Fibromyalgia

CHAPTER 52 

Fibromyalgia Leslie J. Crofford KEY POINTS Fibromyalgia (FM) is a disorder of centrally amplified and maintained musculoskeletal pain with evidence of altered pain processing in the spinal cord and brain. Although pain is the defining symptom of FM, fatigue, unrefreshing sleep, dyscognition, depression, and anxiety also have a significant impact on health-related quality of life. The diagnosis of FM relies on patient report using one of several valid criteria sets. Patients with other rheumatic diseases have a higher prevalence of FM than the general population, and the presence of comorbid FM affects assessment of disease activity. It is important to identify FM in order to develop an overall treatment plan that addresses the different mechanisms responsible for musculoskeletal pain.

health, requiring the clinician to address the patient’s beliefs and behaviors that augment pain symptoms. In some patients, a multidisciplinary approach to treatment will provide significant benefits.7 Because the diagnosis of FM relies solely on patient report and all of the symptoms of FM exist in a continuum in healthy persons, significant controversy has existed regarding the legitimacy of FM as a medical illness.8 What is clear is that pain reports of persons with FM are associated with activation of areas in the brain associated with pain transmission, as determined by advanced neuroimaging studies.9 Thus objective evidence of the veracity of the subjective report of pain exists. From a practical perspective, the treating clinician should be able to identify the symptoms of FM and sort through the differential diagnosis, understand its relationship to comorbid rheumatic diseases, assist the patient in distinguishing central pain from mechanical or inflammatory pain, and provide management approaches that address patient symptoms.

HISTORICAL PERSPECTIVE Fibromyalgia (FM) is a disorder characterized by chronic, widespread musculoskeletal pain often associated with debilitating fatigue, unrefreshing sleep, dyscognition, depression, and anxiety.1 Patients with FM have evidence of disordered sensory processing as manifested by widespread allodynia (i.e., pain elicited by an innocuous stimulus that is not usually painful) and hyperalgesia (i.e., exaggerated pain elicited by a noxious stimulus). Patients often have a personal and family history of regional or visceral pain, such as migraine or tension headaches, temporomandibular disorder, irritable bowel syndrome, interstitial cystitis, pelvic pain syndromes, and depression or anxiety.1-3 A careful history typically reveals a pain-prone phenotype with musculoskeletal pain as only one of the affected body regions.1 The genetic vulnerability to FM and other disorders characterized by amplified pain is associated with polymorphisms in genes involving pain transmission, neurotransmitter, and stress-response pathways.4-6 It is thought that in vulnerable persons, triggering events involving activation of sensory nociceptors lead to long-term changes in pain transmission and descending inhibitory pathways.5 This concept of centrally maintained or amplified pain as the central physiologic alteration in FM has led to treatment strategies that differ from traditional anti-inflammatory or analgesic approaches to musculoskeletal pain.1 Cognitive and emotional factors also play a significant role in the impact of FM on 768

Descriptions of patients with symptoms of FM in the medical literature go back centuries. In early descriptions, the condition was often called “muscular rheumatism” to distinguish it from “articular rheumatism.”10 In 1815, Dr. William Balfour, a surgeon from Edinburgh, described nodules and suggested that inflammation in muscle connective tissue was the cause for nodules and pain. He also first reported focal tenderness, referred to as tender points, in 1824. Sir William Gowers coined the term fibrositis in 1904, sharing in the belief that patients experienced inflammation of fibrous connective tissue that led to tender points in patients with muscular rheumatism.11 An interesting historical treatise by Dr. Philip Hench and Edward Boland published in 1946 described the management of rheumatic diseases in U.S. Army soldiers and provides insights that remain relevant in more modern times.12 They report that muscular rheumatism occurred in 13% of soldiers from the First World War (April 1, 1917 to December 31, 1919). Specialized rheumatism centers were established in the 1940s for soldiers of the Second World War. Hench and Boland published the incidence of rheumatic diseases in the first 1000 cases and differentiated “psychogenic rheumatism,” occurring in 20%, from “fibrositis,” which included regional syndromes such as bursitis and tendonitis, occurring in 13.4%. Hench and Boland noted that most of the patients sent to these specialized centers with muscular rheumatism did not have myositis or



fibrositis but psychogenic rheumatism, which they considered a psychoneurosis manifested by musculoskeletal complaints. They went on to state that primary fibrositis “puts its victims at the mercy of changes in external environment: thus weather, heat, cold, humidity, rest, exercise, etc. characteristically influences most of them for better or for worse.” On the other hand, psychogenic rheumatism “puts its victims at the mercy of changes in the internal environment: thus their symptoms may vary with mood or psyche, pleasure, excitement, mental distraction, worry, or fatigue.” The description of psychogenic rheumatism included an attitude that was tense, anxious, defensive, and antagonistic. The chief symptoms were described as burning, tightness, weakness, numbness, tingling, or tired sensations that were often continuous day and night. They also describe severe fatigue causing disability, worsening of symptoms during and after exercise, and a “touch me not” reaction to examination. Psychotherapy was the preferred treatment approach for these patients. Patients with fibrositis, on the other hand, were treated with physical rehabilitation. In evaluating outcome, 82% of patients with primary fibrositis returned to duty, compared with only 64% of patients with psychogenic rheumatism.12 In our current understanding, FM likely represents a combination of primary fibrositis and psychogenic rheumatism, with both conditions having a component of central pain amplification but diverging in the psychological and behavioral responses to pain. Dr. Hugh Smythe provided the first modern description of widespread pain and tender points in the 1970s.13 The term fibromyalgia was adopted soon thereafter because pathologic studies consistently fail to find evidence of inflammation in tender areas, calling into question the underlying hypothesis of the fibrositis construct. In 1981, Dr. Muhammad Yunus published a more comprehensive description of the symptoms and signs of FM,14 which was recognized as a diagnosis by the American Medical Association in 1987. Yunus made the relevant comment that many patients with fibrositis syndrome, fibromyositis, fibromyalgia, myofibrositis, interstitial myofibrositis, myofascial pain syndrome, myofascitis, muscular rheumatism, nonarticular rheumatism, and tension rheumatism were also diagnosed with the separate entity of psychogenic rheumatism. The American College of Rheumatology (ACR) published classification criteria in 1990 relying on the presence of widespread pain and tender points that allowed researchers to distinguish FM from other rheumatologic diseases and that had the effect of allowing researchers from around the world to identify a more homogenous group of patients for research.15 A revision of the criteria published in 2010 eliminated tender points, placed less emphasis on widespread pain, and placed more emphasis on associated symptoms.16 An additional modification to these criteria allow them to be used in epidemiologic studies.17 Debate is ongoing regarding the most appropriate criteria for clinical and research uses, although in practice either these or other validated criteria sets will allow the clinician to make the diagnosis of FM. Research intended to ascribe an etiology to FM began when Dr. Harvey Moldofsky reported abnormalities in polysomnographic studies of persons with FM in 1975, reporting intrusion of alpha or waking frequency waves in regions of delta or slow wave sleep now known to be nonspecific.18

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Since publication of the 1990 ACR classification criteria, investigators have identified a number of other potential mechanisms associated with FM that may be responsible for symptoms. In 2007, the U.S. Food and Drug Administration (FDA) approved pregabalin, an agent also approved for neuropathic pain, for treatment of FM. This step was followed by approval of the dual norepinephrine-serotonin reuptake inhibitors duloxetine and milnacipran for treatment of FM.19 Throughout the history of FM, controversy has existed regarding the veracity of patients’ complaints and their reported impact on function.8 The controversy has become somewhat contentious in the era of disability and the increased cost of FDA-approved medications. However, identifying FM and understanding the recent advances in mechanisms associated with development of central pain amplification has significant benefits that allow practitioners to educate patients about their symptoms and target pharmacologic and nonpharmacologic treatment to manage FM. With respect to the presence of psychogenic rheumatism in these patients, the most current approach to patients with FM who have excessive thoughts, feelings, and behaviors that are distressing and disruptive to daily life would be to consider an additional diagnosis of somatic symptom disorder, the new terminology in the Diagnostic and Statis­ tical Manual of Mental Disorders (DSM-5) that replaces somatization disorder, hypochondriasis, pain disorder, and undifferentiated somatoform disorder. This way of approaching patients separates the neurobiologic changes resulting in widespread pain amplification from the emotional and behavioral response to these symptoms. Considering both these aspects of FM, which occur in differing proportions in individual patients, may assist the practitioner in developing a treatment plan.

DIAGNOSTIC CRITERIA All of the validated criteria sets for FM include a requirement for chronic musculoskeletal pain. The ACR 1990 criteria focus on the widespread nature of the musculoskeletal pain, requiring that pain be present on both sides of the body, above and below the waist, and including the neck, back, or chest. A demonstration of the presence of widespread allodynia also was required, which was accomplished by a physical examination of 18 defined areas that should be painful with mechanical pressure, at a minimum of 11 sites (Table 52-1).15 The so-called tender point examination has been controversial for several reasons, including differences in the ability to detect tenderness in men compared with women when using this examination. Another criticism of the ACR 1990 criteria is the absence of other important symptoms, such as fatigue and unrefreshing sleep. In 2010, a new preliminary criteria set was published that eliminates the requirement for a physical examination, relying on the patient’s report of the number of painful areas to define a widespread pain index and incorporating a symptom severity score in recognition of the other symptoms of FM (Table 52-2).16 A person can be diagnosed with FM with pain being the dominant symptom or with a predominance of other somatic symptoms. The criticism of the 2010 criteria, as well as a modification published in 2011 intended for use in epidemiologic studies,17 is the loss of the

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TABLE 52-1  American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia* 1.  History of Widespread Pain Definition: Pain is considered widespread when all of the following are present: pain in the left side of the body, pain in the right side of the body, pain above the waist, and pain below the waist. In addition, axial skeletal pain (cervical spine or anterior chest or thoracic spine or low back) must be present. In this definition, shoulder and buttock pain is considered as pain for each involved side. “Low back” pain is considered lower segment pain. 2.  Pain in 11 of 18 Tender Point Sites upon Digital Palpation Definition: Pain, upon digital palpation, must be present in at least 11 of the following 18 sites: • Occiput: bilateral, at the suboccipital muscle insertions • Low cervical: bilateral, at the anterior aspects of the intertransverse spaces at C5-C7 • Trapezius: bilateral, at the midpoint of the upper border • Supraspinatus: bilateral, at origins, above the scapula spine near the medial border • Second rib: bilateral, at the second costochondral junctions, just lateral to the junctions on upper surfaces • Lateral epicondyle: bilateral, 2 cm distal to the epicondyles • Gluteal: bilateral, in upper outer quadrants of buttocks in anterior fold of muscle • Greater trochanter: bilateral, posterior to the trochanteric prominence • Knee: bilateral, at the medial fat pad proximal to the joint line Digital palpation should be performed with an approximate force of 4 kg. For a tender point to be considered “positive,” the subject must state that the palpation was painful. “Tender” is not to be considered “painful.” *For classification purposes, patients will be said to have fibromyalgia if both criteria are satisfied. Widespread pain must have been present for at least 3 months. The presence of a second clinical disorder does not exclude the diagnosis of fibromyalgia. From Wolfe F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 33:160-172, 1990.

TABLE 52-2  American College of Rheumatology 2010 Preliminary Diagnostic Criteria for Fibromyalgia Criteria A patient satisfies diagnostic criteria for fibromyalgia if the following three conditions are met: 1. WPI ≥7 and SSS ≥5 or WPI between 3 and 6 and SSS ≥9. 2. Symptoms have been present at a similar level for at least 3 months. 3. The patient does not have a disorder that would otherwise explain the pain. Ascertainment 1. WPI: Note the number areas in which the patient has had pain during the past week. In how many areas has the patient had pain? Score will be between 0 and 19. Shoulder girdle, L Hip (buttock, trochanter), L Jaw, L Upper back Shoulder girdle, R Hip (buttock, trochanter), R Jaw, R Lower back Upper arm, L Upper leg, L Chest Neck Upper arm, R Upper leg, R Abdomen Lower arm, L Lower leg, L 2. SSS: Fatigue Waking unrefreshed Cognitive symptoms For the each of the three aforementioned symptoms, indicate the level of severity during the past week using the following scale: 0 = No problem 1 = Slight or mild problems; generally mild or intermittent 2 = Moderate; considerable problems; often present and/or at a moderate level 3 = Severe: pervasive, continuous, life-disturbing problems Considering somatic symptoms* in general, indicate whether the patient has: 0 = No symptoms 1 = Few symptoms 2 = A moderate number of symptoms 3 = A great deal of symptoms The SSS is the sum of the severity of the three symptoms (fatigue, waking unrefreshed, and cognitive symptoms) plus the extent (severity) of somatic symptoms in general. The final score is between 0 and 12. *For reference purposes, here is a list of somatic symptoms that might be considered: muscle pain, irritable bowel syndrome, fatigue/tiredness, thinking or remembering problem, muscle weakness, headache, pain/cramps in abdomen, numbness/tingling, dizziness, insomnia, depression, constipation, pain in upper abdomen, nausea, nervousness, chest pain, blurred vision, fever, diarrhea, dry mouth, itching, wheezing, Raynaud’s phenomenon, hives/welts, ringing in ears, vomiting, heartburn, oral ulcers, loss/change in taste, seizures, dry eyes, shortness of breath, loss of appetite, rash, sun sensitivity, hearing difficulties, easy bruising, hair loss, frequent urination, painful urination, and bladder spasms. L, Left; R, right; SSS, Symptom Severity Score; WPI, Widespread Pain Index. From Wolfe F, Clauw DJ, Fitzcharles MA, et al. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 62:600-610, 2010.



requirement that the pain be widespread (as defined in the 1990 criteria) and the potential expansion of the prevalence of FM by including persons with a lower level of pain symptoms, with a possible bias toward persons with somatic symptom disorder. Other criteria sets have been published that include other configurations of symptoms and signs, but the basic clinical manifestations remain unchanged.20,21 At the present time, it remains unclear if the presence of tenderness, identified by tender point examination or other methods that demonstrate allodynia or hyperalgesia, improves the specificity of the diagnosis. It also is not clear how to best define widespread pain; for example, is a high number of painful sites regardless of their distribution the same as having pain all over the body? Although it is clear that symptoms not related to pain occur frequently and are important to patients with FM, the inclusion of patients whose clinical picture is dominated by nonpain symptoms, such as fatigue, unrefreshing sleep, and dyscognition, remains controversial.

EPIDEMIOLOGY A number of epidemiologic studies have been performed using different ways to identify patients with FM. The prevalence depends on the method of ascertainment. Using the ACR 1990 criteria, the worldwide prevalence is estimated at approximately 2% of the population. The first major study was conducted in Wichita, Kansas, using a populationbased mail screening followed by physician assessment.22 In that study, the overall prevalence was 2%, with 3.4% of women and 0.5% of men diagnosed with FM. Subsequently, the prevalence in London, Ontario, Canada, was found to be 4.9% of women and 1.6% of men.23 It is of interest that these same Canadian investigators evaluated an Amish community to determine if litigation or compensation availability had an influence on FM prevalence.24 They found that the age-adjusted point prevalence of FM was 10.4% in women and 3.7% in men, which was greater than that found in rural or nonrural non-Amish adults and was interpreted as providing evidence that FM is present in communities that lack a financial incentive for having the disorder. In France, also using a two-step method of ascertainment, the prevalence was 1.6%; gender was not specified.25 In a Korean hospital study, the prevalence was 1.7%, with 3.2% of females and 0.6% of males being affected.26 The prevalence of FM appears to increase with age to about age 70 years, after which it decreases slightly.22,23 FM can be diagnosed in children—usually in adolescents, and more commonly in girls.27 The prevalence in patients with rheumatic diseases is estimated at 11% to 30%, although a recent large study suggests that the range is between 6% and 13% for the most common rheumatologic conditions.28 When using a modified version of the ACR 2010 criteria developed for use in population studies and without physician examination, the prevalence in Olmstead County, Minnesota, was 6.4%: 7.71% in women and 4.48% in men.29 A German study using these same criteria reported a prevalence of 2.1% overall, with 2.4% in women and 1.8% in men.30 An internet survey in Japan also using the modified 2010 criteria reported an overall prevalence of 2.1%, with 2.3% in women and 0.85% in men.31

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The prevalence of FM is generally greater in clinical settings than in epidemiologic studies. It was noted to be 5.7% in general medical clinics32 and 2.1% in family practice settings.33 In rheumatology clinics, FM prevalence was higher, with between 12% and 20% of new patients having this diagnosis.14,34 The prevalence of FM in children is approximately 1.5% across studies, and it is usually diagnosed in adolescent girls.27,35 The incidence of FM is not easily determined; however, one study using an International Classification of Diseases, Ninth Revision (ICD-9) coding insurance claims database containing 62,000 nationwide enrollees per year between 1997 and 2002 found an age-adjusted incidence of 11.28 per 1000 person years for females and 6.88 cases per 1000 person-years in males.36 In that study, patients with FM were between two and seven times more likely to have comorbid depression, anxiety, headache, irritable bowel syndrome, chronic fatigue syndrome, systemic lupus erythematosus, and rheumatoid arthritis. Contrast these data with the incidence of FM in patients with other rheumatic diseases: In a cohort of approximately 1000 patients in the early stage of arthritis who were followed up by rheumatologists, the incidence of FM was 6.77 per 100 person-years in the first year after the diagnosis. The incidence declined to 3.58 per 100 person-years in the second year.37 This makes FM approximately 10-fold more common in patients with early arthritis than in a general claims dataset.

CLINICAL FEATURES In clinical settings, patients often report that they have pain “all over their body.” They often have difficulty precisely localizing the pain and may describe it as moving from place to place. Patients often describe the pain as “deep,” originating in muscles or bones. Patients may use many different pain descriptors, including “throbbing,” “stabbing,” and “burning.” In a study comparing 100 patients who had FM and met 1990 ACR criteria with 76 control subjects who had widespread pain, four symptoms distinguished patients with FM from control subjects: pain severity, severe fatigue lasting 24 hours after minimal activity, weakness, and selfreported swelling of the neck glands.38 Pain is typically present on most days almost all day, although the intensity may wax and wane. Patients often describe tenderness to light touch or pressure. Pain is typically exacerbated by physical activity, and some patients report that it is worsened with changes in the weather, although this phenomenon has not been confirmed in rigorous studies. In addition to pain, patients report muscular stiffness, tightness, and weakness. The main purpose of the physical examination is to evaluate the patient for other conditions that cause musculoskeletal pain. Patients with FM exhibit tenderness that can be identified by tender point examination. Tender point sites represent specific areas of muscle, tendon, and fat pads that are more tender to palpation than surrounding sites. Sites selected as part of the ACR 1990 criteria represent tender point sites that best discriminated between patients with and without FM. To test for pain with digital palpation, the ACR 1990 criteria indicate that the examiner should press with an approximate force of 4 kg.15 The patient should report pain in response to this level of pressure,

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which in practice is approximately the force it takes for the thumbnail to blanche. In addition to the usual musculoskeletal and connective tissue examination, it is useful to evaluate patients, particularly young patients, for joint hypermobility.39 There are indications that FM may be more common among patients with these findings, and physical measures may be quite useful in management of patients with these associations. If regional pain disorders, such as bursitis, tendonitis, or arthritis, can be identified during the physical examination, treatment of these potentially exacerbating pain generators may help with the more widespread pain. Certainly, any mechanical or inflammatory conditions with the potential to cause musculoskeletal pain should be identified and treated. The pain of FM is often accompanied by other pain amplification syndromes (Table 52-3). These syndromes often have been present for many years and, as with FM, they may wax and wane over time. It may be important for the patient to understand the genetic and physiologic relationships between these diagnoses. In addition, it is clinically important to determine which symptoms have the greatest impact on the patient. Symptom domains have been evaluated by patient and physician Delphi exercises and were generally concordant (Table 52-4).40 Assessing these clinical concerns may help the clinician prioritize management strategies. For example, if sleep is a major

contributor to symptoms, the patient may be counseled on sleep hygiene or, if appropriate, screened for restless leg syndrome or sleep apnea and then referred for evaluation and management of sleep disorder.41 Similarly, if depression or anxiety is a major contributor to the overall symptom complex, then attention should be given to management of these concerns.42 Dyscognition may be of major importance to patients, particularly in the workplace.43,44 These complaints have validity when studied carefully, with abnormalities in executive function and divided attention. Fatigue may be the most difficult symptom to evaluate and treat because it may be due to deconditioning, depression, disrupted sleep, medication adverse effects, or comorbid conditions. TABLE 52-3  Fibromyalgia-Associated Pain Amplification Syndromes Temporomandibular disorder Tension and migraine headaches Irritable bowel syndrome and other functional gastrointestinal disorders Interstitial cystitis/irritable bladder Dysmenorrhea and other pelvic pain syndromes Vulvodynia

TABLE 52-4  Patient-Reported Outcomes (PRO) in Fibromyalgia PRO Concept

Patient Domains*

Clinician Domains and Measures†

Pain

Pain or physical discomfort Joints aching or pain Stiffness Feeling tender where touched

Pain Patient global status Clinician global status Tender point intensity

Treatment side effects

Problems with medication (e.g., medication adverse effects or reliance on medications)‡

Adverse effects

Mobility

Difficulty moving, walking, or exercising

Physical function HRQOL

Cognition

Problems with attention or concentration Disorganized thinking Memory problems

Dyscognition HRQOL

Energy

Lack of energy or fatigue Having to push yourself to do things

Fatigue HRQOL

Impact on daily living

Limited in doing normal daily life and household activities Ability to make plans, accomplish goals, or complete tasks Being sensitive to outside factors Unpredictability of symptoms

HRQOL

Emotional well-being

Depression Having to push yourself to do things Frustration‡ Irritability‡

Depression Anxiety HRQOL

Sleep

Impact on sleep (e.g., difficulty falling asleep, saying asleep, or getting up in the morning)

Sleep quality HRQOL

*Most important fibromyalgia symptoms based on a Delphi exercise involving 100 patients with fibromyalgia and conducted at four different sites in the United States. The original 104 items were extracted from patient focus groups and then consolidated and reduced according to pretest rankings before being tested by Delphi. † Clinician Delphi exercise involving 23 clinicians and outcome filtered through Outcome Measures in Rheumatology Clinical Trials VII (OMERACT VII) fibromyalgia workshop attendees. ‡ Included based on pretest priority rankings. HRQOL, Health-related quality of life; PRO, patient-reported outcomes. From Mease PJ, Arnold LM, Crofford LJ, et al. Identifying the clinical domains of fibromyalgia: contributions from clinician and patient Delphi exercises. Arthritis Rheum 59:952-960, 2008.



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Chronic (>3 months) widespread musculoskeletal pain

History • Personal or family history of pain • Pain quality and anatomic location • Associated symptoms of fatigue, unrefreshing sleep, dyscognition, depression/anxiety, perceived stress • Medications

Physical examination • Tenderness assessment • Musculoskeletal examination for synovitis, degenerative change, soft tissue disorders (bursitis, tendonitis), hypermobility • Connective tissue features such as rash, mucositis, Raynaud’s phenomenon • Neurologic examination

• • • • •

Testing CBC, metabolic panel ESR or CRP TSH Vitamin D Other testing guided by H&P

Determine category

FM • Meets ACR criteria • Physical examination normal except widespread allodynia • Laboratory testing normal • No suspicious medications

Comorbid FM • Other condition contributing to overall clinical picture, but may not explain entire symptom complex • Meets 1990 ACR criteria15

Not FM • Alternative diagnosis is likely to explain clinical findings • Does not meet ACR criteria

Initiate FM treatment • Educate patient • Determine symptom domain(s) for initial treatment focus • Implement nonpharmacologic program of exercise and behavioral management • Begin pharmacologic treatment according to primary symptom profile − Pain/sleep: TCA, gabapentinoid − Fatigue/depression: NSRI

Treat comorbid disorder and nonpharmacologic FM treatment • Initiate treatment of primary disorder • Educate patient about FM • Add exercise program, depression/anxiety treatment, and/or sleep management program if clinically appropriate • Assess need for pharmacologic treatment of FM once primary disorder treated

Treat alternative disorder • Consider re-evaluation for FM if widespread pain persists despite adequate treatment of alternative disorder

Figure 52-1  Strategy for evaluation and initial management of patients with chronic widespread musculoskeletal pain. After initial evaluation, patients may be diagnosed with fibromyalgia (FM), FM comorbid with another diagnosis, or not FM. Strategies for initial management of each category are shown. ACR, American College of Rheumatology; CBC, complete blood cell count; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; H&P, history and physical examination; NSRI, norepinephrine serotonin reuptake inhibitor; TCA, tricyclic anti-depressants; TSH, thyroid-stimulating hormone.

DIFFERENTIAL DIAGNOSIS AND RHEUMATOLOGIC COMORBIDITIES A strategy for diagnosing FM is shown in Figure 52-1.45,46 Common conditions that should be considered in the differential diagnosis are shown in Table 52-5. Most of these conditions should be identified by careful history and physical examination with selected laboratory tests. Medications that may be associated with FM mimics, such as statins, should be noted. Physical findings that should prompt additional testing include prominent focal abnormalities on neurologic examination, such as weakness or numbness, joint inflammation, fever, rash, skin ulcers, or alopecia.45 Hypothyroidism can be excluded using laboratory tests. Seronegative spondyloarthropathies may have elevated inflammatory markers and abnormal results of imaging studies. These patients also typically report that their pain improves rather than worsens with exercise. In older

patients, polymyalgia rheumatic should be excluded using laboratory testing. Screening questions for major depressive disorder should be undertaken. If the history and physical examination suggest inflammatory arthritis or a systemic autoimmune disease, appropriate laboratory and serologic testing should be undertaken. It is not useful to perform repeat diagnostic testing, particularly if symptoms have been present for more than 1 to 2 years and if the symptoms do not change. FM is frequently comorbid with other rheumatologic diseases. In a recent study of 835 patients, the prevalence of FM was 13.4% in 67 patients with systemic lupus erythematosus, 12.6% in 119 patients with ankylosing spondylitis, 12% in 25 patients with Sjögren’s syndrome, 10.1% in 238 patients with osteoarthritis, 6.9% in 29 patients with polymyalgia rheumatica, and 6.6% in 197 patients with rheumatoid arthritis. Significant correlations were found between disease activity indexes and Fibromyalgia Impact

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TABLE 52-5  Differential Diagnosis of Diffuse Myalgias Diagnosis

Findings*

Inflammatory Polymyalgia rheumatica

Elevated ESR and/or CRP

Seronegative spondyloarthropathies

Abnormal imaging

Connective tissue diseases

Positive serologies

Systemic vasculitis

Systemic inflammation, end-organ damage

Infectious Hepatitis C

Positive antibodies

Human immunodeficiency virus

Positive antibodies

Lyme disease

Positive antibodies

Parvovirus B19

Positive antibodies

Epstein-Barr virus

Positive antibodies

Non-inflammatory Degenerative joint/spine disease

Abnormal imaging

Fibromyalgia

Widespread allodynia/ hyperalgesia

Myofascial pain

Localized allodynia/hyperalgesia

Joint hypermobility

Joint hypermobility

Metabolic myopathies

Abnormal muscle biopsy

Endocrine Hypo- or hyperthyroidism

Abnormal thyroid function tests

Hyperparathyroidism

Elevated serum calcium

Addison’s disease

Abnormal serum cortisol

Vitamin D deficiency

Low serum vitamin D

Neurologic Diseases Multiple sclerosis Neuropathic pain

Abnormal neurologic examination and imaging Reasonable cause or abnormal imaging

Psychiatric Diseases Major depressive disorder

Positive depression screening

Drugs Statins

History of exposure

Aromatase inhibitors

History of exposure

*Recommended routine testing includes ESR or CRP and thyroidstimulating hormone. Other diagnostic testing should be guided by risk profile and history and physical examination. Repeated diagnostic testing is discouraged. CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.

Questionnaire (FIQ) scores for most rheumatologic patients.28 Identifying central pain amplification has important implications for evaluation and treatment of comorbid conditions. For example, it is well known that the tender joint component and patient-reported symptoms of the Disease Activity Score (DAS)-28 are higher in patients with FM than in patients without FM. Using more objective criteria for synovitis in those patients, such as ultrasound, may be required to determine if treatment of rheumatoid arthritis should be accelerated. Other comorbidities are frequent in patients with FM and do not vary a great deal with the clinical site in which the patient is seen. Patients with FM have a significantly higher prevalence of visceral pain syndromes, regional pain

syndromes, and mood disorders. In one study using an ICD-9 coding insurance claims database containing 62,000 nationwide enrollees, patients with FM were between two and seven times more likely to have comorbid depression, anxiety, headache, irritable bowel syndrome, chronic fatigue syndrome, systemic lupus erythematosus, and rheumatoid arthritis.36 In a study from the United Kingdom primary care dataset of persons eventually diagnosed with FM, visit rates were highest for depression, fatigue, chest pain, headache, and sleep disturbance.47 A population-based study from the Swedish Twin Registry evaluating 44,897 persons found substantial co-occurrence for chronic widespread pain with chronic fatigue (odds ratio [OR], 23.53; 95% confidence interval [CI], 19.67 to 18.16), depressive symptoms (OR, 5.26; 95% CI, 4.75 to 5.82), and irritable bowel syndrome (OR, 5.17; 95% CI, 4.55 to 5.88).48 Using a co-twin analysis, the associations remained for chronic fatigue and irritable syndrome but not for depressive symptoms. In a rheumatology practice, patients with FM were found to have high lifetime rates of migraine, irritable bowel syndrome, chronic fatigue syndrome, major depression, and panic disorder.49 FM is frequently identified in patients seen primarily for interstitial cystitis, irritable bowel syndrome, migraine and other forms of headache, temporomandibular disorder, multiple chemical sensitivities, and chronic fatigue syndrome. In a systematic review from 2001 of the aforementioned conditions, it was noted that there were many similarities in case definition and symptoms and that the proportion of patients with an unexplained clinical condition meeting criteria for a second unexplained condition was striking.50 Psychiatric conditions associated with FM include major depressive disorder, bipolar disorder, anxiety disorders, including panic disorder, post-traumatic stress disorder, social phobia and obsessive compulsive disorder, and substance abuse disorder.51,52 In a study of 108 persons with FM and 228 persons without FM, the odds ratio for persons with FM having bipolar disorder was 153 (95% CI, 26 to 902; P <0.001); any anxiety disorder, 6.7 (95% CI, 2.3 to 20; P <0.001); substance use disorder, 3.3 (95% CI, 1.1 to 10; P = 0.040); and major depressive disorder, 2.7 (95% CI, 1.2 to 6.0; P = 0.13).51 Should a patient with FM have multiple pain amplification disorders, the practitioner will need to determine if he or she should be treated as having one disorder of central etiology or whether there is a clinical reason for diagnosis of multiple different disorders. Many of the medications and nonpharmacologic treatments for these conditions overlap. To avoid use of multiple medications, if a single agent can be used—for example, an agent with anti-depressant activity—it may be possible to treat comorbidities and FM.

ASSESSMENT OF SEVERITY Symptom severity, physical function, and disability are key status and outcome variables in persons with FM. In the clinic, numeric ratings for pain and fatigue along with a measure of functional status, including those routinely used for rheumatic diseases, such as one of the Health Assessment Questionnaires (HAQ) instruments, work very well in patients with FM.53,54 The revised FIQ (FIQ-R) addresses all of these core domains, as well as FM impact and several



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The revised Fibromyalgia Impact Questionnaire Domain 1 directions: For each of the following nine questions, check the one box that best indicates how much your fibromyalgia made it difficult to do each of the following activities over the past 7 days: Brush or comb your hair Walk continuously for 20 minutes Prepare a homemade meal Vacuum, scrub, or sweep floors Lift and carry a bag full of groceries Climb one flight of stairs Change bed sheets Sit in a chair for 45 minutes Go shopping for groceries

No difficulty No difficulty No difficulty No difficulty No difficulty No difficulty No difficulty No difficulty No difficulty

Very difficult Very difficult Very difficult Very difficult Very difficult Very difficult Very difficult Very difficult Very difficult

Domain 2 directions: For each of the following two questions, check the one box that best describes the overall impact of your fibromyalgia over the past 7 days: Fibromyalgia prevented me from accomplishing goals for the week I was completely overwhelmed by my fibromyalgia symptoms

Never Never

Always Always

Domain 3 directions: For each of the following 10 questions, check the one box that best indicates the intensity of your fibromyalgia symptoms over the past 7 days: Please rate your level of pain Please rate your level of energy Please rate your level of stiffness Please rate the quality of your sleep Please rate your level of depression Please rate your level of memory problems Please rate your level of anxiety Please rate your level of tenderness to touch Please rate your level of balance problems Please rate your level of sensitivity to loud noises, bright lights, odors, and cold

No pain Lots of energy No stiffness Awoke rested No depression Good memory Not anxious No tenderness No imbalance No sensitivity

Unbearable pain No energy Severe stiffness Awoke very tired Very depressed Very poor memory Very anxious Very tender Severe imbalance Extreme sensitivity

Scoring: Step 1. Sum the scores for each of the three domains (function, overall, and symptoms). Step 2. Divide domain 1 score by three, divide domain 2 score by one (that is, it is unchanged), and divide domain score 3 by two. Step 3. Add the three resulting domain scores to obtain the total revised Fibromyalgia Impact Questionnaire score. Figure 52-2  The revised Fibromyalgia Impact Questionnaire (FIQR) assesses functional status as well as the overall impact and fibromyalgia symptoms.55 The FIQR total score can be used as an outcome measure in clinical studies. The FIQR function score and the symptom scores can be used individually to determine severity. Paper and online versions perform similarly, and the FIQR performs similarly to the original version.

other symptoms (Figure 52-2).55 The ACR 2010 criteria modified for epidemiologic studies provide another measure of FM severity; it is called the FM Symptom Scale and combines the Widespread Pain Index (WPI) and the modified Symptom Severity Score (SSS) into a continuous score.16 For research purposes, the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) FM working group has recommended that the domains of pain, fatigue, sleep, depression, physical function, quality of life, multidimensional function, patient’s global impression of change, tenderness, dyscognition, anxiety, and stiffness be assessed.56 This assessment can be accomplished using the FIQ-R and the Medical Outcomes Scale SF-36.57

MECHANISMS The two intrinsic mechanisms associated with the risk of developing chronic painful musculoskeletal disorders, including FM, are pain amplification and psychological distress.5 Pain amplification may be related to sensitization

of afferent pathways in the peripheral or central nervous system that process coded pain information or impairment in the inhibitory systems of the central nervous system.9 Psychological factors include enhanced somatic awareness or the perception and interpretation of sensory information, anxiety, depression, perceived stress, and catastrophizing.58 It is likely that genetic vulnerability coupled with environmental triggers are required to produce the clinical phenotype. The specific environmental triggers may include nonspecific behavioral factors, such as smoking and obesity, stress exposures, and nociceptive musculoskeletal pain. The combination of risk factors is likely to vary among persons who meet the definition of FM.

Genetic Risk A number of studies have demonstrated the importance of genetics in the susceptibility of FM and other syndromes that are often comorbid with FM. A study of familial aggregation reported that first-degree relatives of FM probands are far more likely to have FM (OR, 8.5; 95% CI,

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2.8 to 26; P <0.001). Twin studies have estimated that the contribution of genetic factors to chronic widespread musculoskeletal pain load on two latent traits are best explained by both affective and sensory components.59 These twin studies suggest a modest genetic influence with concordance for chronic widespread pain, with concordance for monozygotic female twins of 30%, and for dizygotic female twins of 16%.60 It is unlikely that a specific gene or set of genes is associated with FM. Rather, similar to autoimmune diseases, there are more general vulnerability genes that interact with environmental exposures to lead to clinical expression of pain conditions. Thus most of the genes associated with FM have also been reported in association with other clinically defined pain syndromes. For example, two major neurotransmitter pathways have been repeatedly associated with musculoskeletal pain.5 The first is the adrenergic pathway, in which COMT, the gene encoding the enzyme catechol-O-methyltransferase that is responsible for the catabolism of catechol neurotransmitters, such as epinephrine, norepinephrine, and dopamine, is most frequently associated with chronic musculoskeletal pain conditions. Most studies of COMT report an increased risk of chronic pain associated with a Val159Met (rs4680) that encodes a protein with lower enzymatic activity.5 More extensive studies have expanded the functional locus to three major haplotypes that modify expression and activity of the enzyme, thus conferring low-risk and high-risk phenotypes for acute pain sensitivity, as well as risk for developing chronic pain.61 Additional genetic variation in the β2-adrenergic receptor gene (ADRB2; rs1042713 and rs1042714) has been associated with an increased risk of FM and chronic widespread pain. Haplotype variants that regulate β2-adrenergic receptor expression and internalization are associated with differences in susceptibility to chronic pain.62 The second pathway associated with chronic pain syndromes is the serotonin pathway. Specific genes include the 5-hydroxytryptamin receptor 2A (HTR2A) and 5HT transporter (SLC6A4).63-65 A 44–base pair insertion/deletion polymorphism in the promoter region of SLC6A4 is most frequently associated with risk of chronic pain conditions, including FM.5 Both of these genetic pathways are also associated with several “endophenotypes” or intermediate measurable phenotypes that are present in patients with FM. These endophenotypes include autonomic dysregulation, altered pain processing and modulation, sleep dysfunction, and anxiety, in the case of the adrenergic pathway.5 Personality and affective traits, such as somatic awareness, depression, and anxiety, have been associated with genetic variation in the serotonin pathway and are associated with risk for chronic pain.5 Candidate gene analysis of patients carrying the diagnosis of FM identified pathways also including genes within the biogenic amine and adrenergic pathways though different from candidates more generally associated with chronic pain, as well as a cannabinoid receptor.6 A genome-wide linkage scan study of families with FM identified chromosome 17p11.2-q11.2, a region that contains the serotonin transporter gene (SLC6A4) and the transient receptor potential vanilloid channel 2 gene (TRPV2).66

Central Pain Amplification and Potential Peripheral Mechanisms Several lines of evidence support the concept of central pain amplification (also called central sensitization), which is generally interpreted as a change in the relationship between stimulus intensity and the perception of the stimulus as noxious or painful.67 In patients with FM, stimuli usually perceived as innocuous are perceived as painful (allodynia), and painful stimuli are given a higher pain rating (hyperalgesia).68 During central sensitization, second-order and higher-order neurons exhibit transcriptional and translational events that lead to heightened sensitivity. Most of the data supporting central sensitization are generated through psychophysical testing using different types of stimuli such as pressure or heat. The investigator may use either a subjective report of pain or an objective measure such as brain imaging. One experimental paradigm called wind-up or temporal summation of pain measures the change in pain intensity after repeated applications of a sensory stimulus.68 Healthy persons will experience an increase in pain in response to identical stimulus intensity if the stimulus is presented with a short interstimulus interval. Patients with FM report the same wind-up phenomenon with longer interstimulus intervals, which is interpreted to mean that patients with FM have presensitized pain transmission neurons.69,70 Patients with FM also have a delayed recovery to baseline, termed aftersensations, which correlates with clinical pain intensity.70 Studies have also implicated a deficiency in descending inhibitory control of noxious stimulation in persons with FM. Normally, endogenous inhibitory mechanisms are activated in response to nociceptive stimuli and involve serotonergic, noradrenergic, and opioidergic inhibitory pathways. Persons with FM do exhibit reduction in these pathways.71 It is difficult to know whether activation of afferent pain pathways, deficiency of descending pathways, or both explain enhanced pain perception in a given person. Positron emission tomographic scanning has demonstrated alterations in mu-opioid receptor availability and increased dopamine activity in persons with FM, both of which could indicate alteration of normal pain inhibitory pathways.72,73 Disagreement exists regarding the role of peripheral nociceptive input in the cause and maintenance of FM, although the increased prevalence of FM in persons with other rheumatic diseases provides an argument that persistent peripheral pain generators may be an important risk factor contributing to the phenotypic changes in pain transmission neurons.74 Other triggering events, such as certain types of infections, trauma, or psychological stress, have been proposed.75,76 Pain is localized to muscle tissues in virtually all persons with FM. Abnormalities in muscle tissues have been reported, including altered metabolisms by phosphorus-31 magnetic resonance spectroscopy (MRS).77 Some data implicate muscle microcirculation and muscle mitochondria in FM.68,78,79 Reports have been made of small fiber neuropathies in persons with FM, which are thought potentially to be a source of persistent nociceptive input.80-83 For example, in a recent study of persons with FM and control subjects, intraepidermal nerve fiber



density was reduced in 32.6% in the former.80 Another study used microneurography to record C-fiber action potentials in persons with FM and control subjects.83 Persons diagnosed with FM had abnormalities in the functioning of type 1B C nociceptors that are normally silent and mechanoinsensitive, including spontaneous activity, prolonged firing in response to mechanical stimulation, and/or a distinctive pattern of activity-dependent slowing of conduction velocity. Whether these data indicate that a subset of persons with FM may in fact have neuropathic pain associated with a non–length-dependent small fiber neuropathy or whether the key element that results in FM is that peripheral pain generators lead to central sensitization is not clear. Altered peripheral and cerebrospinal fluid levels of neurotrophins, chemokines, and cytokines have been reported in persons with FM.68 Mechanisms for the effects of these substances in explaining the pathophysiology of FM remain undetermined. However, the concept that activation of glial cells by cytokines and chemokines may accompany activation of pain transmission neurons can be demonstrated in animal models.84 Functional neuroimaging has contributed much to the understanding of FM and, because the outcome is objective, it has clearly confirmed the validity of patient reports. One of the first studies to address this issue demonstrated that greater regional cerebral blood flow receiving pain pathway input was related to the patient’s report of pain rather than to the stimulus intensity.85 Other neuroimaging techniques have emerged and have provided information in FM and other chronic pain states. Using proton MRS (1HMRS), persons with FM were found to have low levels of N-acetyl-aspartate, a metabolite believed to be a marker of neuronal density and viability, perhaps indicating loss of neural function and activity in the hippocampus.86 Also using 1H-MRS, it was found that the main excitatory neurotransmitter, glutamate/glutamine, was elevated in the posterior insular cortex, and a decrease in the signal correlated with improvements in pain.87,88 Other brain regions of persons with FM, including the amygdala, posterior cingulate, and ventral lateral prefrontal cortex, had elevated levels of glutamate/glutamine, suggesting a possible role for this neurotransmitter in pain and perhaps other symptoms of FM.86

Stress Response Systems A number of studies suggest abnormalities of stress-response systems—the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system—in persons with FM. It is unclear whether these abnormalities are a cause or a consequence of FM. Genetic studies implicating genes in these pathways suggest that lack of resiliency in these pathways may provide a measure of vulnerability, but other studies implicate exposure to acute or chronic stress as a triggering mechanism. One study of patients without chronic widespread pain but who were at risk based on high rates of psychological distress and somatization provided evidence that HPA axis dysfunction may precede the development of chronic pain89 and that HPA axis dysfunction was associated with the subsequent development of chronic widespread pain.90 There is a striking lack of

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consistency in the specific HPA axis measures associated with FM.91 Many studies, however, consistently demonstrate alterations of measures of autonomic function, especially heart rate variability. These alterations are most often said to demonstrate predominance of the sympathetic nervous system, a characteristic shared by other pain amplification syndromes.92 Other studies are interpreted as demonstrating stronger parasympathetic decline, a finding associated with the tendency to exhibit defensive behaviors.93

SOCIAL AND PSYCHOLOGICAL FACTORS Life Stress and Socioeconomic Factors In many longitudinal epidemiologic studies, chronic pain and other somatic symptoms can be predicted by childhood abuse and traumas, low educational attainment, social isolation, depression, and anxiety.94 In a population-based study to determine psychosocial factors that predicted new-onset chronic widespread pain, investigators identified a random sample of subjects from sociodemographically disparate backgrounds and then identified more than 3000 who did not have pain at baseline and more than 300 who had new widespread musculoskeletal pain at follow-up.95 The strongest predictors were premorbid somatic symptoms, illness behaviors, and sleep problems. In another community-based study, perceived physical and emotional trauma as precipitating factors for FM were associated with health care seeking rather than pain severity.96 Lower socioeconomic status predicts greater symptom severity and functional impairment in persons with FM, even controlling for levels of pain, depression, and anxiety.97 The biopsychosocial model of pain posits that pain experience and its impact on the individual is a function of interacting combinations of nociceptive input; psychological processes, including beliefs; coping repertoire; and mood; and environmental contingencies that would include family, community, and cultural rules or expectations.98 All of these factors are likely to play a key role in the clinical expression and health impact of FM.

Personality, Cognitive, and Psychological Factors Persons with FM may have a specific personality profile characterized, for example, by high levels of neuroticism. However, many studies include state variables, such as catastrophizing, self-esteem, and motivation or coping strategies, with personality traits. It is sometimes unclear whether a personality feature is a state or a trait; for example, catastrophizing may be seen as a personality feature, a cognitive error, or a coping strategy.99 A recent study using a standard five-factor personality scale (neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) showed that patients with FM were not different from patients with other rheumatic pain conditions or other chronic illnesses.100 Furthermore, the scores fell within the normal range for the general population. However, a cluster of patients with FM was identified with a personality profile (high neuroticism and lower extraversion) that reflects a proneness to experience emotional distress, a difficulty for

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positive emotion, and a tendency to ineffective use of emotional regulation processes rather exhibiting rumination and maladaptive behaviors. The patients in this cluster also exhibited more psychosocial problems.100 Another way of stratifying patients is the psychological and behavioral response to chronic pain. Persons with FM have been characterized and divided into groups that predict outcome based on psychological characteristics.101 Persons classified as “dysfunctional” exhibit the highest pain intensity, interference, and distress and the lowest control and activity levels. The “adaptive coper” groups report the lowest levels of pain and interference, as well as the highest activity levels. The “interpersonally distressed” patients report high levels of affective distress and more negative spousal responses to pain. It is likely that important relationships exist between psychological and physiologic pathways in persons with FM. This likelihood is certainly not surprising because regulation of domains characterized as psychological and physiologic use common mediators. For example, in a recent study of persons with FM, investigators performed a cluster analysis based on pain characteristics and cognitive, affective, and behavioral responses to pain and stress.102 The study demonstrated that psychophysiologic responses of blood pressure, heart rate, and skin conductance were associated with specific types of psychological coping and psychiatric diagnoses.103

TREATMENT APPROACHES Education and Self-Management Treatment guidelines for persons with FM typically emphasize the need to incorporate principles of selfmanagement.104,105 Making the diagnosis of FM provides an intellectual framework for educating patients about their symptoms and engaging them as an active participant in the treatment plan (Figure 52-3).105 Providing the diagnosis can provide relief from health-related anxiety, and no studies have suggested that labeling with FM is harmful for health or health care expenditures.106,107 Educating patients regarding the physiology of chronic pain in FM, as well as the importance of nonpharmacologic therapies for its management, is likely to be beneficial. One key goal is to assist the patient in differentiating peripheral pain generators from the centrally maintained diffuse pain. In addition, educating patients about which treatment is intended to target which pain symptom may help with adherence and satisfaction with treatment. For example, nonsteroidal antiinflammatory drugs (NSAIDs) or disease-modifying agents may be intended for peripheral mechanical or inflammatory pain but would not be expected to effectively treat FM pain.104 A comparison of network meta-analyses of different treatment strategies found that multicomponent therapies incorporating pharmacologic therapies with aerobic exercise

Educate the patient Core set of information about FM pathophysiology, treatment, and prognosis Direct patient and family to credible FM information sources Discuss expectations for clinician/patient roles and responsibilities

Define individual goals Collaborate with patient to identify 1-2 most important symptoms Document baseline status Discuss expectations for pharmacologic and nonpharmacologic treatments

Know your patient: Reflect patient priorities and preferences in treatment plan Know your team: Identify specialists or ancillary providers that can work with you Know your community: Identify community resources the patient can utilize for self-management

Pharmacologic treatment Start low and titrate slowly to effective dose Manage expectations Treat FM-associated syndromes Mood disorders Sleep disorders Associated pain conditions

Nonpharmacologic treatment Write as “prescriptions” and be specific Physical activity and sleep hygiene Cognitive behavioral therapy Self-management support Treat comorbid conditions

Re-evaluate Evaluate progress toward goals Evaluate medication efficacy and adverse events Assess adherence and barriers to adherence to nonpharmacologic treatments Adjust treatment plan Continue education and goal-setting Figure 52-3 Integrated approach to fibromyalgia (FM) management. (Modified from Arnold LM, Clauw DJ, Dunegan LJ, et al: A framework for fibromyalgia management for primary care providers. Mayo Clinic Proceedings. 87[5]:488–96, 2012.)



and cognitive behavioral therapy (CBT) seems most promising.108 Many of the nonpharmacologic strategies useful for FM may not be available locally but lend themselves to Internet-based programs or written materials.105 The provider and patient should collaborate to prioritize individual treatment goals and develop a plan to achieve those goals. Focusing on longer term goals, while acknowledging that FM symptoms tend to wax and wane in response to both external and internal environmental stressors, is advised.105

Exercise and Body-Based Therapies A number of systematic reviews have been conducted to assess the benefits of exercise for persons with FM.109-112 In evaluating exercise interventions, a recent umbrella systematic review synthesized physical activity interventions for adults with FM, focusing on four outcomes, including pain, multidimensional function, physical function, and adverse effects.113 The researchers found positive results of diverse exercise interventions for all outcomes and no adverse effects. The variability of the interventions did not allow for recommendations regarding the mode of exercise or the frequency, intensity, and duration of treatments. It is not possible to rigorously determine whether land- or waterbased exercise is superior. All major outcomes, including function, pain, stiffness, muscle strength, and fitness, improved after aquatic exercise training compared with control subjects, although the quality of the evidence was rated as low to moderate; however, land-based training was superior to aquatic training for improving muscle strength.112 Tai chi, yoga, qigong, and a variety of other movement therapies have also been reported to be safe and effective for overall symptoms and physical functioning in persons with FM.114 In general, active physical exercise strategies of any type will be helpful. Finding the exercise to which the patient is most likely to adhere will be the most important factor. More passive strategies may be useful as an adjunct but should not replace active physical exercise. A meta-analysis of balneotherapy and hydrotherapy reported evidence for a small reduction in pain and a small improvement in health related to quality of life, although the investigators recommend that high-quality studies with larger sample sizes be performed.115 A recent systematic review of massage suggested moderate evidence that myofascial release is beneficial for FM symptoms, but only limited evidence supports the application of connective tissue massage and Shiatsu. Swedish massage did not improve outcomes.116 Acupuncture has been compared with sham acupuncture, and a meta-analysis including nine trials concluded that there was not enough evidence to prove the efficacy of acupuncture therapy compared with sham acupuncture.117 Neurostimulatory therapies, including transcutaneous electrical nerve stimulation and central neurostimulatory therapies, may be helpful in persons with FM.118,119

Cognitive Behavioral Therapy CBT includes interventions that are based on the basic premise that chronic pain is maintained by cognitive and behavioral factors and that psychological treatment leads to changes in these factors through training in specific techniques.120 These interventions would include cognitive

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restructuring and behavioral training, such as relaxation and social skills training. CBT provides benefit for reducing pain, negative mood, and disability in patients with FM.121 CBT is typically delivered in group therapy over variable periods. Mindfulness-based stress reduction is a cognitive therapy that helps persons self-manage and reframe worrisome and intrusive thoughts through mindfulness medi­ tation. This technique reduced perceived stress, sleep disturbance, and symptom severity, although there was no improvement in pain or physical functioning in a randomized, controlled clinical trial.122 Operant behavioral treatment focuses on the modification of pain behavior by increasing activity levels, reducing health care–seeking behavior, and reducing pain-reinforcing behaviors in significant relationships.120 Overall, the magnitude of benefit for CBT is small across the symptom domains of FM, with pain coping, depressed mood, and health care–seeking behavior having the most significant improvement.

Pharmacologic Approaches The major classes of drugs useful for patients with FM are anti-depressants, particularly those with mixed reuptake inhibition of serotonin and norepinephrine, such as duloxetine and milnacipran, and other agents useful for neuropathic pain, such as gabapentin and pregabalin (Table 52-6).104 Evidence-based guidelines have been formulated by the American Pain Society (2005),123 the European League Against Rheumatism (2007),124 the Association of the Scientific Medical Societies in Germany (2008),125 the Canadian National Fibromyalgia Guideline Advisory Panel (2012),104 and the Israeli Rheumatology Association (2013).126 These recent treatment guidelines and reviews emphasize the need for selecting a treatment approach based on predominant symptoms and initiating treatment in low doses with slow dose escalation.1 Indirect comparison among the three agents approved by the FDA for FM with regard to efficacy and harms demonstrate that pregabalin, duloxetine, and milnacipran are superior to placebo for all outcomes of interest (pain, fatigue, sleep disturbance, depressed mood, and reduced health-related quality of life) except pregabalin for depressed mood, duloxetine for fatigue, and milnacipran for sleep disturbance. Adjusted indirect comparisons indicated no significant differences between these drugs for 30% pain relief and dropout rates due to adverse events.127 Drugs with anti-depressant activity have been a mainstay for FM treatment. Comparisons of older and newer agents have not found large differences in treatment effects, although adverse effect profiles differ.128 Older agents, such as amitriptyline and cyclobenzaprine, may improve a wide range of symptoms, although adverse effects such as dry mouth, weight gain, constipation, and sedation may limit their tolerability.128 Selective serotonin reuptake inhibitors typically have not been as useful as mixed reuptake inhibitors with respect to analgesic activity, although they are helpful for symptoms of depression and anxiety.1 Older agents such as fluoxetine, paroxetine, sertraline, and venlafaxine that are not as serotonin selective thus are favored over newer, more serotonin-specific agents such as citalopram and escitalopram. These drugs are associated with nausea, sexual dysfunction, weight gain, and sleep

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TABLE 52-6  Evidence-Based Recommendations for Pharmacologic Treatments Class

Drug

Evidence Level*

Adverse Effects

Tricyclic compounds

Amitriptyline, cyclobenzaprine

1A

Dry mouth, weight gain, constipation, “groggy” feeling; avoid in older patients

Serotonin norepinephrine reuptake inhibitors

Duloxetine,† milnacipran†

1A

Nausea, palpitations, headache, fatigue, tachycardia, hypertension

SSRI‡

Fluoxetine, sertraline, paroxetine, venlafaxine

1A

Nausea, sexual dysfunction, weight gain, sleep disturbance

Gabapentinoids

Gabapentin, pregabalin†

1A

Sedation, dizziness, weight gain, peripheral edema

Cannabinoids

Nabilone, dronabinol

3C

Sedation, dizziness, dry mouth

NSAIDs

 

5D

Gastrointestinal, renal, cardiovascular adverse effects

Opioids

Tramadol, other opioids

2D, 5D

Sedation, constipation, addiction, opioid-induced hyperalgesia

*As rated in the 2012 Canadian Fibromyalgia Guidelines. † Approved by the U.S. Food and Drug Administration. ‡ Highly selective SSRIs (e.g., citalopram and escitalopram) are not effective as analgesics. NSAIDs, Nonsteroidal anti-inflammatory drugs; SSRI, selective serotonin reuptake inhibitor.

disturbance. The norepinephrine serotonin reuptake inhibitors duloxetine and milnacipran are approved by the FDA for treatment of FM. The addition of norepinephrine reuptake inhibition is important for achieving analgesic efficacy.129 Time to effect for these drugs is generally 2 to 4 weeks, and thus dose adjustment and assessment of efficacy after institution of treatment should be performed within several months. Providers are cautioned to ensure that high doses or combinations of anti-depressants and concomitant medications or supplements do not result in the serotonin syndrome, which can cause agitation, tachycardia and hypertension, sweating/shivering, diarrhea, muscle rigidity, fever, seizures, and even death. In general, agents tested and used for neuropathic pain have been more useful in FM than agents targeting peripheral mechanical and inflammatory sources of pain. Gabapentin and pregabalin are both approved by the FDA for use in postherpetic neuralgia and painful diabetic neuropathy.130 Although only pregabalin has been approved by the FDA for use in FM, a study of gabapentin found that it also was effective.131-133 Both gabapentin and pregabalin bind to a receptor subunit, the α2δ subunit of a calcium channel on the cell surface of neurons, to inhibit excitatory neurotransmitters.129 There are pharmacokinetic and pharmacodynamic advantages for pregabalin that may make dosing somewhat simpler than for gabapentin, but the mechanism of actions for these drugs is the same. Both drugs may reduce pain, improve sleep, and improve health-related quality of life; however, they have substantial adverse effects, including dizziness, grogginess, weight gain, and edema of the extremities.134 Other anticonvulsant agents have less evidence to support their use in persons with FM. Cannabinoids are used by persons with many forms of chronic pain. A systematic review of smoked cannabis, cannabis extracts, nabilone, and dronabinol suggests modest efficacy in persons with FM and other chronic pain conditions.135,136 NSAIDs are not effective treatments for central pain, although they may be helpful in treating inflammatory or mechanical peripheral pain generators that contribute to the overall burden of pain. Tramadol with or without acetaminophen has been studied in persons with FM,

although there is increasing concern that opioids are less effective than previously thought, and their risk-benefit profile is worse than that of other classes of analgesics.1,124 A Cochran review found no evidence to support the use of oxycodone for treatment of FM.130 Treatment recommendations from professional societies uniformly advise against the use of strong opioids in persons with FM.104 This recommendation is based, at least in part, on mechanistic studies demonstrating elevated cerebrospinal fluid enkephalins and evidence that mu-opioid receptors are either occupied or downregulated in the brain of persons with FM.137 Low-dose naltrexone has been evaluated in very small trials and is thought to perhaps act on glial cells rather than on neurons.138

Practical Advice Persons with FM are likely to benefit from multimodal treatment that includes nonpharmacologic treatment, especially if one component includes exercise. In practice, it is crucial that patients be informed that there is no pharmacologic treatment that can alleviate the symptoms of FM. A general rule is that effective medications only improve pain by 30% to 50% in only 30% to 50% of patients, which includes the placebo response rate. Little information is available about combinations of approved medications, although patients with FM often use multiple medications. In general, efforts should be made to consolidate treatments and use the fewest number of medications possible. Patients should be involved in choosing nonpharmacologic strategies that will be most accepted and that are practical to employ. In addition to general nonpharmacologic approaches, it may be useful to target specific symptoms, such as sleep, with efforts to improve sleep hygiene and regulation of circadian rhythms.105 Many drugs and alternative therapies are used by persons who have FM and other forms of chronic musculoskeletal pain. Widespread use of nonapproved treatments reflects the generally poor effectiveness and tolerability of currently available drugs. For any treatment of FM, there is also likely to be a significant placebo effect in addition to the specific



efficacy of a therapeutic agent. It is certainly reasonable to work with patients on individual “n-of-1” trials, although it is important to assess both efficacy and harm and to discontinue use of ineffective medications or treatments with adverse effects.

OUTCOME The outcome of FM can be studied in terms of the change in the level of symptoms, use of services, and work disability. An early study of patients with FM who were followed up for 4.5 years found that an adequate physical activity level and increasing age predicted a positive outcome, while receiving a permanent disability pension or having experienced an excess of major negative life events predicted a negative outcome.139 A six-center, 7-year study of 538 patients published in 1997 found that functional disability worsened slightly and health satisfaction improved slightly. Correlations between first and last assessment were often highly correlated with values for disease measures at the initial assessment predictive of final values. The authors concluded that little change in FM symptoms occurred over time.140 A 2003 prospective study of patients with FM who were referred to a specialty clinic, 70 of 82 were reassessed after 3 years. Of these patients, 47% reported overall moderate to marked improvement, whereas the remaining 53% reported slight improvement, no change, or deterioration. The baseline predictors for a favorable outcome were younger age and less sleep disturbance.141 Another study in the same year evaluated 27 of 48 patients who were reassessed over a 2-year time frame. In general, the patients showed no improvement in their symptoms over the observation period, regardless of the type of therapy they had received. No change occurred in either work capacity or disability-pension status. General satisfaction with quality of life improved, as did satisfaction regarding health status and the family situation.142 In a 2006 study intended to assess utilization of health services, 2260 patients who were seen in a primary care setting and newly diagnosed with FM were studied from 10 years before until 4 years after FM diagnosis.47 Patients with FM had considerably higher rates of visits, prescriptions, and testing from at least 10 years prior to diagnosis compared with control subjects, and these rates accelerated to twice the numbers of visits and prescriptions at the time of diagnosis. Visit rates were highest for depression, fatigue, chest pain, headache, and sleep disturbance. After diagnosis, visits for most symptoms and health care use markers declined, but within 2 to 3 years, most visits rose to levels at or higher than those at diagnosis. The authors concluded that being diagnosed with FM may help patients cope with some symptoms but that the diagnosis has a limited impact on health care resource use in the longer term. In a more recent longitudinal study of 1555 patients with FM during semiannual observations for up to 11 years, there was minimal improvement in symptoms overall. However, 25% reported at least moderate improvement in symptoms. These data suggested that the course of FM was one of continuous high levels of self-reported symptoms and distress.143 Taken as a whole, although some patients improve, the data tend to suggest minimal improvement in most cases despite treatment.

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A study of patients with juvenile FM (JFM) was recently reported. In this study, patients with JFM and healthy control subjects were assessed approximately 6 years after diagnosis and with an average age of 21 years. Patients with JFM had more pain, poorer physical function, and greater anxiety and depression than did healthy control subjects. They were more likely to be married and less likely to have a college education. More than 80% of patients with JFM continued to experience symptoms into adulthood, and more than half met the criteria for FM at follow-up. Those who met adult FM criteria exhibited the highest levels of physical and emotional impairment.27 Overall, patients with FM typically have a lifelong problem with chronic pain. Assisting patients in the selfmanagement of their symptoms, reducing health care– seeking behaviors, and improving healthy behaviors are important goals of treatment. Perhaps the most important function of the rheumatologist is to confirm the diagnosis and determine if the patient has a comorbid rheumatic condition that should be treated. If FM is complicating another rheumatic condition, specific management of FM may improve overall health outcomes. The references for this chapter can also be found on ExpertConsult.com.

SELECTED REFERENCES 1. Clauw DJ: Fibromyalgia: a clinical review. JAMA 311:1547–1555, 2014. 2. Arnold LM, Hudson JI, Hess EV, et al: Family study of fibromyalgia. Arthritis Rheum 50:944–952, 2004. 4. Buskila D, Sarzi-Puttini P: Biology and therapy of fibromyalgia. Genetic aspects of fibromyalgia syndrome. Arthritis Res Ther 8:218, 2006. 5. Diatchenko L, Fillingim RB, Smith SB, et al: The phenotypic and genetic signatures of common musculoskeletal pain conditions. Nat Rev Rheumatol 9:340–350, 2013. 6. Smith SB, Maixner DW, Fillingim RB, et al: Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia. Arthritis Rheum 64:584–593, 2012. 7. Arnold LM, Bradley LA, Clauw DJ, et al: Multidisciplinary care and stepwise treatment for fibromyalgia. J Clin Psychiatry 69:e35, 2008. 8. Wolfe F, Walitt B: Culture, science and the changing nature of fibromyalgia. Nat Rev Rheumatol 9:751–755, 2013. 9. Clauw DJ, Arnold LM, McCarberg BH: The science of fibromyalgia. Mayo Clin Proc 86:907–911, 2011. 10. Inanici F, Yunus MB: History of fibromyalgia: past to present. Curr Pain Headache Rep 8:369–378, 2004. 12. Hench P, Boland E: The management of chronic arthritis and other rheumatic diseases among soldiers of the United States army. Ann Rheum Dis 5:106–114, 1946. 15. Wolfe F, Smythe HA, Yunus MB, et al: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Arthritis Rheum 33:160–172, 1990. 16. Wolfe F, Clauw DJ, Fitzcharles MA, et al: The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res 62:600–610, 2010. 17. Wolfe F, Clauw DJ, Fitzcharles MA, et al: Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia. J Rheu­ matol 38:1113–1122, 2011. 19. Clauw DJ: Pain management: fibromyalgia drugs are “as good as it gets” in chronic pain. Nat Rev Rheumatol 6:439–440, 2010. 20. Arnold LM, Stanford SB, Welge JA, et al: Development and testing of the fibromyalgia diagnostic screen for primary care. J Womens Health (Larchmt) 21:231–239, 2012.

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PART 6    DIFFERENTIAL DIAGNOSIS OF REGIONAL AND DIFFUSE MUSCULOSKELETAL PAIN

21. Bennett RM, Friend R, Marcus D, et al: Criteria for the diagnosis of fibromyalgia: validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria. Arthritis Care Res 66:1364–1373, 2014. 22. Wolfe F, Ross K, Anderson J, et al: The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 38:19– 28, 1995. 23. White KP, Speechley M, Harth M, et al: The London Fibromyalgia Epidemiology Study: the prevalence of fibromyalgia syndrome in London, Ontario. J Rheumatol 26:1570–1576, 1999. 24. White KP, Thompson J: Fibromyalgia syndrome in an Amish community: a controlled study to determine disease and symptom prevalence. J Rheumatol 30:1835–1840, 2003. 25. Perrot S, Vicaut E, Servant D, et al: Prevalence of fibromyalgia in France: a multi-step study research combining national screening and clinical confirmation: the DEFI study (Determination of Epidemiology of FIbromyalgia). BMC Musculoskelet Disord 12:224, 2011. 26. Kim C, Kim H, Kim J: Prevalence of chronic widespread pain and fibromyalgia syndrome: a Korean hospital-based study. Rheumatol Int 32:3435–3442, 2012. 27. Kashikar-Zuck S, Cunningham N, Sil S, et al: Long-term outcomes of adolescents with juvenile-onset fibromyalgia in early adulthood. Pediatrics 133:e592–e600, 2014. 28. Haliloglu S, Carlioglu A, Akdeniz D, et al: Fibromyalgia in patients with other rheumatic diseases: prevalence and relationship with disease activity. Rheumatol Int 34:1275–1280, 2014. 29. Vincent A, Lahr BD, Wolfe F, et al: Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project. Arthritis Care Res 65:786–792, 2013. 30. Wolfe F, Brahler E, Hinz A, et al: Fibromyalgia prevalence, somatic symptom reporting, and the dimensionality of polysymptomatic distress: results from a survey of the general population. Arthritis Care Res 65:777–785, 2013. 31. Nakamura I, Nishioka K, Usui C, et al: An epidemiologic internet survey of fibromyalgia and chronic pain in Japan. Arthritis Care Res 66:1093–1101, 2014. 32. Campbell SM, Clark S, Tindall EA, et al: Clinical characteristics of fibrositis. I. A “blinded” controlled study of symptoms and tender points. Arthritis Rheum 26:817–824, 1983. 33. Hartz A, Kirchdoerfer E: Undetected fibrositis in primary care practice. J Fam Pract 25:365–369, 1987. 34. Wolfe F, Cathey MA: Prevalence of primary and secondary fibrositis. J Rheumatol 10:965–968, 1983. 35. Buskila D: Pediatric fibromyalgia. Rheum Dis Clin North Am 35:253– 261, 2009. 36. Weir PT, Harlan GA, Nkoy FL, et al: The incidence of fibromyalgia and its associated comorbidities: a population-based retrospective cohort study based on International Classification of Diseases, 9th Revision codes. J Clin Rheumatol 12:124–128, 2006. 37. Lee YC, Lu B, Boire G, et al: Incidence and predictors of secondary fibromyalgia in an early arthritis cohort. Ann Rheum Dis 72:949–954, 2013. 39. Gedalia A, Press J, Klein M, et al: Joint hypermobility and fibromyalgia in schoolchildren. Ann Rheum Dis 52:494–496, 1993. 40. Mease PJ, Arnold LM, Crofford LJ, et al: Identifying the clinical domains of fibromyalgia: contributions from clinician and patient Delphi exercises. Arthritis Rheum 59:952–960, 2008. 41. Civelek GM, Ciftkaya PO, Karatas M: Evaluation of restless legs syndrome in fibromyalgia syndrome: an analysis of quality of sleep and life. J Back Musculoskelet Rehabil 27:537–544, 2014. 42. Arnold LM, Bradley LA, Clauw DJ, et al: Evaluating and diagnosing fibromyalgia and comorbid psychiatric disorders. J Clin Psychiatry 69:e28, 2008. 43. Kravitz HM, Katz RS: Fibrofog and fibromyalgia: a narrative review and implications for clinical practice. Rheumatol Int 35:1115–1125, 2015. 44. Glass JM: Cognitive dysfunction in fibromyalgia and chronic fatigue syndrome: new trends and future directions. Curr Rheumatol Rep 8:425–429, 2006. 45. Arnold LM, Clauw DJ, McCarberg BH: Improving the recognition and diagnosis of fibromyalgia. Mayo Clin Proc 86:457–464, 2011. 47. Hughes G, Martinez C, Myon E, et al: The impact of a diagnosis of fibromyalgia on health care resource use by primary care patients in the UK: an observational study based on clinical practice. Arthritis Rheum 54:177–183, 2006.

48. Kato K, Sullivan PF, Evengard B, et al: Chronic widespread pain and its comorbidities: a population-based study. Arch Intern Med 166: 1649–1654, 2006. 51. Arnold LM, Hudson JI, Keck PE, et al: Comorbidity of fibromyalgia and psychiatric disorders. J Clin Psychiatry 67:1219–1225, 2006. 54. Wolfe F, Pincus T, Fries JF: Usefulness of the HAQ in the clinic. Ann Rheum Dis 60:811, 2001. 55. Bennett RM, Friend R, Jones KD, et al: The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties. Arthritis Res Ther 11:R120, 2009. 56. Choy EH, Arnold LM, Clauw DJ, et al: Content and criterion validity of the preliminary core dataset for clinical trials in fibromyalgia syndrome. J Rheumatol 36:2330–2334, 2009. 58. McBeth J, Jones K: Epidemiology of chronic musculoskeletal pain. Best Pract Res Clin Rheumatol 21:403–425, 2007. 59. Kato K, Sullivan PF, Evengard B, et al: A population-based twin study of functional somatic syndromes. Psychol Med 39:497–505, 2009. 60. Kato K, Sullivan PF, Evengard B, et al: Importance of genetic influences on chronic widespread pain. Arthritis Rheum 54:1682–1686, 2006. 61. Diatchenko L, Slade GD, Nackley AG, et al: Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum Mol Genet 14:135–143, 2005. 66. Arnold LM, Fan J, Russell IJ, et al: The fibromyalgia family study: a genome-wide linkage scan study. Arthritis Rheum 65:1122–1128, 2013. 67. Geisser ME, Casey KL, Brucksch CB, et al: Perception of noxious and innocuous heat stimulation among healthy women and women with fibromyalgia: association with mood, somatic focus, and catastrophizing. Pain 102:243–250, 2003. 68. Staud R: Peripheral pain mechanisms in chronic widespread pain. Best Pract Res Clin Rheumatol 25:155–164, 2011. 70. Staud R, Weyl EE, Riley JL 3rd, et al: Slow temporal summation of pain for assessment of central pain sensitivity and clinical pain of fibromyalgia patients. PLoS One 9:e89086, 2014. 71. Julien N, Goffaux P, Arsenault P, et al: Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition. Pain 114: 295–302, 2005. 72. Harris RE, Clauw DJ, Scott DJ, et al: Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci 27:10000–10006, 2007. 73. Wood PB, Patterson JC 2nd, Sunderland JJ, et al: Reduced presynaptic dopamine activity in fibromyalgia syndrome demonstrated with positron emission tomography: a pilot study. J Pain 8:51–58, 2007. 74. Phillips K, Clauw DJ: Central pain mechanisms in the rheumatic diseases: future directions. Arthritis Rheum 65:291–302, 2013. 75. Buskila D, Atzeni F, Sarzi-Puttini P: Etiology of fibromyalgia: the possible role of infection and vaccination. Autoimmun Rev 8:41–43, 2008. 76. Buskila D, Neumann L, Vaisberg G, et al: Increased rates of fibromyalgia following cervical spine injury. Arthritis Rheum 40:446–452, 1997. 77. Park JH, Phothimat P, Oates CT, et al: Use of P-31 magnetic resonance spectroscopy to detect metabolic abnormalities in muscles of patients with fibromyalgia. Arthritis Rheum 41:406–413, 1998. 78. Shang Y, Gurley K, Symons B, et al: Noninvasive optical characterization of muscle blood flow, oxygenation, and metabolism in women with fibromyalgia. Arthritis Res Ther 14:R236, 2012. 79. Srikuea R, Symons TB, Long DE, et al: Association of fibromyalgia with altered skeletal muscle characteristics which may contribute to postexertional fatigue in postmenopausal women. Arthritis Rheum 65:519–528, 2013. 80. Kosmidis ML, Koutsogeorgopoulou L, Alexopoulos H, et al: Reduction of Intraepidermal Nerve Fiber Density (IENFD) in the skin biopsies of patients with fibromyalgia: a controlled study. J Neurol Sci 347:143–147, 2014. 81. Caro XJ, Winter EF: Evidence of abnormal epidermal nerve fiber density in fibromyalgia: clinical and immunologic implications. Arthritis Rheumatol 66:1945–1954, 2014. 82. Oaklander AL, Herzog ZD, Downs HM, et al: Objective evidence that small-fiber polyneuropathy underlies some illnesses currently labeled as fibromyalgia. Pain 154:2310–2316, 2013. 83. Serra J, Collado A, Sola R, et al: Hyperexcitable C nociceptors in fibromyalgia. Ann Neurol 75:196–208, 2014.

84. Milligan ED, Twining C, Chacur M, et al: Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 23:1026–1040, 2003. 85. Gracely RH, Petzke F, Wolf JM, et al: Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 46:1333–1343, 2002. 86. Napadow V, Harris RE: What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of “centralized” pain? Arthritis Res Ther 16:425, 2014. 87. Harris RE, Sundgren PC, Craig AD, et al: Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum 60:3146–3152, 2009. 89. McBeth J, Chiu YH, Silman AJ, et al: Hypothalamic-pituitaryadrenal stress axis function and the relationship with chronic widespread pain and its antecedents. Arthritis Res Ther 7:R992–R1000, 2005. 90. McBeth J, Silman AJ, Gupta A, et al: Moderation of psychosocial risk factors through dysfunction of the hypothalamic-pituitary-adrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study. Arthritis Rheum 56:360–371, 2007. 92. Martinez-Martinez LA, Mora T, Vargas A, et al: Sympathetic nervous system dysfunction in fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, and interstitial cystitis: a review of casecontrol studies. J Clin Rheumatol 20:146–150, 2014. 93. Eisenlohr-Moul TA, Crofford LJ, Howard TW, et al: Parasympathetic reactivity in fibromyalgia and temporomandibular disorder: associations with sleep problems, symptom severity, and functional impairment. J Pain 16:247–257, 2015. 94. Nicholl BI, Macfarlane GJ, Davies KA, et al: Premorbid psychosocial factors are associated with poor health-related quality of life in subjects with new onset of chronic widespread pain—results from the EPIFUND study. Pain 141:119–126, 2009. 95. Gupta A, Silman AJ, Ray D, et al: The role of psychosocial factors in predicting the onset of chronic widespread pain: results from a prospective population-based study. Rheumatology (Oxford) 46:666– 671, 2007. 97. Fitzcharles MA, Rampakakis E, Ste-Marie PA, et al: The association of socioeconomic status and symptom severity in persons with fibromyalgia. J Rheumatol 41:1398–1404, 2014. 98. Blyth FM, Macfarlane GJ, Nicholas MK: The contribution of psychosocial factors to the development of chronic pain: the key to better outcomes for patients? Pain 129:8–11, 2007. 99. Hassett AL, Cone JD, Patella SJ, et al: The role of catastrophizing in the pain and depression of women with fibromyalgia syndrome. Arthritis Rheum 43:2493–2500, 2000. 100. Torres X, Bailles E, Valdes M, et al: Personality does not distinguish people with fibromyalgia but identifies subgroups of patients. Gen Hosp Psychiatry 35:640–648, 2013. 102. Thieme K, Turk DC, Gracely RH, et al: The relationship among psychological and psychophysiological characteristics of fibromyalgia patients. J Pain 16:186–196, 2015. 104. Fitzcharles MA, Ste-Marie PA, Goldenberg DL, et al: 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary. Pain Res Manag 18:119–126, 2013. 105. Arnold LM, Clauw DJ, Dunegan LJ, et al: A framework for fibromyalgia management for primary care providers. Mayo Clin Proc 87:488– 496, 2012. 106. White KP, Nielson WR, Harth M, et al: Does the label “fibromyalgia” alter health status, function, and health service utilization? A prospective, within-group comparison in a community cohort of adults with chronic widespread pain. Arthritis Rheum 47:260–265, 2002. 107. Annemans L, Wessely S, Spaepen E, et al: Health economic consequences related to the diagnosis of fibromyalgia syndrome. Arthritis Rheum 58:895–902, 2008. 108. Nuesch E, Hauser W, Bernardy K, et al: Comparative efficacy of pharmacological and non-pharmacological interventions in fibromyalgia syndrome: network meta-analysis. Ann Rheum Dis 72:955–962, 2013. 111. Busch AJ, Schachter CL, Overend TJ, et al: Exercise for fibromyalgia: a systematic review. J Rheumatol 35:1130–1144, 2008.

CHAPTER 52    Fibromyalgia

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113. Bidonde J, Busch AJ, Bath B, et al: Exercise for adults with fibromyalgia: an umbrella systematic review with synthesis of best evidence. Curr Rheumatol Rev 10:45–79, 2014. 114. Mist SD, Firestone KA, Jones KD: Complementary and alternative exercise for fibromyalgia: a meta-analysis. J Pain Res 6:247–260, 2013. 115. Naumann J, Sadaghiani C: Therapeutic benefit of balneotherapy and hydrotherapy in the management of fibromyalgia syndrome: a qualitative systematic review and meta-analysis of randomized controlled trials. Arthritis Res Ther 16:R141, 2014. 116. Yuan SL, Matsutani LA, Marques AP: Effectiveness of different styles of massage therapy in fibromyalgia: a systematic review and metaanalysis. Man Ther 20:257–264, 2015. 117. Yang B, Yi G, Hong W, et al: Efficacy of acupuncture on fibromyalgia syndrome: a meta-analysis. J Tradit Chin Med 34:381–391, 2014. 118. Noehren B, Dailey DL, Rakel BA, et al: Effect of transcutaneous electrical nerve stimulation on pain, function, and quality of life in fibromyalgia: a double-blind randomized clinical trial. Phys Ther 95:129–140, 2015. 119. Hargrove JB, Bennett RM, Simons DG, et al: A randomized placebocontrolled study of noninvasive cortical electrostimulation in the treatment of fibromyalgia patients. Pain Med 13:115–124, 2012. 120. Bernardy K, Fuber N, Kollner V, et al: Efficacy of cognitive-behavioral therapies in fibromyalgia syndrome—a systematic review and metaanalysis of randomized controlled trials. J Rheumatol 37:1991–2005, 2010. 122. Cash E, Salmon P, Weissbecker I, et al: Mindfulness meditation alleviates fibromyalgia symptoms in women: results of a randomized clinical trial. Ann Behav Med 49:319–330, 2015. 123. Goldenberg DL, Burckhardt C, Crofford L: Management of fibromyalgia syndrome. JAMA 292:2388–2395, 2004. 124. Carville SF, Arendt-Nielsen S, Bliddal H, et al: EULAR evidencebased recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis 67:537–541, 2008. 125. Hauser W, Arnold B, Eich W, et al: Management of fibromyalgia syndrome—an interdisciplinary evidence-based guideline. Ger Med Sci 6:Doc14, 2008. 126. Ablin J, Fitzcharles MA, Buskila D, et al: Treatment of fibromyalgia syndrome: recommendations of recent evidence-based interdisciplinary guidelines with special emphasis on complementary and alternative therapies. Evid Based Complement Alternat Med 2013:485272, 2013. 127. Hauser W, Petzke F, Sommer C: Comparative efficacy and harms of duloxetine, milnacipran, and pregabalin in fibromyalgia syndrome. J Pain 11:505–521, 2010. 128. Hauser W, Petzke F, Uceyler N, et al: Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheuma­ tology (Oxford) 50:532–543, 2011. 129. Schmidt-Wilcke T, Clauw DJ: Fibromyalgia: from pathophysiology to therapy. Nat Rev Rheumatol 7:518–527, 2011. 134. Hauser W, Bernardy K, Uceyler N, et al: Treatment of fibromyalgia syndrome with gabapentin and pregabalin—a meta-analysis of randomized controlled trials. Pain 145:69–81, 2009. 135. Lynch ME, Campbell F: Cannabinoids for treatment of chronic noncancer pain; a systematic review of randomized trials. Br J Clin Phar­ macol 72:735–744, 2011. 138. Younger J, Noor N, McCue R, et al: Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, doubleblind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum 65:529–538, 2013. 139. Wigers SH: Fibromyalgia outcome: the predictive values of symptom duration, physical activity, disability pension, and critical life events—a 4.5 year prospective study. J Psychosom Res 41:235–243, 1996. 140. Wolfe F, Anderson J, Harkness D, et al: Health status and disease severity in fibromyalgia. Arthritis Rheum 40:1571–1579, 1997. 141. Fitzcharles MA, Costa DD, Poyhia R: A study of standard care in fibromyalgia syndrome: a favorable outcome. J Rheumatol 30:154– 159, 2003. 143. Walitt B, Fitzcharles MA, Hassett AL, et al: The longitudinal outcome of fibromyalgia: a study of 1555 patients. J Rheumatol 38: 2238–2246, 2011.



CHAPTER 52    Fibromyalgia 783.e1

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