Fibromyalgia 

Fibromyalgia (FM) is a syndrome of persistent widespread pain, stiffness, fatigue, disrupted and unrefreshing sleep, and cognitive difficulties, often accompanied by multiple other unexplained symptoms, anxiety and/or depression, and functional impairment of activities of daily living (ADLs). It typically presents in young or middle-aged women.

Fibromyalgia was once often dismissed by physicians and the public as a psychological disorder or "wastebasket" diagnosis because of an absence of objective findings on physical examination and usual laboratory and imaging evaluations. Many physicians still do not accept fibromyalgia as a discrete illness. However, basic and clinical investigations have clarified the neurophysiologic bases for fibromyalgia and led to its current classification as a central sensitivity syndrome (CSS).^{[1, 2]}

Indeed, fibromyalgia can now be considered a neurosensory disorder characterized in part by abnormalities in pain processing by the central nervous system (CNS).^[3] Increased understanding of the biological bases underlying fibromyalgia is rapidly leading to a new era of specific pharmacologic therapy for the condition.

At a clinical level, fibromyalgia is much more than widespread pain. It overlaps substantially with other central sensitivity syndromes, such as the following:

• Chronic fatigue syndrome
• Irritable bowel syndrome
• Chronic pelvic pain syndrome/primary dysmenorrhea
• Temporomandibular joint pain
• Tension-type headaches/migraine
• Posttraumatic stress disorder [PTSD]
• Multiple chemical sensitivity
• Periodic limb movement disorder/restless legs syndrome
• Interstitial cystitis

Fibromyalgia also overlaps with other regional pain syndromes and mood and anxiety disorders. Indeed, the diagnostic label attached to a particular case may be determined largely by the first specialist that the patient sees. For example, a rheumatologist might diagnosis fibromyalgia, whereas a gastroenterologist may diagnose irritable bowel syndrome.

In addition, fibromyalgia coexists in unusually high frequency with certain illnesses characterized by systemic inflammation, such as rheumatoid arthritis (RA),^[4] systemic lupus erythematosus (SLE),^[5] and chronic hepatitis C infection,^[6] among others. In such cases, both disorders must be recognized and treated for optimum therapeutic outcome.

Even as evidence-based medicine supplies a growing array of tools for the management of fibromyalgia, however, the art of medicine retains a central role. To successfully care for patients with fibromyalgia, the physician must demonstrate compassion as well as skill. Taking a careful history, listening to the patient's concerns, and performing a thorough examination are the foundation for diagnosing and treating fibromyalgia.

Management of fibromyalgia begins with a detailed history and a thorough physical examination (see Presentation). Making a correct diagnosis is crucial, and patients need to know that a name exists for the mysterious symptoms that they are experiencing.

The physician should inform the patient that no cure exists for fibromyalgia but that education, lifestyle changes, and proper rehabilitation can help the individual to regain control and achieve significant improvement. The overall approach for chronic pain in fibromyalgia involves a multifaceted treatment plan that incorporates various adjuvant medicines, aerobic exercise, and psychological and behavioral approaches to reduce distress and promote self-efficacy and self-management. (See Treatment.)

Historical background

Although fibromyalgia was not defined until the late 20th century, it was discovered much earlier. Descriptions in the medical literature date as far back as the early 17th century.

Until recent decades, many physicians questioned the existence of fibromyalgia. Over time, however, a growing body of evidence established fibromyalgia as a syndrome comprising a specific set of signs and symptoms.

In 1987, the American Medical Association (AMA) acknowledged fibromyalgia as a true illness and a potential cause of disability. Many well-respected organizations, such as the AMA, the National Institutes of Health (NIH), and the World Health Organization (WHO), have accepted fibromyalgia as a legitimate clinical entity.

Before 1990, no guidelines for evaluating and diagnosing fibromyalgia existed. To reduce misdiagnosis and confusion, the American College of Rheumatology (ACR) sponsored a multicenter study to develop these criteria; the results were published in 1990.^[7] In 1992, at the Second World Congress on Myofascial Pain and Fibromyalgia, the diagnostic criteria for fibromyalgia were expanded and refined.

Despite this progress, the typical patient with fibromyalgia has seen an average of 15 physicians and has had the condition for approximately 5 years before receiving a correct diagnosis. More than 50% of cases are misdiagnosed, and many patients undergo unnecessary surgery or endure costly treatments that provide little benefit.

At some point, most patients have been told that nothing is medically wrong with them and that their condition is imaginary. Therefore, many patients become frustrated and skeptical. Although most patients are relieved when a correct diagnosis is finally made, the patient may need to be convinced that the clinician actually knows what is wrong and has formulated a treatment plan.

Nomenclature

Although the syndrome has been known by other names, the term fibromyalgia was introduced in 1976. This word is derived from the Latin root fibro (fibrous tissue) and the Greek roots myo (muscles) and algos (pain). Previously, fibromyalgia was most commonly described as fibrositis; this was a misnomer, as "itis" indicates an inflammatory component. Chaitrow asserts that no inflammatory process has ever been found to be part of this disease.^[8]

Fibromyalgia is currently understood to be a disorder of central pain processing or a syndrome of central sensitivity. Clauw describes the syndrome as a diffuse problem of sensory “volume control” such that patients have a lower threshold of pain and of other stimuli, such as heat, noise, and strong odors. Clauw also suggests that patients may have hypersensitivity because of neurobiologic changes that affect the perception of pain or because of expectancy or hypervigilance, which may be related to psychological factors.^[9]

Although the pathogenesis of fibromyalgia is not completely understood, research shows biochemical, metabolic, and immunoregulatory abnormalities. These substantiate the proposal that fibromyalgia can no longer be considered a subjective pain condition.

Pain

The International Association for the Study of Pain defines pain as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”^[10] Implicit here is the threat associated with pain, which can be trivial or profound.

Neurophysiologically, the pain experience derives from a complex sensation-perception interaction involving the simultaneous parallel processing of nociceptive input from the spinal cord to multiple regions of the brain (see the image below).

In addition to strictly sensory-discriminative elements of nociception and afferent input from somatic reflexes, major contributions from pathways and regions of the brain that are associated with emotional, motivational, and cognitive aspects of pain are evident and help determine the subjective intensity of pain. The 2 principal effectors of the stress response, the hypothalamic-pituitary-adrenocortical (HPA) axis and the sympathetic nervous system (SNS), are also activated.

Although normally adaptive, the stress response may become maladaptive in patients with chronic pain and fatigue syndromes such as fibromyalgia.^{[11, 12, 13, 14]} Negative emotions (eg, depression and anxiety) and other negative psychological factors (eg, loss of control, unpredictability in one's environment) and certain cognitive aspects (eg, negative beliefs and attributions, catastrophizing) can all function as stressors with actions in these systems.

Furthermore, negative emotions, such as anger and sadness, have been shown to be direct amplifiers of pain in women with and without fibromyalgia.^[15] Thus, therapeutic approaches to regulate emotion may attenuate pain sensitization in patients with fibromyalgia.

In some patients with fibromyalgia, such negative emotional, motivational, and cognitive stressors may dominate the clinical picture, potentially leading to a self-sustaining neuroendocrine cascade that contributes to flulike symptoms, depressed mood, fatigue, myalgias, cognitive difficulties, and poor sleep.

The important biologic elements here include proinflammatory cytokines, the HPA axis, other neuroendocrine axes, and the autonomic nervous system. Growth hormone abnormalities are also thought to contribute to symptoms in fibromyalgia.^[16]

Pain in patients with fibromyalgia derives partly from a generalized decrease in the pain perception threshold, with reduced discrimination of a nociceptive quality from a nonnociceptive quality (eg, touch, warmth, cold), and in the threshold for pain tolerance, resulting in an unwillingness to receive more-intense stimulation.

These phenomena can be demonstrated clinically by pressure algometry (dolorimetry) or in research settings with quantitative sensory testing (QST) using pressure, heat, cold, or electricity as stimuli. Underlying these changes in thresholds is altered processing of nociceptive stimuli in the CNS (central sensitization).

A number of abnormalities in pain processing have been demonstrated in fibromyalgia.^{[17, 18, 19, 20, 21]} Among them are the following:

• Excess excitatory (pronociceptive) neurotransmitters (eg, substance P, glutamate levels in the insula)
• Low levels of inhibitory neurotransmitters (eg, serotonin and norepinephrine) in descending antinociceptive pathways in the spinal cord
• Maintained enhancement of temporal summation of second pain
• Altered endogenous opioid analgesic activity in several brain regions known to play a role in pain modulation
• Dopamine dysregulation

High-throughput genotyping is rapidly identifying a series of single-nucleotide polymorphism (SNP) haplotypes that influence neurotransmitter levels and receptor levels in the brain and thus contribute to the various abnormalities in pain processing.^[22] Such SNP haplotypes constitute vulnerability elements in the development of fibromyalgia and other central sensitivity syndromes.

Pharmacologic agents that reduce pain in fibromyalgia function in this regard by either increasing levels of inhibitory neurotransmitters (eg, duloxetine) or decreasing levels of excitatory neurotransmitters (eg, gabapentin).^{[17, 23]} Because fibromyalgia is a polygenic syndrome with multiple different underlying genetic polymorphisms, genetic testing to tailor therapy and to predict response to therapy will soon become available.

The biochemical changes seen in the CNS, the low levels of serotonin, the fourfold increase in nerve growth factor, and the elevated levels of substance P all lead to a whole-body hypersensitivity to pain and suggest that fibromyalgia may be a condition of central sensitization or of abnormal central processing of nociceptive pain input.^[2] Ongoing research will continue to provide a clearer picture of the pathophysiology of this complex syndrome.

Pain sensitivity in women

Fibromyalgia is most common in women. Among the mechanisms that may contribute to increased pain sensitivity in women are the following^[24] :

• Differences in primary afferent input to the CNS, with developmental and menstrual cycle–dependent enhancement
• Developmental and phasic gonadal-hormonal modulation of pain regulatory systems, stress-induced analgesia, and opioid receptors
• Higher levels of trait and state anxiety
• Increased prevalence of depression
• Use of maladaptive coping strategies
• Increased behavioral activity in response to pain

Central processes

Plasticity in the function of N -methyl-D -aspartate (NMDA) subtype glutamate receptors is necessary for central sensitization to occur. Increased sensitivity of central NMDA receptors were implicated in earlier studies as playing a primary role in fibromyalgia. However, subsequent evidence has suggested that suppression of the normal activity of dopamine-releasing neurons in the limbic system is the primary pathology in fibromyalgia. Increasing evidence indicates that fibromyalgia may represent a dysregulation of dopaminergic neurotransmission.

Serotonin

The most widely acknowledged biochemical abnormality associated with fibromyalgia is abnormally low serotonin levels. Many studies have linked serotonin, a neurotransmitter, to sleep, pain perception, headaches, and mood disorders. Lower-than-normal levels of serotonin have been observed in patients with fibromyalgia. A low platelet serotonin value is believed to be the cause of the low serum levels, which have been correlated with painful symptoms.

Low serotonin levels in the CNS are thought to result from low levels of tryptophan (the amino acid precursor to serotonin) and 5-hydroxyindole acetic acid (a metabolic by-product) in the cerebrospinal fluid (CSF). Investigators have proposed a link between low serotonin levels and symptoms of fibromyalgia^[25] ; indeed, many propose that low serotonin levels may cause fibromyalgia in whole or in part.

Substance P

Substance P is a neurotransmitter that is released when axons are stimulated. Elevated levels of substance P increase the sensitivity of nerves to pain or heighten awareness of pain. Four independent studies have found that levels of substance P are 2 to 3 times higher than normal in the CSF of patients with fibromyalgia.^[26] These elevated levels cause fairly normal stimuli to result in exaggerated nociception.

Some authors believe that neither elevated substance P levels nor low serotonin levels alone can be the primary cause. Instead, the dual dysfunction may be responsible for fibromyalgia.

Adenosine triphosphate

Researchers have found low levels of adenosine triphosphate (ATP) in red blood cells of patients with fibromyalgia. Although the significance is unknown, it has been suggested that low platelet serotonin levels can be explained if platelet ATP levels are also low. ATP is necessary to move and then hold serotonin in platelets. More investigation into ATP and the link to serotonin is needed.

Dysfunction of the hypothalamic-pituitary-adrenal axis

Studies of the neuroendocrine aspects of fibromyalgia have found dysfunction of the HPA axis.^[27] The HPA axis is a critical component of the stress-adaptation response. The sequence of HPA action is that corticotropin-releasing hormone (CRH) from the hypothalamus stimulates the anterior pituitary to release adrenocorticotropic hormone (ACTH). In turn, ACTH stimulates the adrenal cortex to produce glucocorticoids (eg, cortisol).

Some authors have noted that 5 main measurable neuroendocrine abnormalities are associated with dysfunction of the HPA axis.^[28] These are as follows:

• Low free cortisol levels in 24-hour urine samples
• Loss of the normal circadian rhythm, with an elevated evening cortisol level (when it should be at its lowest level)
• Insulin-induced hypoglycemia associated with an overproduction of ACTH
• Low levels of growth hormone
• Stimulated ACTH secretion leading to insufficient adrenal release of glucocorticoids

Circadian regulation and the stress-induced stimulation of the HPA axis are, in part, regulated by serotonin. Perturbations in serotonin metabolism (as well as premorbid abnormalities of the HPA axis) may explain the abnormalities of the HPA axis in fibromyalgia. Dysfunction of the HPA axis may exaggerate the effects of abnormal serotonin metabolism. Hypoactivity of the HPA axis may cause low central serotonin levels.

Growth hormone

Growth hormone, produced during delta sleep, is involved in tissue repair. Therefore, disrupted stage 4 (delta) sleep associated with fibromyalgia may account for low levels of growth hormone. Growth hormone stimulates the production of insulinlike growth factor I (IGF-I) in the liver. Some authors have found that most patients with fibromyalgia have low levels of IGF-I and that low levels are specific and sensitive for fibromyalgia.^[29]

Nerve growth factor

In some studies, nerve growth factor was found to be 4 times higher in the CSF of patients with fibromyalgia than it was in the CSF of individuals without the condition. Nerve growth factor enhances the production of substance P in afferent neurons, increasing an individual's sensitivity to or awareness of pain. Nerve growth factor also may play a role in spreading or redistributing perceived pain signals.

Cognitive impairment

Fibromyalgia is associated with a decline in short-term, working, episodic, semantic (predominantly verbal), and procedural (skills) memory. Imaging modalities such as single-photon emission computed tomography (SPECT) scanning have helped to define some of the abnormalities linked to this cognitive dysfunction. SPECT shows decreased blood flow in the right and left caudate nuclei and thalami.

Functional magnetic resonance imaging (fMRI) can show brain activity by depicting increased blood flow to areas actively engaged in a task. Increased blood flow and, hence, increased oxygenation have different magnetic properties. These properties can be detected and measured using fMRI.

In a study of persons performing a task requiring memory (alphabetization), persons with fibromyalgia performed almost as well as controls, but fMRI showed that more brain areas were activated during the memory task in persons with fibromyalgia than in controls, because the task was harder for the patients to perform. In another study, working memory and episodic memory scores of patients with fibromyalgia were similar to those of healthy controls who were 20 years older.^[30]

Another study measured neural activation during response inhibition using fMRI. Patients with fibromyalgia had lower activation in the inhibition and attention networks but increased activation in other areas. The study indicates that inhibition and pain perception may use overlapping networks, which may cause resources to be unavailable for other processes when they are taken up by pain processing.^[31]

Cognitive dysfunction has been linked to CNS imbalances. Abnormal levels of such neurotransmitters as substance P, serotonin, dopamine, norepinephrine, and epinephrine may cause cognitive dysfunction. Neuroendocrine imbalance of the HPA axis may play a role. Another possible cause of cognitive dysfunction is the distracting quality of pain in fibromyalgia. Cognitive performance of patients with fibromyalgia is correlated with their reported level of pain.

Brain damage from the effects of stress hormones may be involved in the cognitive dysfunction in fibromyalgia. Researchers are exploring this possibility by measuring tissue volumes in the hippocampus. Others studies have implicated yeast overload, water retention, and glial cell abnormalities as causes of cognitive dysfunction in fibromyalgia.

Sleep disruption

Sleep dysfunction is considered an integral feature of fibromyalgia. About 70% of patients recognize a connection between poor sleep and increased pain, along with feeling unrefreshed, fatigued, and emotionally distressed.^{[32, 33]} Several studies have linked abnormal sleep with these symptoms. Sleep studies have shown that patients with fibromyalgia have disordered sleep physiology.

Sleep is not a state of massive system shutdown. On the contrary, the brain is active during sleep, constantly communicating with the body. Many neurohormones, antibodies, and other molecules are synthesized during sleep; therefore, when sleep is disrupted, biochemical abnormalities can occur, leading to multisystem disturbances.

To understand abnormal sleep architecture, it is essential to know the basics of normal sleep. Sleep can be divided into 2 main parts: nonrapid eye movement (NREM) and rapid eye movement (REM), which alternate cyclically through the night, always starting with NREM sleep. In each successive cycle through the night, NREM sleep decreases, and REM sleep increases. Each cycle, NREM plus REM, lasts about 90 minutes.

NREM is divided into 4 stages:

• Stage 1 is initial drowsiness
• Stage 2 is light sleep
• Stages 3 and 4 are progressively deeper levels of sleep.

In stages 3 and 4, an electroencephalogram (EEG) will show delta waves, which are high-amplitude (>75 mV) waves that move slowly (0.5-2 Hz). Much of the body's regulatory work, as well as the synthesis of many substances (eg, antibodies, growth hormone, other neurochemicals), occurs during NREM sleep.

REM sleep has a low-voltage, mixed-frequency pattern on EEGs and is considered dream sleep. In this stage, the body has a complete loss of muscle tone, known as flaccid paralysis, and it cannot move. During this part of sleep, consolidation of memories may occur, but disagreement still exists as to what takes place with regard to memory during REM sleep. Some investigators have found that during waking hours, the brain generates alpha waves with a frequency of 7.5-11 Hz.

The disordered sleep physiology in fibromyalgia has been identified as a sleep anomaly of alpha-wave intrusion, which occurs during NREM stage 4 sleep. This intrusion into deep sleep causes the patient to awaken or to be aroused to a lighter level of sleep. Some investigators describe the altered sleep physiology and somatic symptoms as a nonrestorative sleep syndrome.

Sleep dysfunction is believed to be linked to the numerous metabolic disturbances associated with fibromyalgia, including abnormal levels of neurotransmitters (serotonin, substance P) and neuroendocrine and immune substances (growth hormone, cortisol, interleukin-1). These metabolic imbalances are thought to be responsible—through impairment of tissue repair and disturbance of the immunoregulatory role of sleep—for the increased symptoms associated with this sleep disorder of alpha-wave intrusion.

Most alpha-wave intrusions occur during the first few hours of sleep, decreasing throughout the night to normal levels by early morning. This hypothesis correlates well with patients' frequent reporting that their best sleep is obtained in the early morning hours, just before arising.

The etiology of fibromyalgia is multifactorial and includes both environmental and genetic factors. While the causes of fibromyalgia have not yet been fully clarified, remarkable progress in the understanding of this disorder has been made. For example, with the identification of central sensitization and abnormal central nociceptive processing in affected patients, fibromyalgia pain can now be classified as a neurosensory disorder.

Engel's biopsychosocial model of chronic illness (ie, health status and outcomes in chronic illness are influenced by the interaction of biologic, psychological, and sociologic factors) provides a useful way to conceptualize fibromyalgia.^[34] The model is pictured in the image below.

Biologic variables

Certain biologic variables contribute to the development and persistence of fibromyalgia, although none, as a single element, explains all facets of fibromyalgia. Certain variables (eg, physical trauma, exposure to toxins) have been widely incriminated by the public, particularly in medicolegal settings, but are actually of little significance in the etiology of fibromyalgia, as shown by prospective studies.

Inheritance

The extremely important genetic contribution to fibromyalgia and related central sensitivity syndromes was first suggested by family studies.^{[35, 36]} Subsequently, the application of sophisticated genotyping and statistical methodology has provided a detailed view of this relationship.^{[37, 38]}

For example, altered serotonin metabolism in a subgroup of patients with fibromyalgia has been linked to a genotype of the promoter region of the serotonin transporter gene.^[39] Single-nucleotide polymorphisms in the genes for catecholamine-O-methyltransferase (which inactivates catecholamines) and β2-adrenergic receptors have been linked to increased pain perception.^{[22, 40, 25]}

Female sex

Sex-related effects are important in fibromyalgia and with pain in general.^[41] Central pain modulatory systems in females are influenced by phasic alterations in reproductive hormone levels. Aversive stimuli and stressful tasks are more likely to evoke SNS, HPA axis, and psychological responses in females than in males.

Sleep

Almost all patients with fibromyalgia sleep poorly—hence, the common report that a night of poor sleep is followed by a more painful day. Indeed, intrusion of alpha waves into slow delta wave stage III/IV (deep) sleep was the first objective abnormality observed in fibromyalgia.^[42] Although not the proximate cause of fibromyalgia, abnormal sleep affects both limbs of the stress response system and contributes to negative mood and cognitive difficulties.

Trauma and tissue injury

Trauma as a trigger of fibromyalgia has been a highly contentious and medicolegally charged issue in American society. Until very recently, physical trauma as a causative factor in the development of fibromyalgia was an open question because properly designed prospective studies had not been performed and little experimental evidence explained the presence of pain in the absence of tissue injury.

Setting aside case series and other anecdotal observations that do not provide valid evidence concerning causation, numerous controlled investigations on this issue are now available. The preponderance of current evidence does not support physical trauma as a significant causative factor in the development of fibromyalgia.^{[43, 44, 45, 46, 47]} At a clinical level, however, patients who attribute their fibromyalgia to trauma have more perceived disability, self-reported pain, life interference, and affective distress than patients with idiopathic onset.

Stress/neuroendocrine and autonomic dysregulation

A large body of data suggests that fibromyalgia, chronic fatigue syndrome, regional chronic pain syndromes, and certain emotional disorders that frequently coexist with fibromyalgia all involve central dysregulation of the stress response system.^{[37, 48, 49, 12, 14]} In these disorders, various forms of stress function as initiators or perpetuators of functional alterations in the corticotropin-releasing hormone (CRH) neuron, with associated effects on the HPA axis, other neuroendocrine axes, and the SNS.

Subtle abnormalities in the stress response system, which cannot be detected by routine clinical and laboratory assessments, may contribute to the diverse clinical manifestations in this spectrum of illnesses. Although incomplete, the emerging evidence is beginning to clarify how the brain, endocrine, and immune systems (especially proinflammatory cytokines) interact in the pathophysiology of pain, fatigue, neurally mediated hypotension, depression, anxiety, and poor sleep.

The extremely high prevalence of stress-related disorders in society may reflect maladaptation of the stress response system in the face of the almost universal stress and consequent distress that characterizes modern life.

Other variables

Age is a variable; most cases occur between the ages of 20 and 50 years. Physical deconditioning is also a variable. While considered unlikely to be sole triggers, infection may contribute to exacerbation of symptoms via cytokine–vagus nerve stimulation of the corticotropin-releasing hormone neuron/stress response system in bidirectional brain–immune system communication.^[6]

Variables with an uncertain relationship to the development of fibromyalgia include the following:

• Decreased collagen cross-linking
• Hypermobility
• Chiari malformation
• Environmental chemicals

Psychological variables

Although not significant in all patients with fibromyalgia, cognitive-behavioral variables can be pivotal in the development and maintenance of persistent pain and functional disability.^[24] The repertoire of operant cognitive-behavioral variables in adults have antecedents in earlier life (eg, childhood abuse, parental alcoholism, learned behaviors from living as children with dysfunctional or chronically ill parents).

By early adulthood, a failure in goal-oriented behavior may develop, leading to lower self-efficacy, the inability to achieve goals, and a fear of failure. In turn, this may presage reporting of chronic pain as a socially acceptable excuse for failure to achieve goals in later life.

Meaning structures

Qualitative research shows that some patients with fibromyalgia exhibit meaning structures that facilitate their "invisible," "capricious" illness for which they cannot be blamed. Unwittingly, this may serve as an excuse for not meeting the demands and challenges of life, with accompanying strong rejection of any notion that fibromyalgia could have psychological antecedents. When this occurs, physicians and/or counselors should assist the patient in avoiding the choice of illness as a way to deal with difficult personal-life situations.

Pain beliefs and attributions

Negative beliefs (eg, self-blame for the mysterious enduring pain) are associated with a range of adverse consequences, as follows:

• Increased subjective pain intensity
• Reduced compliance with treatment
• Low self-esteem
• Somatization
• Psychological distress

In patients with chronic pain, the expected degree of tolerance to stimuli or activities that evoke pain or fatigue predicts actual tolerance. Expected danger (damage) predicts avoidance.

Self-assessed inability to work, helplessness, low perceived control over pain, and maladaptive coping all affect pain severity and the overall impact of fibromyalgia. Thus, some patients with fibromyalgia perceive that they are using excessive effort during formal exercise testing of muscle, even though their actual muscle function is electrophysiologically normal.

Similarly, the discordance between self-reported disability versus observed functional disability can be high in some patients with fibromyalgia. In contrast, such discordance is generally low or absent in patients with other rheumatic diseases, such as ankylosing spondylitis and rheumatoid arthritis.

Hypervigilance

Certain data support a hypervigilance model of pain in patients with fibromyalgia.^[50] Heightened sensitivity to pain results at least in part to increased attention to external stimuli and a preoccupation with pain sensations. Thus, pain is amplified by hypervigilance to pain. Patients with fibromyalgia may become what they perceive themselves to be.

Self-efficacy and coping

Perceived self-efficacy is the level of confidence that the patient requires to control pain effectively. People with high self-efficacy beliefs engage in coping behaviors until success is achieved. People with low self-efficacy beliefs anticipate failure and stop using effective coping strategies. Higher coping self-efficacy is associated with less negative mood and less pain.

Treatments that improve coping reduce pain and enhance a positive mood. Excessive use of active coping may actually be detrimental in patients with fibromyalgia who have low self-efficacy for pain control.

Self-efficacy may be a significant determinant of pain itself, particularly with respect to its emotional arousal and unpleasant effects. In a study of patients with osteoarthritis, those scoring high for self-efficacy about arthritis pain control exhibited higher thresholds and tolerance for thermal pain compared with those who had low scores.^[51] Conversely, maladaptive coping strategies, such as catastrophizing about pain, worsen the pain experience, especially with respect to the development of depression.

Pain catastrophizing, defined as characterizing pain as unbearable or horrible, is an important factor in the experience of pain. Research using functional magnetic resonance imaging (fMRI) to measure regional cerebral blood flow (rCBF) and quantitative sensory testing (QST) techniques has demonstrated that in persons with high catastrophizing, pain perception is augmented by increased activity in response to painful stimuli in brain areas involved in the following^[52] :

• Anticipation of pain (medial frontal cortex, cerebellum)
• Attention to pain (dorsal anterior cingulate gyrus, dorsolateral prefrontal cortex)
• Emotional aspects of pain (claustrum, closely connected to the amygdala)

Depression and anxiety

Lifetime psychiatric comorbidity is common in individuals with fibromyalgia, including the following^{[53, 54]} :

• Mood disorders (bipolar disorder, major depressive disorder)
• Anxiety disorders (generalized anxiety disorder, obsessive-compulsive disorder, panic disorder, PTSD, social phobia)
• Eating disorders
• Substance use disorders

Pressure-pain thresholds (degree of tenderness with application of pressure) correlate with psychological comorbidity in patients with fibromyalgia, as follows^[55] :

• Low tenderness is associated with moderate depression/anxiety, moderate catastrophizing, and moderate control over pain
• High tenderness is associated with high depression/anxiety, high catastrophizing, and low control over pain
• Extremely high tenderness is associated with normal levels of depression/anxiety, very low catastrophizing, and highest control over pain

Depression contributes to the subjective unpleasantness and distress of pain through parallel, somewhat independent neural pain processing networks for purely sensory and affective pain elements. People who are healthy and people who have fibromyalgia but no depression exhibit increased rCBF only in the somatosensory cortices and the anterior insula, whereas people with fibromyalgia and depression also show increased rCBF in the amygdala and contralateral anterior insula, which are involved in affective pain processing.^[56]

However, chronic pain is not simply a manifestation of depression. Despite common reports of pain and other somatic symptoms, patients with pure major depression, compared with patients with fibromyalgia, actually have fewer tender points, increased pain thresholds, and more stoic responses to pain stimuli.^[57] In addition, negative emotions such as sadness and anger have been shown to be general risk factors for pain amplification independent of a diagnosis of fibromyalgia.^[15]

Personality traits and disorders

Personality traits have the largest effect on the cognitive processes by which people attach meanings and implications to their pain.^[24] For example, neuroticism, which is associated with hypochondriasis, irritability, and emotional disturbance, has no influence on the discrimination of thermal pain but exerts powerful influences in the delayed reflective stage of pain (ie, at the level of emotions related to suffering, including depression, anxiety, and, especially, frustration).

Several personality styles among patients with fibromyalgia are encountered in clinical practice.^{[58, 59]} Most common is a perfectionism-compulsiveness personality, characterized by a rigid belief system in the need to be perfect, high underlying anxiety, and an unawareness of feelings and emotions. Another common personality style is the self-sacrificing type, characterized by a tendency to put everyone else’s needs before one’s own.

Less common is the "wounded warrior" type. These patients, who may be totally helpless and disabled physically and psychologically, carry a great burden of adverse psychosocial experiences and psychiatric comorbidity.

These 3 personality styles are difficult to treat and often require counseling or psychiatric intervention. The "resilient" patient who lacks maladaptive schemas and psychiatric comorbidity has a much better prognosis.

Pain behaviors

At one level, pain behaviors are the various signals that serve to communicate the pain experience to the outside world and include nonverbal expressions of pain (eg, grimacing, bracing, sighing, rubbing, groans, histrionic behavior). Increased pain behaviors are associated with more depression, reduced self-efficacy for pain control, and more negative thoughts.

Pain behaviors can be important perpetuators of illness through reinforcement of the responses that patients with fibromyalgia induce as a means to get attention, to obtain medication, or to avoid work or activity. This can lead to limitation of physical and social activity, dependence on narcotics and alcohol, and unemployment.

A common pain behavior in patients with fibromyalgia is an excessive use of medical services. Care seekers exhibit lower pain thresholds and greater psychiatric morbidity than patients without fibromyalgia who do not have chronic pain, an observation consistent with the idea that care seeking reduces the emotional distress consequent to symptoms and life stressors.

Environmental and sociocultural variables

Multiple experiences and forces in a person's environment and social culture influence the pain experience, either positively (eg, high job satisfaction in a person who strains his or her back at work) or negatively (eg, physician who medicalizes a minor injury by diagnostic waffling and inappropriate diagnostic testing).^[24] Environmental and sociocultural variables include the following:

• Psychosocial experiences during childhood
• Spousal and family support
• Ethnologic factors
• Focus on definable causes
• Media hype
• Primary and secondary gain

Developmental variables

Developmental variables include the psychosocial experiences during childhood (eg, school stress, role models, unhappy families, abuse) that shape the cognitive, affective, and behavioral aspects of pain in adults. Some studies show that two thirds of patients with chronic pain have first-degree relatives with chronic pain, one third have a family member with an affective illness, and one third have a family member with alcohol abuse.

Childhood physical, emotional, or sexual abuse appears to be a common antecedent of anxiety, somatization, and chronic pain in many adults. For example, in a community population–based screening survey, the association of childhood abuse and the presence of more than 5 tender points (a characteristic of fibromyalgia) in adults was very strong (odds ratio, 6.9).^[60] Biologic vulnerability likely derives, in part, from persisting effects of early life stresses on the stress response system.

Family and work variables

Spousal and family support can either mitigate or adversely affect the various dimensions of chronic pain. Training of spouses to enhance their ill partner's coping skills improves self-efficacy for pain control and reduces pain and psychological distress. Spousal reinforcement of pain behaviors can lower experimentally determined pain thresholds.

Job satisfaction and a healthy work environment lessen the emotional distress associated with chronic pain. Conversely, job dissatisfaction strongly predicts the progression of acute back pain to chronic low back pain. Similarly, workers' compensation and disability benefits can be significant disincentives for recovery from chronic pain.

Sociocultural factors

Pain tolerance may be profoundly influenced by culture. The prevalence of widespread chronic pain is zero in Pima Indians but is approximately 10% in white populations on both sides of the Atlantic. The current epidemic of fibromyalgia, chronic fatigue syndrome, sick building syndrome, and multiple chemical sensitivity syndrome is arguably due, at least in part, to media hype, fear, suggestibility, and a focus on definable causes by patients and physicians.

Cases of fibromyalgia have been reported by researchers from around the world. Fibromyalgia exhibits no race predilection. Researchers have reported the condition in all ethnic groups and cultures.

In the United States, chronic pain and fatigue are extremely prevalent in the general population,^{[61, 62, 63]} especially among women and persons of lower socioeconomic status. The prevalence of regional pain is 20%; widespread pain, 11%; and chronic fatigue, approximately 20%.

Fibromyalgia, as defined by the American College of Rheumatology (ACR) criteria,^[7] has a prevalence of 3-5% in females and 0.5-1.6% in males. Because the ACR criteria are relatively insensitive, the actual prevalence of fibromyalgia is higher.

Consequently, fibromyalgia is the second most common disorder that rheumatologists encounter. Primary care physicians may find that approximately 8% of their patients have fibromyalgia. In a rheumatology and physiatry practice, however, as many as 15% of evaluated patients have fibromyalgia. This implies that 1 of every 10 patients evaluated in a medical practice has fibromyalgia.

The annual economic burden of fibromyalgia in 2005 was $10,199 per patient per year, nearly double that of matched controls.^[64] It has been estimated that overall, fibromyalgia costs the US economy over $9 billion annually.^[65]

Sex- and age-related differences in incidence

Fibromyalgia as defined by the ACR criteria is far more common in women than in men, with a female-to-male ratio of approximately 9:1. No universally accepted explanation exists for this predilection, since in pediatric cases, differences between boys and girls are hardly evident.

Males with fibromyalgia tend to have lower health perception and more physical limitations than females. Females with fibromyalgia have greater pain sensitivity^[41] and may exhibit greater life interference due to pain.

Fibromyalgia can occur in individuals of all ages. Although usually considered a disorder of women aged 20-50 years, fibromyalgia is observed in pediatric populations,^[66] especially in adolescents, and in older persons.^[67]

Fibromyalgia is a chronic relapsing condition. In academic medical centers, long-term follow-up care of patients with fibromyalgia reportedly averages 10 outpatient visits per year and 1 hospitalization every 3 years. Chronic pain and fatigue in fibromyalgia increases the risk for metabolic syndrome.

Although entirely reversing the allodynia and hyperalgesia in patients with fibromyalgia may be impossible, the response to therapy improves significantly in many patients if ongoing stressors are relieved and self-efficacy for pain control can be achieved. The treatment goal that responds least to therapy is improvement in daily functioning. A positive therapeutic response usually requires resolution of pending litigation (personal injury or workers’ compensation claims).

Three distinct subsets of patients with varying prognoses have been termed adaptive copers, interpersonally distressed, and dysfunctional.^{[68, 69]} Adaptive copers, who often do not seek care for their symptoms, do well with respect to pain, sleep, and fatigue. Interpersonally distressed patients may respond to resolution of life stressors and interdisciplinary therapeutic approaches, including counseling.

Dysfunctional patients have high levels of pain and anxiety, major impairment in daily functioning, and, quite often, opioid dependence. These patients have a poor prognosis.

Other patient characteristics associated with guarded prognosis include the following:

• High levels of distress
• Long-standing fibromyalgia
• Major psychiatric disease or severe depression and anxiety that responds poorly to treatment
• An ingrained pattern of work avoidance
• Marked functional impairment despite multidisciplinary approaches to treatment
• Opioid or alcohol dependence

Fibromyalgia is not a life-threatening, deforming, or progressive disease. Without proper diagnosis and treatment, however, a patient with fibromyalgia may have the illusion of disease progression. This illusion does not occur as a result of disease but is instead caused by sleep deprivation and physical deconditioning.

Approximately one third of patients with fibromyalgia reportedly modify their work to keep their job. Some patients shorten their workday and/or workweek, and many persons with fibromyalgia change to a job that is less physically and mentally taxing than their previous one. Patients have also reported an inability to achieve career or educational advancement, and some have reported career loss. Such changes often lead to a decreased income and increased financial burdens.

One study of patient perspectives confirmed that fibromyalgia has a significant negative impact on the quality of social and economic functions in patients' lives. One report suggested that approximately 15% of the people with fibromyalgia are receiving disability benefits. Disability rates as high as 44% have been reported.

A prospective study from Denmark reported a 10-fold increased risk of death from suicide in patients with fibromyalgia who were followed for as long as 16 years.^[70] This study also found a sixfold increased risk of liver cirrhosis/biliary tract disease and a threefold increased risk of cerebrovascular disease.^[70] This association also needs to be studied in other populations.

Education is an essential element in therapy for fibromyalgia. It begins with an empathetic manner on the part of the physician, who must affirm the patient's pain, explore social and behavioral variables (both in childhood and current) that influence this illness, and explain to the patient how stress and distress can amplify pain and fatigue. Scheduling time to provide this education at early visits saves time in subsequent visits.

The patient should make an effort to foster self-efficacy, with diminishing dependence on health care providers. The physician can help by teaching patients about the following:

• Identifying triggers of flare-ups, so as to avoid and manage them
• Sleep hygiene
• Diet

Excellent educational resources include the Arthritis Foundation, various fibromyalgia advocacy groups, and certain Internet sites, such as the following:

• Arthritis Foundation
• MedlinePlus Health Information, a service of the US National Library of Medicine and the National Institutes of Health
• American College of Rheumatology
• Missouri Arthritis Rehabilitation Research and Training Center
• The National Fibromyalgia Association
• The American Fibromyalgia Syndrome Association
• Chronic Fatigue Syndrome and Fibromyalgia
• Fibromyalgia.com
• FamilyDoctor.org, an American Academy of Family Physicians Web site, has patient education pages on several aspects of fibromyalgia

Friends International Support is an online support group for people with chronic pain, fibromyalgia, and chronic fatigue syndrome. Local patient support groups can also be helpful if the overall tenor of meetings is one of optimism and realism rather than pessimism and quick-fix orientation.

For patient education information, see the Muscle Disorders Center; Mental Health and Behavior Center; and Back, Ribs, Neck, and Head Center; also see Fibromyalgia, Chronic Fatigue Syndrome, Chronic Pain, Fatigue, and Pain Medications.