              6. Walitt B, Fitzcharles M-A, Hassett AL, Katz RS, Hauser W, Wolfe F: The longitudinal outcome of fibromyalgia: a study of 1555 patients. J Rheumatol 2011, 38:2238–2246.PubMedView Article
              7. Wolfe F, Anderson J, Harkness D, Bennett RM, Caro XJ, Goldenberg DL, Russell IJ, Yunus MB: Health status and disease severity in fibromyalgia: results of a six-center longitudinal study. Arthritis Rheum 1997, 40:1571–1579.PubMedView Article
              8. Humphrey L, Arbuckle R, Mease P, Williams DA, Samsoe BD, Gilbert C: Fatigue in fibromyalgia: a conceptual model informed by patient interviews. BMC Musculoskelet Disord 2010, 11:216.PubMedPubMed CentralView Article
              9. Connolly D, O'Toole L, Redmond P, Smith SM: Managing fatigue in patients with chronic conditions in primary care. Fam Pract 2013, 30:123–124.PubMedView Article
              10. Sharpe M, Wilks D: Fatigue. BMJ 2002, 325:480–483.PubMedPubMed CentralView Article
              11. Nijrolder I, van der Windt DAWM, van der Horst HE: Prognosis of fatigue and functioning in primary care: a 1-year follow-up study. Ann Fam Med 2008, 6:519–527.PubMedPubMed CentralView Article
              12. Mease P, Arnold LM, Choy EH, Clauw DJ, Crofford LJ, Glass JM, Martin SA, Morea J, Simon L, Strand CV, Williams DA, OMERACT Fibromyalgia Working Group: Fibromyalgia syndrome module at OMERACT 9: domain construct. J Rheumatol 2009, 36:2318–2329.PubMedPubMed CentralView Article
              13. Choy EH: Clinical domains of fibromyalgia syndrome: determination through the OMERACT process. J Musculoskelet Pain 2010, 18:380–386.View Article
              14. Choy EH, Arnold LM, Clauw DJ, Crofford LJ, Glass JM, Simon LS, Martin SA, Strand CV, Williams DA, Mease PJ: Content and criterion validity of the preliminary core dataset for clinical trials in fibromyalgia syndrome. J Rheumatol 2009, 36:2330–2334.PubMedPubMed CentralView Article
              15. Mease PJ, Clauw DJ, Christensen R, Crofford LJ, Gendreau RM, Martin SA, Simon LS, Strand V, Williams DA, Arnold LM, OMERACT Fibromyalgia Working Group: Toward development of a fibromyalgia responder index and disease activity score: OMERACT module update. J Rheumatol 2011, 38:1487–1495.PubMedPubMed CentralView Article
              16. Cella D, Yount S, Rothrock N, Gershon R, Cook K, Reeve B, Ader D, Fries JF, Bruce B, Rose M, PROMIS Cooperative Group: The Patient-Reported Outcomes Measurement Information System (PROMIS): progress of an NIH Roadmap cooperative group during its first two years. Med Care 2007, 45:S3-S11.PubMedPubMed CentralView Article
              17. Lai JS, Cella D, Choi S, Junghaenel DU, Christodoulou C, Gershon R, Stone A: How item banks and their application can influence measurement practice in rehabilitation medicine: a PROMIS fatigue item bank example. Arch Phys Med Rehabil 2011, 92:S20-S27.PubMedPubMed CentralView Article
              18. Soderberg S, Lundman B, Norberg A: The meaning of fatigue and tiredness as narrated by women with fibromyalgia and healthy women. J Clin Nurs 2002, 11:247–255.PubMedView Article
              19. Sturge-Jacobs M: The experience of living with fibromyalgia: confronting an invisible disability. Res Theory Nurs Pract 2002, 16:19–31.PubMedView Article
              20. Yunus MB, Inanici F, Aldag JC, Mangold RF: Fibromyalgia in men: comparison of clinical features with women. J Rheumatol 2000, 27:485–490.PubMed
              21. Nicassio PM, Moxham EG, Schuman CE, Gevirtz RN: The contribution of pain, reported sleep quality, and depressive symptoms to fatigue in fibromyalgia. Pain 2002, 100:271–279.PubMedView Article
              22. Nicassio PM, Schuman CC: The prediction of fatigue in fibromyalgia. J Musculoskelet Pain 2005, 13:15–25.View Article
              23. Finan PH, Zautra AJ: Fibromyalgia and fatigue: central processing, widespread dysfunction. PM R 2010, 2:431–437.PubMedView Article
              24. Arranz L, Canela MA, Rafecas M: Relationship between body mass index, fat mass and lean mass with SF-36 quality of life scores in a group of fibromyalgia patients. Rheumatol Int 2012, 32:3605–3611.PubMedView Article
              25. Guymer EK, Maruff P, Littlejohn GO: Clinical characteristics of 150 consecutive fibromyalgia patients attending an Australian public hospital clinic. Int J Rheum Dis 2012, 15:348–357.PubMedView Article
              26. Finan PH, Zautra AJ, Davis MC: Daily affect relations in fibromyalgia patients reveal positive affective disturbance. Psychosom Med 2009, 71:474–482.PubMedView Article
              27. Davis MC, Zautra AJ, Reich JW: Vulnerability to stress among women in chronic pain from fibromyalgia and osteoarthritis. Ann Behav Med 2001, 23:215–226.PubMedView Article
              28. Bellamy N, Sothern RB, Campbell J: Aspects of diurnal rhythmicity in pain, stiffness, and fatigue in patients with fibromyalgia. J Rheumatol 2004, 31:379–389.PubMed
              29. Zautra AJ, Fasman R, Parish BP, Davis MC: Daily fatigue in women with osteoarthritis, rheumatoid arthritis, and fibromyalgia. Pain 2007, 128:128–135.PubMedView Article
              30. Staud R: Peripheral pain mechanisms in chronic widespread pain. Best Pract Res Clin Rheumatol 2011, 25:155–164.PubMedPubMed CentralView Article
              31. Kurtze N, Svebak S: Fatigue and patterns of pain in fibromyalgia: correlations with anxiety, depression and co-morbidity in a female county sample. Br J Med Psychol 2001, 74:523–537.PubMedView Article
              32. Hughes L: Physical and psychological variables that influence pain in patients with fibromyalgia. Orthop Nurs 2006, 25:112–119. quiz 120–111PubMed
              33. Wolfe F: Determinants of WOMAC function, pain and stiffness scores: evidence for the role of low back pain, symptom counts, fatigue and depression in osteoarthritis, rheumatoid arthritis and fibromyalgia. Rheumatology (Oxford) 1999, 38:355–361.View Article
              34. Hamilton NA, Affleck G, Tennen H, Karlson C, Luxton D, Preacher KJ, Templin JL: Fibromyalgia: the role of sleep in affect and in negative event reactivity and recovery. Health Psychol 2008, 27:490–497.PubMedView Article
              35. Parrish BP, Zautra AJ, Davis MC: The role of positive and negative interpersonal events on daily fatigue in women with fibromyalgia, rheumatoid arthritis, and osteoarthritis. Health Psychol 2008, 27:694–702.PubMedPubMed CentralView Article
              36. Okifuji A, Bradshaw DH, Donaldson GW, Turk DC: Sequential analyses of daily symptoms in women with fibromyalgia syndrome. J Pain 2011, 12:84–93.PubMedPubMed CentralView Article
              37. Landis CA, Frey CA, Lentz MJ, Rothermel J, Buchwald D, Shaver JLF: Self-reported sleep quality and fatigue correlates with actigraphy in midlife women with fibromyalgia. Nurs Res 2003, 52:140–147.PubMedView Article
              38. Gur A, Cevik R, Sarac AJ, Colpan L, Em S: Hypothalamic-pituitary-gonadal axis and cortisol in young women with primary fibromyalgia: the potential roles of depression, fatigue, and sleep disturbance in the occurrence of hypocortisolism. Ann Rheum Dis 2004, 63:1504–1506.PubMedPubMed CentralView Article
              39. White KP, Nielson WR, Harth M, Ostbye T, Speechley M: Chronic widespread musculoskeletal pain with or without fibromyalgia: psychological distress in a representative community adult sample. J Rheumatol 2002, 29:588–594.PubMed
              40. Kurtze N, Gundersen KT, Svebak S: The role of anxiety and depression in fatigue and patterns of pain among subgroups of fibromyalgia patients. Br J Med Psychol 1998, 71:185–194.PubMedView Article
              41. Suhr JA: Neuropsychological impairment in fibromyalgia: relation to depression, fatigue, and pain. J Psychosom Res 2003, 55:321–329.PubMedView Article
              42. Droegemueller CJ, Brauer DJ, van Buskirk DJ: Temperament and fatigue management in persons with chronic rheumatic disease. Clin Nurse Spec 2008, 22:19–27. quiz 28–29PubMedView Article
              43. Malin K, Littlejohn GO: Psychological control is a key modulator of fibromyalgia symptoms and comorbidities. J Pain Res 2012, 5:463–471.PubMedPubMed Central
              44. Schaefer C, Chandran A, Hufstader M, Baik R, McNett M, Goldenberg D, Gerwin R, Zlateva G: The comparative burden of mild, moderate and severe fibromyalgia: results from a cross-sectional survey in the United States. Health Qual Life Outcomes 2011, 9:71.PubMedPubMed CentralView Article
              45. McLean SA, Williams DA, Harris RE, Kop WJ, Groner KH, Ambrose K, Lyden AK, Gracely RH, Crofford LJ, Geisser ME, Sen A, Biswas P, Clauw DJ: Momentary relationship between cortisol secretion and symptoms in patients with fibromyalgia. Arthritis Rheum 2005, 52:3660–3669.PubMedView Article
              46. McLean SA, Williams DA, Stein PK, Harris RE, Lyden AK, Whalen G, Park KM, Liberzon I, Sen A, Gracely RH, Baraniuk JN, Clauw DJ: Cerebrospinal fluid corticotropin-releasing factor concentration is associated with pain but not fatigue symptoms in patients with fibromyalgia. Neuropsychopharmacology 2006, 31:2776–2782.PubMedView Article
              47. Srikuea R, Symons TB, Long DE, Lee JD, Shang Y, Chomentowski PJ, Yu G, Crofford LJ, Peterson CA: Association of fibromyalgia with altered skeletal muscle characteristics which may contribute to postexertional fatigue in postmenopausal women. Arthritis Rheum 2013, 65:519–528.PubMedPubMed CentralView Article
              48. Light KC, White AT, Tadler S, Iacob E, Light AR: Genetics and gene expression involving stress and distress pathways in fibromyalgia with and without comorbid chronic fatigue syndrome. Pain Res Treat 2012, 2012:427869.PubMedPubMed Central
              49. Swain MG: Fatigue in chronic disease. Clin Sci (Lond) 2000, 99:1–8.View Article
              50. Lukkahatai N, Majors B, Reddy S, Walitt B, Saligan LN: Gene expression profiles of fatigued fibromyalgia patients with different categories of pain and catastrophizing: a preliminary report. Nurs Outlook 2013, 61:216–224. e2PubMedPubMed CentralView Article
              51. O'Toole L, Connolly D, Smith S: Impact of an occupation-based self-management programme on chronic disease management. Aust Occup Ther J 2013, 60:30–38.PubMedView Article
              52. Schwartz TL, Rayancha S, Rashid A, Chlebowksi S, Chilton M, Morell M: Modafinil treatment for fatigue associated with fibromyalgia. J Clin Rheumatol 2007, 13:52.PubMedView Article
              53. Cleeland CS, Ryan KM: Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994, 23:129–138.PubMed
              54. Smets EM, Garssen B, Bonke B, De Haes JC: The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995, 39:315–325.PubMedView Article
              55. Ware JE Jr: SF-36 health survey update. Spine 2000, 25:3130–3139.PubMedView Article
              56. Ware JE Jr, Sherbourne CD: The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992, 30:473–483.PubMedView Article
              57. Spitzer RL, Kroenke K, Williams JBW, Lowe B: A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Int Med 2006, 166:1092–1097.View Article
              58. Kroenke K, Spitzer RL, Williams JB: The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med 2001, 16:606–613.PubMedPubMed CentralView Article
              59. Smarr KL, Keefer AL: Measures of depression and depressive symptoms: Beck Depression Inventory-II (BDI-II), Center for Epidemiologic Studies Depression Scale (CES-D), Geriatric Depression Scale (GDS), Hospital Anxiety and Depression Scale (HADS), and Patient Health Questionnaire-9 (PHQ-9). Arthritis Care Res 2011, 63:S454-S466.View Article
              60. Radloff LS: The CES-D Scale. Appl Psychol Measurement 1977, 1:385–401.View Article
              61. Sletten DM, Suarez GA, Low PA, Mandrekar J, Singer W: COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc 2012, 87:1196–1201.PubMedPubMed CentralView Article
              62. Cappelleri JC, Bushmakin AG, McDermott AM, Dukes E, Sadosky A, Petrie CD, Martin S: Measurement properties of the Medical Outcomes Study Sleep Scale in patients with fibromyalgia. Sleep Med 2009, 10:766–770.PubMedView Article
              63. Crawford BK, Piault EC, Lai C, Bennett RM: Assessing fibromyalgia-related fatigue: content validity and psychometric performance of the Fatigue Visual Analog Scale in adult patients with fibromyalgia. Clin Exp Rheumatol 2011, 29:S34-S43.PubMed
              64. Multidimensional Assessment of Fatigue (MAF). [http://​www.​son.​washington.​edu/​research/​maf/​default.​asp]
              65. Bennett RM, Friend R, Jones KD, Ward R, Han BK, Ross RL: The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther 2009, 11:R120. A published erratum appears in Arthritis Res Ther 2009, 11:415PubMedPubMed CentralView Article
              66. Hewlett S, Dures E, Almeida C: Measures of fatigue: Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF MDQ), Bristol Rheumatoid Arthritis Fatigue Numerical Rating Scales (BRAF NRS) for severity, effect, and coping, Chalder Fatigue Questionnaire (CFQ), Checklist Individual Strength (CIS20R and CIS8R), Fatigue Severity Scale (FSS), Functional Assessment Chronic Illness Therapy (Fatigue) (FACIT-F), Multi-Dimensional Assessment of Fatigue (MAF), Multi-Dimensional Fatigue Inventory (MFI), Pediatric Quality Of Life (PedsQL) Multi-Dimensional Fatigue Scale, Profile of Fatigue (ProF), Short Form 36 Vitality Subscale (SF-36 VT), and Visual Analog Scales (VAS). Arthritis Care Res 2011, 63:S263-S286.View Article
              67. Cella M, Chalder T: Measuring fatigue in clinical and community settings. J Psychosom Res 2010, 69:17–22.PubMedView Article
              68. Chalder T, Berelowitz G, Pawlikowska T, Watts L, Wessely S, Wright D, Wallace EP: Development of a fatigue scale. J Psychosom Res 1993, 37:147–153.PubMedView Article
              69. Vercoulen JH, Swanink CM, Fennis JF, Galama JM, van der Meer JW, Bleijenberg G: Dimensional assessment of chronic fatigue syndrome. J Psychosom Res 1994, 38:383–392.PubMedView Article
              70. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD: The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989, 46:1121–1123.PubMedView Article
              71. Lera S, Gelman SM, Lopez MJ, Abenoza M, Zorrilla JG, Castro-Fornieles J, Salamero M: Multidisciplinary treatment of fibromyalgia: does cognitive behavior therapy increase the response to treatment? J Psychosom Res 2009, 67:433–441.PubMedView Article
              72. Karper WB, Stasik SC: A successful, long-term exercise program for women with fibromyalgia syndrome and chronic fatigue and immune dysfunction syndrome. Clin Nurse Spec 2003, 17:243–248.PubMedView Article
              73. Hauser W, Klose P, Langhorst J, Moradi B, Steinbach M, Schiltenwolf M, Busch A: Efficacy of different types of aerobic exercise in fibromyalgia syndrome: a systematic review and meta-analysis of randomised controlled trials. Arthritis Res Ther 2010, 12:R79.PubMedPubMed CentralView Article
              74. Busch AJ, Schachter CL, Overend TJ, Peloso PM, Barber KA: Exercise for fibromyalgia: a systematic review. J Rheumatol 2008, 35:1130–1144.PubMed
              75. Valkeinen H, Alen M, Hakkinen A, Hannonen P, Kukkonen-Harjula K, Hakkinen K: Effects of concurrent strength and endurance training on physical fitness and symptoms in postmenopausal women with fibromyalgia: a randomized controlled trial. Arch Phys Med Rehabil 2008, 89:1660–1666.PubMedView Article
              76. Bircan C, Karasel SA, Akgun B, El O, Alper S: Effects of muscle strengthening versus aerobic exercise program in fibromyalgia. Rheumatol Int 2008, 28:527–532.PubMedView Article
              77. Hakkinen A, Hakkinen K, Hannonen P, Alen M: Strength training induced adaptations in neuromuscular function of premenopausal women with fibromyalgia: comparison with healthy women. Ann Rheum Dis 2001, 60:21–26.PubMedPubMed CentralView Article
              78. van Wilgen CP, Bloten H, Oeseburg B: Results of a multidisciplinary program for patients with fibromyalgia implemented in the primary care. Disabil Rehabil 2007, 29:1207–1213.PubMedView Article
              79. Havermark AM, Langius-Eklof A: Long-term follow up of a physical therapy programme for patients with fibromyalgia syndrome. Scand J Caring Sci 2006, 20:315–322.PubMedView Article
              80. Cedraschi C, Desmeules J, Rapiti E, Baumgartner E, Cohen P, Finckh A, Allaz AF, Vischer TL: Fibromyalgia: a randomised, controlled trial of a treatment programme based on self management. Ann Rheum Dis 2004, 63:290–296.PubMedPubMed CentralView Article
              81. Mannerkorpi K, Nyberg B, Ahlmen M, Ekdahl C: Pool exercise combined with an education program for patients with fibromyalgia syndrome. A prospective, randomized study. J Rheumatol 2000, 27:2473–2481.PubMed
              82. Luciano JV, Martínez N, Peñarrubia-María MT, Fernández-Vergel R, García-Campayo J, Verduras C, Blanco ME, Jiménez M, Ruiz JM, López del Hoyo Y, Serrano-Blanco A, FibroQoL Study Group: Effectiveness of a psychoeducational treatment program implemented in general practice for fibromyalgia patients: a randomized controlled trial. Clin J Pain 2011, 27:383–391.PubMedView Article
              83. Carbonell-Baeza A, Aparicio VA, Chillon P, Femia P, Delgado-Fernandez M, Ruiz JR: Effectiveness of multidisciplinary therapy on symptomatology and quality of life in women with fibromyalgia. Clin Exp Rheumatol 2011, 29:S97-S103.PubMed
              84. Lorig KR, Ritter PL, Laurent DD, Plant K: The internet-based arthritis self-management program: a one-year randomized trial for patients with arthritis or fibromyalgia. Arthritis Rheum 2008, 59:1009–1017.PubMedView Article
              85. Hauser W, Bernardy K, Arnold B, Offenbacher M, Schiltenwolf M: Efficacy of multicomponent treatment in fibromyalgia syndrome: a meta-analysis of randomized controlled clinical trials. Arthritis Rheum 2009, 61:216–224.PubMedView Article
              86. Langhorst J, Klose P, Musial F, Irnich D, Hauser W: Efficacy of acupuncture in fibromyalgia syndrome - a systematic review with a meta-analysis of controlled clinical trials. Rheumatology (Oxford) 2010, 49:778–788.View Article
              87. Langhorst J, Klose P, Dobos GJ, Bernardy K, Hauser W: Efficacy and safety of meditative movement therapies in fibromyalgia syndrome: a systematic review and meta-analysis of randomized controlled trials. Rheumatol Int 2013, 33:193–207.PubMedView Article
              88. Arnold LM, Wang F, Ahl J, Gaynor PJ, Wohlreich MM: Improvement in multiple dimensions of fatigue in patients with fibromyalgia treated with duloxetine: secondary analysis of a randomized, placebo-controlled trial. Arthritis Res Ther 2011, 13:R86.PubMedPubMed CentralView Article
              89. Chappell AS, Bradley LA, Wiltse C, Detke MJ, D'Souza DN, Spaeth M: A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia. Int J Gen Med 2008, 1:91–102.PubMedPubMed CentralView Article
              90. Arnold LM, Lu Y, Crofford LJ, Wohlreich M, Detke MJ, Iyengar S, Goldstein DJ: A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004, 50:2974–2984.PubMedView Article
              91. Clauw DJ, Mease P, Palmer RH, Gendreau RM, Wang Y: Milnacipran for the treatment of fibromyalgia in adults: a 15-week, multicenter, randomized, double-blind, placebo-controlled, multiple-dose clinical trial. Clin Ther 2008, 30:1988–2004.PubMedView Article
              92. Branco JC, Zachrisson O, Perrot S, Mainguy Y: A European multicenter randomized double-blind placebo-controlled monotherapy clinical trial of milnacipran in treatment of fibromyalgia. J Rheumatol 2010, 37:851–859.PubMedView Article
              93. Mease PJ, Clauw DJ, Gendreau RM, Rao SG, Kranzler J, Chen W, Palmer RH: The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, double-blind, placebo-controlled trial. J Rheumatol 2009, 36:398–409. Published erratum appears in J Rheumatol 2009, 36:661PubMedView Article
              94. Gendreau RM, Thorn MD, Gendreau JF, Kranzler JD, Ribeiro S, Gracely RH, Williams DA, Mease PJ, McLean SA, Clauw DJ: Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol 2005, 32:1975–1985.PubMed
              95. Arnold LM, Gendreau RM, Palmer RH, Gendreau JF, Wang Y: Efficacy and safety of milnacipran 100 mg/day in patients with fibromyalgia: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010, 62:2745–2756.PubMedView Article
              96. Vitton O, Gendreau M, Gendreau J, Kranzler J, Rao SG: A double-blind placebo-controlled trial of milnacipran in the treatment of fibromyalgia. Hum Psychopharmacol 2004, 19:S27-S35.PubMedView Article
              97. Branco JC, Cherin P, Montagne A, Bouroubi A: Long-term therapeutic response to milnacipran treatment for fibromyalgia. A European 1-year extension study following a 3-month study. J Rheumatol 2011, 38:1403–1412.PubMedView Article
              98. Pauer L, Atkinson G, Murphy TK, Petersel D, Zeiher B: Long-term maintenance of response across multiple fibromyalgia symptom domains in a randomized withdrawal study of pregabalin. Clin J Pain 2012, 28:609–614.PubMedView Article
              99. Mease PJ, Russell IJ, Arnold LM, Florian H, Young JP Jr, Martin SA, Sharma U: A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 2008, 35:502–514.PubMed
              100. Crofford LJ, Rowbotham MC, Mease PJ, Russell IJ, Dworkin RH, Corbin AE, Young JP Jr, LaMoreaux LK, Martin SA, Sharma U, Pregabalin 1008–105 Study Group: Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005, 52:1264–1273.PubMedView Article
              101. Donmez A, Karagulle MZ, Tercan N, Dinler M, Issever H, Karagulle M, Turan M: SPA therapy in fibromyalgia: a randomised controlled clinic study. Rheumatol Int 2005, 26:168–172.PubMedView Article
              102. Altan L, Bingol U, Aykac M, Koc Z, Yurtkuran M: Investigation of the effects of pool-based exercise on fibromyalgia syndrome. Rheumatol Int 2004, 24:272–277.PubMedView Article
              103. Buskila D, Abu-Shakra M, Neumann L, Odes L, Shneider E, Flusser D, Sukenik S: Balneotherapy for fibromyalgia at the Dead Sea. Rheumatol Int 2001, 20:105–108.PubMedView Article
              104. Huuhka MJ, Haanpaa ML, Leinonen EV: Electroconvulsive therapy in patients with depression and fibromyalgia. Eur J Pain 2004, 8:371–376.PubMedView Article
              105. Gur A, Karakoc M, Nas K, Cevik R, Sarac J, Demir E: Efficacy of low power laser therapy in fibromyalgia: a single-blind, placebo-controlled trial. Lasers Med Sci 2002, 17:57–61.PubMedView Article
              106. Gur A, Karakoc M, Nas K, Cevik R, Sarac J, Ataoglu S: Effects of low power laser and low dose amitriptyline therapy on clinical symptoms and quality of life in fibromyalgia: a single-blind, placebo-controlled trial. Rheumatol Int 2002, 22:188–193.PubMedView Article
              107. Maddali Bongi S, Di Felice C, Del Rosso A, Landi G, Maresca M, Giambalvo Dal Ben G, Matucci-Cerinic M: Efficacy of the “body movement and perception” method in the treatment of fibromyalgia syndrome: an open pilot study. Clin Exp Rheumatol 2011, 29:S12-S18.PubMed
              108. Hargrove JB, Bennett RM, Simons DG, Smith SJ, Nagpal S, Deering DE: A randomized placebo-controlled study of noninvasive cortical electrostimulation in the treatment of fibromyalgia patients. Pain Med 2012, 13:115–124.PubMedView Article
              109. Almeida TF, Roizenblatt S, Benedito-Silva AA, Tufik S: The effect of combined therapy (ultrasound and interferential current) on pain and sleep in fibromyalgia. Pain 2003, 104:665–672.PubMedView Article
              110. Chen KW, Hassett AL, Hou F, Staller J, Lichtbroun AS: A pilot study of external qigong therapy for patients with fibromyalgia. J Altern Complement Med 2006, 12:851–856.PubMedView Article
              111. Kayiran S, Dursun E, Dursun N, Ermutlu N, Karamursel S: Neurofeedback intervention in fibromyalgia syndrome; a randomized, controlled, rater blind clinical trial. Appl Psychophysiol Biofeedback 2010, 35:293–302.PubMedView Article
              112. Carbonario F, Matsutani LA, Yuan SL, Marques AP: Effectiveness of high-frequency transcutaneous electrical nerve stimulation at tender points as adjuvant therapy for patients with fibromyalgia. Eur J Phys Rehabil Med 2013, 49:197–204.PubMed
              113. Mhalla A, Baudic S, Ciampi de Andrade D, Gautron M, Perrot S, Teixeira MJ, Attal N, Bouhassira D: Long-term maintenance of the analgesic effects of transcranial magnetic stimulation in fibromyalgia. Pain 2011, 152:1478–1485.PubMedView Article
              114. Passard A, Attal N, Benadhira R, Brasseur L, Saba G, Sichere P, Perrot S, Januel D, Bouhassira D: Effects of unilateral repetitive transcranial magnetic stimulation of the motor cortex on chronic widespread pain in fibromyalgia. Brain 2007, 130:2661–2670.PubMedView Article
              115. Donaldson MS, Speight N, Loomis S: Fibromyalgia syndrome improved using a mostly raw vegetarian diet: an observational study. BMC Altern Med 2001, 1:7.View Article
              116. Azad KA, Alam MN, Haq SA, Nahar S, Chowdhury MA, Ali SM, Ullah AK: Vegetarian diet in the treatment of fibromyalgia. Bangladesh Med Res Counc Bull 2000, 26:41–47.PubMed
              117. Alentorn-Geli E, Padilla J, Moras G, Lazaro Haro C, Fernandez-Sola J: Six weeks of whole-body vibration exercise improves pain and fatigue in women with fibromyalgia. J Altern Complement Med 2008, 14:975–981.PubMedView Article
              118. Broderick JE, Junghaenel DU, Schwartz JE: Written emotional expression produces health benefits in fibromyalgia patients. Psychosom Med 2005, 67:326–334.PubMedView Article
              119. Carson JW, Carson KM, Jones KD, Bennett RM, Wright CL, Mist SD: A pilot randomized controlled trial of the Yoga of Awareness program in the management of fibromyalgia. Pain 2010, 151:530–539.PubMedView Article
              120. Braz AS, Morais LC, Paula AP, Diniz MF, Almeida RN: Effects of Panax ginseng extract in patients with fibromyalgia: a 12-week, randomized, double-blind, placebo-controlled trial. Rev Bras Psiquiatr 2013, 35:21–28.PubMedView Article
              121. Nishishinya B, Urrutia G, Walitt B, Rodriguez A, Bonfill X, Alegre C, Darko G: Amitriptyline in the treatment of fibromyalgia: a systematic review of its efficacy. Rheumatology (Oxford) 2008, 47:1741–1746.View Article
              122. Uceyler N, Hauser W, Sommer C: A systematic review on the effectiveness of treatment with antidepressants in fibromyalgia syndrome. Arthritis Rheum 2008, 59:1279–1298.PubMedView Article
              123. Schwartz TL, Siddiqui UA, Raza S, Morell M: Armodafinil for fibromyalgia fatigue. Ann Pharmacother 2010, 44:1347–1348.PubMedView Article
              124. Tofferi JK, Jackson JL, O'Malley PG: Treatment of fibromyalgia with cyclobenzaprine: a meta-analysis. Arthritis Rheum 2004, 51:9–13.PubMedView Article
              125. Arnold LM, Hirsch I, Sanders P, Ellis A, Hughes B: Safety and efficacy of esreboxetine in patients with fibromyalgia: a fourteen-week, randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum 2012, 64:2387–2397.PubMedView Article
              126. Arnold LM, Chatamra K, Hirsch I, Stoker M: Safety and efficacy of esreboxetine in patients with fibromyalgia: an 8-week, multicenter, randomized, double-blind, placebo-controlled study. Clin Ther 2010, 32:1618–1632.PubMedView Article
              127. Arnold LM, Hess EV, Hudson JI, Welge JA, Berno SE, Keck PE Jr: A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med 2002, 112:191–197.PubMedView Article
              128. Scharf MB, Hauck M, Stover R, McDannold M, Berkowitz D: Effect of gamma-hydroxybutyrate on pain, fatigue, and the alpha sleep anomaly in patients with fibromyalgia. Preliminary report. J Rheumatol 1998, 25:1986–1990.PubMed
              129. Russell IJ, Holman AJ, Swick TJ, Alvarez-Horine S, Wang YG, Guinta D: Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: results from a 14-week, randomized, double-blind, placebo-controlled study. Pain 2011, 152:1007–1017.PubMedView Article
              130. Moldofsky H, Inhaber NH, Guinta DR, Alvarez-Horine SB: Effects of sodium oxybate on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study. J Rheumatol 2010, 37:2156–2166.PubMedView Article
              131. Scharf MB, Baumann M, Berkowitz DV: The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J Rheumatol 2003, 30:1070–1074.PubMed
              132. Spitzer AR, Broadman M: Treatment of the narcoleptiform sleep disorder in chronic fatigue syndrome and fibromyalgia with sodium oxybate. Pain Pract 2010, 10:54–59.PubMedView Article
              133. Samborski W, Lezanska-Szpera M, Rybakowski JK: Open trial of mirtazapine in patients with fibromyalgia. Pharmacopsychiatry 2004, 37:168–170.PubMedView Article
              134. Holman AJ, Myers RR: A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum 2005, 52:2495–2505.PubMedView Article
              135. Jones KD, Burckhardt CS, Deodhar AA, Perrin NA, Hanson GC, Bennett RM: A six-month randomized controlled trial of exercise and pyridostigmine in the treatment of fibromyalgia. Arthritis Rheum 2008, 58:612–622.PubMedPubMed CentralView Article
              136. Hidalgo J, Rico-Villademoros F, Calandre EP: An open-label study of quetiapine in the treatment of fibromyalgia. Prog Neuropsychopharmacol Biol Psychiatry 2007, 31:71–77.PubMedView Article
              137. Sadreddini S, Molaeefard M, Noshad H, Ardalan M, Asadi A: Efficacy of Raloxifen in treatment of fibromyalgia in menopausal women. Eur J Intern Med 2008, 19:350–355.PubMedView Article
              138. Stratz T, Farber L, Varga B, Baumgartner C, Haus U, Muller W: Fibromyalgia treatment with intravenous tropisetron administration. Drugs Exp Clin Res 2001, 27:113–118.PubMed
              139. Rossini M, Di Munno O, Valentini G, Bianchi G, Biasi G, Cacace E, Malesci D, La Montagna G, Viapiana O, Adami S: Double-blind, multicenter trial comparing acetyl l-carnitine with placebo in the treatment of fibromyalgia patients. Clin Exp Rheumatol 2007, 25:182–188.PubMed
              140. Cordero MD, Alcocer-Gomez E, de Miguel M, Culic O, Carrion AM, Alvarez-Suarez JM, Bullon P, Battino M, Fernandez-Rodriguez A, Sanchez-Alcazar JA: Can coenzyme Q improve clinical and molecular parameters in fibromyalgia? Antioxid Redox Signal 2013, 19:1356–1361.PubMedView Article
              141. Finckh A, Berner IC, Aubry-Rozier B, So AK: A randomized controlled trial of dehydroepiandrosterone in postmenopausal women with fibromyalgia. J Rheumatol 2005, 32:1336–1340.PubMed
              142. Massey PB: Reduction of fibromyalgia symptoms through intravenous nutrient therapy: results of a pilot clinical trial. Altern Ther Health Med 2007, 13:32–34.PubMed
              143. Citera G, Arias MA, Maldonado-Cocco JA, Lazaro MA, Rosemffet MG, Brusco LI, Scheines EJ, Cardinalli DP: The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheum 2000, 19:9–13.View Article
              144. Volkmann H, Norregaard J, Jacobsen S, Danneskiold-Samsoe B, Knoke G, Nehrdich D: Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-L-methionine in patients with fibromyalgia. Scand J Rheumatol 1997, 26:206–211.PubMedView Article
              145. Jacobsen S, Danneskiold-Samsoe B, Andersen RB: Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol 1991, 20:294–302.PubMedView Article
              146. Geel SE, Robergs RA: The effect of graded resistance exercise on fibromyalgia symptoms and muscle bioenergetics: a pilot study. Arthritis Rheum 2002, 47:82–86.PubMedView Article
              147. Sanudo B, Galiano D, Carrasco L, Blagojevic M, de Hoyo M, Saxton J: Aerobic exercise versus combined exercise therapy in women with fibromyalgia syndrome: a randomized controlled trial. Arch Phys Med Rehabil 2010, 91:1838–1843.PubMedView Article
              148. Kollner V, Hauser W, Klimczyk K, Kuhn-Becker H, Settan M, Weigl M, Bernardy K: Psychotherapy for patients with fibromyalgia syndrome. Systematic review, meta-analysis and guideline. Schmerz 2012, 26:291–296.PubMedView Article
              149. Nuesch E, Hauser W, Bernardy K, Barth J, Juni P: Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis. Ann Rheum Dis 2013, 72:955–962.PubMedView Article
              150. Lami MJ, Martinez MP, Sanchez AI: Systematic review of psychological treatment in fibromyalgia. Curr Pain Headache Rep 2013, 17:345.PubMedView Article
              151. Langhorst J, Hauser W, Bernardy K, Lucius H, Settan M, Winkelmann A, Musial F: Complementary and alternative therapies for fibromyalgia syndrome. Systematic review, meta-analysis and guideline. Schmerz 2012, 26:311–317.PubMedView Article
              152. Frost J, Okun S, Vaughan T, Heywood J, Wicks P: Patient-reported outcomes as a source of evidence in off-label prescribing: analysis of data from PatientsLikeMe. J Med Internet Res 2011, 13:e6.PubMedPubMed CentralView Article
              153. Fitzcharles MA, Ste-Marie PA, Goldenberg DL, Pereira JX, Abbey S, Choinière M, Ko G, Moulin DE, Panopalis P, Proulx J, Shir Y, National Fibromyalgia Guideline Advisory Panel: Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome: Executive summary. Pain Res Manag 2012, 2013:119–126.
              154. Priori R, Iannuccelli C, Alessandri C, Modesti M, Antonazzo B, Di Lollo AC, Valesini G, Di Franco M: Fatigue in Sjogren’s syndrome: relationship with fibromyalgia, clinical and biologic features. Clin Exp Rheumatol 2010, 28:S82-S86.PubMed
              155. Iannuccelli C, Spinelli FR, Guzzo MP, Priori R, Conti F, Ceccarelli F, Pietropaolo M, Olivieri M, Minniti A, Alessandri C, Gattamelata A, Valesini G, Di Franco M: Fatigue and widespread pain in systemic lupus erythematosus and Sjogren’s syndrome: symptoms of the inflammatory disease or associated fibromyalgia? Clin Exp Rheumatol 2012, 30:117–121.PubMed

              Copyright

              © BioMed Central Ltd 2013