Fibromyalgia 

Updated: Nov 14, 2018
Author: Chad S Boomershine, MD, PhD, CPI, CPT; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Fibromyalgia is a disorder of chronic, widespread pain and tenderness (see the image below). It typically presents in young or middle-aged women but can affect patients of either sex and at any age.

Tender points in fibromyalgia. Tender points in fibromyalgia.

See Fibromyalgia: Slideshow, a Critical Images slideshow, for more information on strategies for accurately diagnosing and treating fibromyalgia.

Signs and symptoms

Fibromyalgia is a syndrome that consists of the following signs and symptoms[1] :

  • Persistent (≥3 mo) widespread pain (pain/tenderness on both sides of the body, above and below the waist, including the axial spine [usually the paraspinus, scapular, and trapezius muscles])

  • Stiffness

  • Fatigue; disrupted and unrefreshing sleep

  • Cognitive difficulties

  • Multiple other unexplained symptoms, anxiety and/or depression, and functional impairment of activities of daily living (ADLs)

See Presentation for more detail.

Diagnosis

Fibromyalgia is a diagnosis of exclusion and patients must be thoroughly evaluated for the presence of other disorders that could be the cause of symptoms before a diagnosis of fibromyalgia is made. The clinical assessment may reveal objective evidence for a discrete or comorbid illness, such as the following:

  • Hypothyroidism

  • Rheumatoid arthritis

  • Systemic lupus erythematosus

  • Polymyalgia rheumatic

  • Other inflammatory or autoimmune disorders

  • Serious cardiac conditions in those with chest pain, dyspnea, and palpitations

Laboratory testing

Although patients with fibromyalgia do not have characteristic or consistent abnormalities on laboratory testing, routine laboratory and imaging studies can help to rule out diseases with similar manifestations and to assist in diagnosis of certain inflammatory diseases that frequently coexist with fibromyalgia. Such tests include the following:

  • Complete blood count with differential

  • Metabolic panel

  • Urinalysis

  • Thyroid-stimulating hormone level

  • 25-hydroxy vitamin D level

  • Vitamin B12 level

  • Iron studies, including iron level, total iron binding capacity, percent saturation, and serum ferritin level

  • Magnesium level

  • Erythrocyte sedimentation rate

  • Antipolymer antibody assay: May provide conclusive evidence for a subgroup of people with fibromyalgia; about 50% of fibromyalgia patients have antipolymer antibodies

Patient self-report forms, clinical psychometric testing

Self-report forms, for assessing patients’ pain, fatigue, and overall status, include the following:

  • Modified Health Assessment Questionnaire

  • Fibromyalgia Impact Questionnaire

  • Checklist of current symptoms

  • Scales for helplessness and cognitive performance

  • The Physician Health Questionnaire–9 for depression

  • The Generalized Anxiety Disorder–7 questionnaire for anxiety

  • The Mood Disorder Questionnaire to screen for bipolar disease

Psychometric testing provides a more comprehensive assessment and includes the following:

  • Minnesota Multiphasic Personality Inventory

  • Social Support Questionnaire

  • Sickness Impact Profile

  • Multidimensional Pain Inventory

See Workup for more detail.

Management

There is no cure for fibromyalgia, but education, lifestyle changes, and proper medications can help the individual to regain control and achieve significant improvement.

Models of pain behavior that interrelate biologic, cognitive, emotional, and behavioral variables form the basis for cognitive-behavioral and operant-behavioral approaches to adult pain management. Fibromyalgia in children responds to a combination of psychotherapy, exercise, relaxation techniques, and education. Pharmacotherapy is generally not indicated in children.

Nonpharmacotherapy

  • Diet (eg, promote good nutrition, vitamin supplementation, bone health, weight loss)

  • Stress management

  • Aerobic exercise (eg, low-impact aerobics, walking, water aerobics, stationary bicycle)

  • Sleep therapy (eg, education/instruction on sleep hygiene)

  • Psychologic/behavioral therapy (eg, cognitive-behavioral, operant-behavioral)

Pharmacotherapy

Always combine pharmacologic and nonpharmacologic therapy in the treatment of fibromyalgia. Aggressively treat comorbid depression.

Medications used in the management of fibromyalgia include the following:

  • Analgesics (eg, tramadol)

  • Antianxiety/hypnotic agents (eg, alprazolam, clonazepam, zolpidem, zaleplon, trazodone, buspirone, temazepam, sodium oxybate)

  • Skeletal muscle relaxants (eg, cyclobenzaprine)

  • Antidepressants (eg, amitriptyline, duloxetine, milnacipran, venlafaxine, desvenlafaxine)

  • Anticonvulsants (eg, pregabalin, gabapentin, tiagabine)

  • Alpha 2 agonists (eg, clonidine)

Medications that may prove helpful for sleep problems that do not respond to nonpharmacotherapy include the following:

  • Antidepressants (eg, trazodone, SSRIs, SNRIs, tricyclic antidepressants)

  • Anticonvulsants (eg, clonazepam, gabapentin, tiagabine)

  • Nonbenzodiazepine hypnotics (eg, zolpidem, zaleplon, eszopiclone)

  • Muscle relaxants (eg, cyclobenzaprine, tizanidine)

  • Dopamine agonists (eg, pramipexole)

Other agents used in fibromyalgia may include the following:

  • Vitamins and minerals

  • Malic acid and magnesium combination

  • Antioxidants

  • Amino acids

  • Herbs and supplements

See Treatment and Medication for more detail.

Background

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).[1, 2] It typically presents in young or middle-aged women, but it can affect patients of either sex and at any age.

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. Some 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).[3, 4]

Indeed, fibromyalgia can now be considered a neurosensory disorder characterized in part by abnormalities in pain processing by the central nervous system (CNS).[5] 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 (systemic exertion intolerance disease [SEID])

  • 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 diagnose fibromyalgia, whereas a gastroenterologist may diagnose irritable bowel syndrome or an infectious disease specialist may diagnose chronic fatigue syndrome.

In addition, fibromyalgia coexists in unusually high frequency with certain illnesses characterized by systemic inflammation, such as rheumatoid arthritis (RA),[6] systemic lupus erythematosus (SLE),[7] and chronic hepatitis C infection,[8] among others. In such cases, both disorders must be recognized and treated for optimum therapeutic outcome, as treatment of one will not necessarily improve the other.

Even as evidence-based medicine supplies a growing array of tools for the management of fibromyalgia, 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 and laboratory examination (see Presentation and Workup). 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 treatment 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 inflammation 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 and in the lay literature to ancient times with descriptions of the condition in the biblical book of Job.

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 accepted guidelines for identifying fibromyalgia patients for study existed. The American College of Rheumatology (ACR) sponsored a multicenter study to develop classification criteria; the results were published in 1990.[9] In 1992, at the Second World Congress on Myofascial Pain and Fibromyalgia, these classification criteria for fibromyalgia were expanded and refined. However, the criteria performed poorly in the clinic, failing to identify nearly half of fibromyalgia patients.[10] To improve diagnosis, new fibromyalgia diagnostic criteria were provisionally accepted by the ACR in 2010.[11]

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 descriptions of the symptom complex now termed fibromyalgia have existed since earliest recorded history, the terminology used to refer to the condition has changed numerous times.

The first specific term, muscular rheumatism , was used in the early 19th century by surgeon William Balfour to describe a condition comprising disturbed sleep, fatigue, stiffness, and pain for which there was no explanation.[12] Balfour later described anatomic tender points accompanying the disorder that could be used in identification. In 1880, neurologist George Beard coined a new term, neurasthenia, characterized by a combination of symptoms including fatigue, widespread pain, and anhedonia.[13]

In 1904, Gowers renamed the disorder fibrositis after his incorrect belief that the disorder was caused by inflammation in muscle fascia.[14] Chaitrow asserts that no inflammatory process has ever been found to be part of this disease.[15] The syndrome was renamed fibromyalgia by Yunus et al in their seminal 1981 article derived from the Latin root fibro (fibrous tissue) and the Greek roots myo (muscles) and algos (pain).[16]

Pathophysiology

Fibromyalgia is currently understood to be a disorder of central pain processing or a syndrome of central sensitivity.  Research has provided evidence for altered functional connectivity and chemistry in the pain-processing system of the brain.[17]

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.[18]

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.”[19] 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).

A neurophysiologist's view of pain. Courtesy of Al A neurophysiologist's view of pain. Courtesy of Alan R. Light, PhD.

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.[20, 21, 22, 23] 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.[24] 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.[25]

Pain in patients with fibromyalgia derives partly from a generalized decrease in the pain perception threshold, with reduced discrimination of nociceptive sensations from non-nociceptive sensations (eg, touch, warmth, cold), and in the threshold for pain tolerance, resulting in an unwillingness to receive more-intense stimulation.[26]

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 or with functional magnetic resonance imaging (fMRI) using pain stimuli.[5] 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.[27, 28, 29, 30, 31] 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.[32, 33] 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, pregabalin).[27, 34] 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 four-fold 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.[4] 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[35] :

  • 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 was 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[36] ; 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.[37] 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.[38] 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.[39] 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.[40]

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.

Glial activation

A functional brain imaging study has demonstrated activation of glial cells in patients with fibromalgia; these cells release inflammatory mediators that are thought to sensitize pain pathways and contribute to symptoms such as fatigue. Albrecht et al demonstrated brain inflammation in fibromyalgia by using hybrid magnetic resonance/positron emission tomography (MR/PET) and the radioligand (11C)PBR28, which binds to the translocator protein (TSPO). Expression of TSPO is low in healthy CNS tissue, but TSPO is widely upregulated in microglia and astrocytes under inflammatory conditions.[41, 42]

In the study, which included 31 patients with fibromyalgia and 27 healthy controls, the patients had higher levels of TSPO, most pronounced in the medial and lateral walls of the frontal and parietal lobes. The degree of glial activation correlated with the degree of fatigue the patients reported.[41, 42]

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.[43]

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.[44]

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 correlates 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. Other 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.[45, 46] 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 – Initial drowsiness

  • Stage 2 – Light sleep

  • Stages 3 and 4 – 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.

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.

Many fibromyalgia patients also have primary sleep disorders that can reduce sleep quality, such as obstructive sleep apnea, restless legs syndrome, or periodic limb movement disorder. All patients should be screened for the presence of primary sleep disorders before assuming that reduced sleep quality is due to fibromyalgia.

Etiology

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.[47] The model is pictured in the image below.

Biopsychosocial model of fibromyalgia. Biopsychosocial model of fibromyalgia.

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.[48, 49] Subsequently, the application of sophisticated genotyping and statistical methodology has provided a detailed view of this relationship.[50, 51]

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.[52] Single-nucleotide polymorphisms in the genes for catecholamine-O-methyltransferase (which inactivates catecholamines) and β2-adrenergic receptors have been linked to increased pain perception.[32, 36, 53]

Female sex

Sex-related effects are important in fibromyalgia and with pain in general.[54] 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.[55] 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.[56, 57, 58, 59, 60] 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.[21, 23, 50, 61, 62] 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 an important variable. While most patients begin to experience symptoms between the ages of 20 and 50 years, the prevalence of the syndrome increases with age. The highest prevalence occurs between ages 60 and 79 years.[63]

Physical deconditioning is also an important variable. Moldofsky et al showed that disrupting stage 4 sleep in sedentary healthy controls elicited the appearance of musculoskeletal and mood symptoms similar to those seen in fibromyalgia patients.[55] However, when similar sleep disruption was performed in healthy controls who were regular exercisers, fibromyalgia symptoms did not develop.[64] This implies that regular physical activity may be protective and underscores the importance of maintaining physical activity in fibromyalgia patients.

While considered unlikely to be sole triggers, infection may also 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.[8]

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.[35] 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.[65] Heightened sensitivity to pain leads 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. However, 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.[66] 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[67] :

  • 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[68, 69] :

  • 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[70] :

  • 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.[71]

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, higher pain thresholds, and more stoic responses to pain stimuli.[72] 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.[24]

Personality traits and disorders

Personality traits have the largest effect on the cognitive processes by which people attach meanings and implications to their pain.[35] 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.[73, 74] 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, a physician who medicalizes a minor injury by diagnostic waffling and inappropriate diagnostic testing).[35] 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 with the presence of more than 5 tender points (a characteristic of fibromyalgia) in adults was very strong (odds ratio, 6.9).[75] 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 exacerbate 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.

Epidemiology

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,[63, 76, 77] 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 1990 American College of Rheumatology (ACR) classification criteria,[9] has a prevalence of 3-5% in females and 0.5-1.6% in males. Because the ACR criteria are insensitive, the actual prevalence of fibromyalgia is higher, particularly in men.

Fibromyalgia is the second most common disorder that rheumatologists encounter, seen in 15% of evaluated patients. Approximately 8% of patients cared for in primary care clinics have fibromyalgia.

The annual economic burden of fibromyalgia in 2005 was $10,199 per patient per year, nearly double that of matched controls.[78] It has been estimated that overall, fibromyalgia costs the US economy over $9 billion annually.[79]

United States prevalence

Wolfe et al estimated that the prevalence of fibromyalgia in the US general population was 2% (3.5% in women and 0.5% in men).[63] However, this estimation was reached using the original 1990 American College of Rheumatology (ACR) classification criteria,[9] and those classification criteria miss nearly half the patients clinically diagnosed with fibromyalgia,[10] Thus, this estimate is probably low. It is especially likely to have underestimated the prevalence in men, who have fewer positive tender points and so are less likely to meet the classification criteria.

A study by Vincent et al using the 2010 ACR diagnostic criteria estimated the prevalence of fibromyalgia at 6.4% (7.7% in women and 4.9% in men).[80] It is likely that this higher prevalence rate is a more accurate estimate.

International prevalence

Using data from 5 countries (France, Germany, Italy, Portugal, and Spain), Branco et al estimated the prevalence of fibromyalgia in Europe at 4.7%.[81] Prevalence was estimated to be 5.8% in women and 3.5% in men. However, this estimate used the London Fibromyalgia Epidemiological Study Screening Questionnaire (LFESSQ), a nonstandard method of identifying fibromyalgia patients. Another study using the LFESSQ estimated the prevalence of fibromyalgia in Tunisia at least at 8.3%.[82]

White et al estimated the prevalence of fibromyalgia at 3.3% in Ontario, Canada (4.9% women vs 1.6% men).[83] However, this estimate was derived using the 1990 ACR classification criteria,[9] so it is likely this estimate is low, particularly in the male population.

The prevalence of fibromyalgia in the general population of Brazil has been estimated at 4.5%.[84] A similar Brazilian study in the elderly population estimated the prevalence at 5.5%.[85] Interestingly, all fibromyalgia patients identified in both Brazilian studies were female, despite a large percentage of male participants. Since both studies used the 1990 ACR classification criteria, it is likely the number of both male and female patients were underestimated.

Race-related differences in incidence

While studies have identified patients with fibromyalgia in countries around the world, most have been done in developed countries and few have looked specifically at the effect of race.

In the United States, African-American women have a higher prevalence of fibromyalgia than white women.[86] However, increased body pain and tenderness are associated with decreased socioeconomic status, so this may be an important influence on racial differences. Another study comparing Sephardic and Ashkenazic Israeli women found that education, rather than ethnic identity, was a determining factor in clinical features of fibromyalgia.[87] Studies of persons in China appear to demonstrate a consistently lower prevalence of fibromyalgia than persons in the United States and Europe.[88]

Much work needs to be done to better understand racial differences, but it has been limited by the need to perform tender-point examinations to identify patients. The demonstration that a patient self-report questionnaire using the modified 2010 ACR criteria fibromyalgia can reliably identify fibromyalgia patients should allow for more studies on race and fibromyalgia to be conducted.[89]

Sex-related differences in incidence

In pediatric cases, differences in fibromyalgia prevalence between boys and girls are hardly evident. In adults, women tend to develop fibromyalgia more often than men. However, the true difference in prevalence between women and men depends on how the disorder is defined. If fibromyalgia is defined as fulfillment of the original 1990 ACR classification criteria that require pain on palpation of at least 11 of 18 tender points,[9] fibromyalgia prevalence displays a 7:1 female:male ratio.[63]

However, the 1990 ACR classification criteria miss nearly half of patients clinically diagnosed with fibromyalgia and perform particularly poorly in men since they tend to have fewer painful tender points.[10] If instead fibromyalgia is defined using the 2010 ACR diagnostic criteria that do not use tender points, the difference in prevalence of fibromyalgia between women and men is only about 2:1.[80]

Males with fibromyalgia tend to have lower health perception and more physical limitations than females. Females with fibromyalgia have greater pain sensitivity[54] and may exhibit greater life interference due to pain.

Among the mechanisms that may contribute to increased pain sensitivity in women are the following[35] :

  • 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

Age-related differences in incidence

Although usually considered a disorder of women aged 20-50 years, fibromyalgia can occur at any age and in persons of either sex. Fibromyalgia occurs in pediatric populations, especially during adolescence.[90] The prevalence of fibromyalgia increases with age, and the peak prevalence is not seen in women until age 60-70 years.[63] All patients with widespread pain, regardless of age, should be evaluated for fibromyalgia.

Prognosis

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.

Entirely reversing the allodynia and hyperalgesia in patients with fibromyalgia may be impossible. Nevertheless, symptoms can be significantly improved in many patients, particularly 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). While most patients assume that stopping work will improve their symptoms, numerous studies have shown that symptoms worsen when fibromyalgia patients go on disability.[91]

The following three distinct subsets of patients with varying prognoses have been identified[92, 93] :

  • 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 very 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% in fibromyalgia patients 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.[94] This study also found a six-fold increased risk of liver cirrhosis/biliary tract disease and a three-fold increased risk of cerebrovascular disease.[94] Owing to the severity of these risks, these associations need to be studied in other populations and all patients should be monitored for suicide risk.

Patient Education

Education is an essential element in fibromyalgia management. 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 the illness, and explain to the patient how stress and distress can amplify the severity of symptoms. Scheduling time to provide this education at early visits can save time in subsequent visits.

The patient should be encouraged to foster self-efficacy, and healthcare providers should work to diminish dependence over time. Providers can help by teaching patients about the following:

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

  • Sleep hygiene

  • Diet

  • Physical activity recommendations including stretching, resistance, and aerobic activity

For patient education information, see the Fibromyalgia Health Center. Other valuable educational resources include 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

  • National Fibromyalgia & Chronic Pain Association

  • The American Fibromyalgia Syndrome Association

  • FamilyDoctor.org, an American Academy of Family Physicians Web site

Friends International Support is an online support group for people with chronic pain, fibromyalgia, chronic fatigue syndrome (myalgic encephalopathy), and back pain. 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.

 

 

Presentation

History

By definition, fibromyalgia is a disorder of chronic, widespread pain and tenderness. Chronic indicates the pain and tenderness have been present continuously for at least 3 months. Widespread means the pain and tenderness are on both sides of the body, above and below the waist, including the axial spine (usually the paraspinal, scapular, and trapezius muscles). While identification of fibromyalgia patients by the original 1990 American College of Rheumatology (ACR) classification criteria required a specialized physical examination to quantify tender-point count that many providers have not been trained to perform,[9] the 2010 ACR diagnostic criteria allow for diagnosis by history without specialized training.[11]

In addition to chronic, widespread pain and tenderness, the 2010 diagnostic criteria require that fibromyalgia patients have significant symptoms of fatigue, unrefreshed sleep, and cognitive dysfunction (difficulties with thinking and remembering), along with numerous somatic symptoms. However, fibromyalgia is a diagnosis of exclusion and patients must be thoroughly evaluated for the presence of other disorders that could be the cause of symptoms before a diagnosis of fibromyalgia is made.

For this reason, all patients require a thorough history, physical examination, and laboratory evaluation before they are diagnosed with fibromyalgia. Approximately one third of patients identify a specific event (eg, illness, stress or injury) that precipitated the development of fibromyalgia. However, most patients spontaneously develop symptoms without an identifiable stressor. In addition, while some patients have a history of childhood trauma, the majority do not and it should not be assumed that all fibromyalgia patients have a history of abuse.

2010 ACR diagnostic criteria: Physician assessment

The 2010 ACR diagnostic criteria require physicians to evaluate patients by questioning to determine scores on a widespread pain index (WPI) and a symptom severity (SS) scale.

The WPI quantifies the extent of bodily pain on a 0-19 scale by asking patients if they have had pain or tenderness in 19 different body regions (shoulder girdle, hip, jaw, upper arm, upper leg, lower arm, and lower leg on each side of the body, as well as upper back, lower back, chest, neck, and abdomen) over the past week, with each painful or tender region scoring 1 point.

The SS scale quantifies symptom severity on a 0-12 scale by scoring problems with fatigue, cognitive dysfunction and unrefreshed sleep over the past week each on a scale from 0-3, as follows:

  • 0 = No problem
  • 1 = A slight or mild problem (generally mild or intermittent)
  • 2 = A moderate or considerable problem (often present and/or at a moderate level)
  • 3 = A severe, continuous, life-disturbing problem

These scores are summed for a measure of the physician’s impression of the number of somatic symptoms the patient has on a 0-3 scale, as follows:

  • 0 = No symptoms
  • 1 = A few symptoms
  • 2 = A moderate number of symptoms
  • 3 = A great deal of symptoms.

A patient is diagnosed with fibromyalgia if the following three conditions are met:

  1.  The WPI score is 7 or higher and the SS scale score is 5 or higher or the WPI is 3-6 and the SS scale score is 9 or higher
  2. The symptoms have been present at a similar level for at least 3 months
  3. The patient does not have another disorder that would otherwise explain his or her pain

Modified 2010 ACR diagnostic criteria: Patient self-assessment questionnaire

In the 2010 ACR diagnostic criteria, symptom severity is determined by the physician. However, since fibromyalgia is a subjective disorder, patients are the ultimate source of information on the severity of their symptoms. Physicians tend to underestimate patient symptom severity,[95] and physician scoring of symptom severity can lead to underdiagnosis.

By their nature, the fibromyalgia diagnostic criteria are amenable to administration as a patient self-report questionnaire that can limit underdiagnosis and speed clinical evaluation since patients can complete the assessment prior to entering the examination room. Such a self-administered patient questionnaire based on the fibromyalgia diagnostic criteria has been shown to accurately identify fibromyalgia patients.[96] This questionnaire is divided into 3 sections.

The first section assesses the distribution of bodily pain using the same 19 body areas as in the WPI, with patients marking each area yes or no to indicate the presence of pain or tenderness in that area over the past week. Patients score 1 point for each painful or tender body area, yielding a self-report WPI score between 0 and 19, analogous to the WPI score in the physician-assessed diagnostic criteria.

The second section evaluates the severity of problems with daytime fatigue, nonrestorative sleep, and cognitive dysfunction (trouble thinking and remembering) using separate questions scored on 0-3 scales that range from 0 = no problem to 3 = a severe problem.

The third section asks patients whether they have experienced pain or cramps in the lower abdomen, depression, or headache during the past 6 months, with patients scoring 1 point for each positive symptom.

Scores from the second and third sections are summed to yield a 0-12 SS scale score analogous to the SS scale score in the physician-assessed diagnostic criteria. Scores from the WPI and SS scale sections are summed to yield a 0-31 index termed the polysymptomatic distress scale (PSD). Patients with a PSD scale score of 13 or more are diagnosed with fibromyalgia if the symptoms have been present at a similar level for at least 3 months and the patient does not have another disorder that would otherwise explain the symptoms.

Physical Examination

The goal of the physical examination is to confirm the diagnosis, rule out concomitant systemic diseases, and recognize common coexisting conditions. Except for painful tender points and, perhaps, signs of deconditioning, physical examination findings are typically normal in fibromyalgia patients. The tender-point examination should be performed first during the physical examination, because other aspects of the examination may influence sensitivity of tender points.

Performance of the tender-point examination can be improved by using the manual tender-point survey (MTPS) method.[97] The MTPS has been shown to reduce variability in performance of the tender-point examination and identify fibromyalgia patients with high sensitivity and specificity.

The MTPS consists of standardized components including the following:

  1. Location of the tender-point sites
  2. Patient and examiner positioning
  3. Order of tender-point examination
  4. Pressure application technique
  5. Pain severity rating scores

Eighteen tender points are palpated at standard locations arranged symmetrically on the body, along with 3 control points. See the image below.

Tender points in fibromyalgia. Tender points in fibromyalgia.

The thumb pad of the examiner's dominant hand is used to apply pressure to each evaluation site one at a time during the tender-point examination. This allows the examiner to use important tactile cues and is as reliable as the use of a dolorimeter (see Pressure algometry, below).

The procedure is as follows: First, visually locate the evaluation site. Then, with the thumb pad, press perpendicularly into the evaluation site with gradually increased pressure for 4 seconds until a pressure of 4 kg is reached, roughly enough force to blanch the examiner's nail bed. Each tender-point site should be palpated only once to avoid sensitization. The patient is asked to respond with a "yes" or "no" if he or she has pain at the site being examined. If the patient's response is "yes," the individual is asked to rate the pain on a scale of 0 (no pain) to 10 (worst pain), and record each response. A pain severity score of at least 2 is required to count a tender point as positive.

Pain scores from each of the 18 tender-point sites can be averaged to yield a Fibromyalgia Intensity Score (FIS) that varies from 0-10, with higher scores indicating more severe tenderness. The FIS can be monitored over time to evaluate response to therapy.

It is important to emphasize that pain upon light pressure may not be restricted to specific tender points. Many patients feel pain virtually anywhere that pressure is applied, including at the control points (eg, forehead, thumbnail, and distal right forearm) that are relatively insensitive to pain in healthy patients. Pain to palpation at control points should not be considered abnormal in fibromyalgia patients and should not be taken as proof that the patient is "faking" the examination.

Site locations

The standard 18 fibromyalgia tender points exist as 9 pairs (in addition to 3 control sites; see below), 4 on the anterior of the body and 5 on the posterior of the body.[9] The sites are as follows:

  • 1 (control site) - Forehead

  • 2 and 3 (diagnostic sites) - Occiput at the nuchal ridge

  • 4 and 5 (diagnostic sites) - Trapezius

  • 6 and 7 (diagnostic sites) - Supraspinatus

  • 8 and 9 (diagnostic sites) - Gluteal

  • 10 and 11 (diagnostic sites) - Low cervical

  • 12 and 13 (diagnostic sites) - Second rib

  • 14 and 15 (diagnostic sites) - Lateral epicondyle

  • 16 (control site) - Distal middle third of the right forearm

  • 17 (control site) - Nail of the left thumb

  • 18 and 19 (diagnostic sites) - Greater trochanter

  • 20 and 21 (diagnostic sites) - Medial knee

The American College of Rheumatology (ACR) specifies the location of tender points on the anterior body as follows:

  • At the fifth through seventh inter-transverse spaces of the cervical spine

  • In the pectoral muscle, at the second costochondral junctions

  • Approximately 3 finger breadths (2 cm) below the lateral epicondyle

  • At the medial fat pad, proximal to the joint line

The ACR specifies the location of tender points on the posterior body as follows:

  • At the upper border of the shoulder in the trapezius muscle, midway from the neck to the shoulder joint

  • At the craniomedial border of the scapula, at the origin of the supraspinatus

  • In the upper outer quadrant of the gluteus medius

  • Just posterior to the prominence of the greater trochanter at the piriformis insertion

Pressure algometry

A useful device for rough quantitation of pain perception and pain tolerance is a pressure algometer, or dolorimeter, as depicted in the image below. Pressure algometry (dolorimetry) provides a simple determination of pressure pain thresholds at 4 tender points associated with fibromyalgia (ie, both lateral epicondyles, midpoints of the trapezii). Normal values are 4 kg/cm2 or greater.

Pressure algometer (dolorimeter). Pressure algometer (dolorimeter).

Pressure algometry can also serve as a useful tool for educating the patient regarding the nature of altered central nociceptive processing, allodynia (pain with stimuli that should not cause pain, such as gentle touching) and hyperalgesia (amplification of pain experienced from peripheral stimuli that are expected to be painful). On follow-up visits, it can provide a semi-quantitative guide to therapy

Other evaluations

After completing the tender-point examination, the physician should include neurologic, joint, and musculoskeletal evaluations, as follows:

  • Check the joints for swelling, deformities, and erythema
  • Examine the patient's gait, joint range of motion (ROM), and posture for structural asymmetry and skeletal deficiencies
  • Palpate the soft issues for tone or spasm

Complications

Potential complications of fibromyalgia include the following:

  • Extreme allodynia with high levels of distress
  • Opioid or alcohol dependence
  • Marked functional impairment
  • Severe depression and anxiety
  • Obesity and physical deconditioning
  • Metabolic syndrome
 

DDx

Diagnostic Considerations

Although no basis for many of the multiple symptoms of patients with fibromyalgia will be found upon physical examination or laboratory testing, the physician must remain alert for organic illness (eg, colon carcinoma in a patient with irritable bowel syndrome).

The clinical assessment may reveal objective evidence for a discrete illness, such as hypothyroidism, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), polymyalgia rheumatica, or another inflammatory or autoimmune disorder. Such findings do not exclude comorbid fibromyalgia. Indeed, approximately 25% of patients with RA and approximately 50% of patients with SLE also have fibromyalgia, and the provision of optimum care in such cases impels recognition and treatment of both illnesses.

It is important to recognize that treatment of an autoimmune disorder in a patient with comorbid fibromyalgia usually does not improve fibromyalgia symptoms. Recognition and treatment of fibromyalgia in these patients is vitally important to avoid overtreatment with immunosuppressive drugs, which can result when providers falsely ascribe symptoms of fibromyalgia to the autoimmune condition.

Other problems to consider in the differential diagnosis of fibromyalgia include the following:

  • Atypical chest pain
  • Chronic fatigue syndrome
  • Multiple chemical sensitivity
  • Sick building syndrome
  • Vulvodynia
  • Vulvar vestibulitis

Because complaints of chest pain, shortness of breath, and palpitations are common, serious cardiac problems should be considered and may require extensive evaluation. Many symptoms in patients with fibromyalgia can be related to mitral valve prolapse syndrome.

Fibromyalgia Rapid Screening Tool

 A self-administered questionnaire developed by French researchers, the Fibromyalgia Rapid Screening Tool (FiRST) consists of six questions regarding the presence or absence of the following dimensions of fibromyalgia:

  • Widespread pain
  • Fatigue
  • Pain characteristics
  • Nonpainful abnormal sensations
  • Functional somatic symptoms
  • Sleep and cognitive problems

Questions require only a "yes" or "no" answer, with each "yes" answer worth 1 point. A score of 5 or more has the highest sensitivity and specificity for fibromylagia.[98, 99]

Although initially used only to discriminate between fibromyalgia and other painful conditions, FiRST has also proved useful in helping detect concomitant fibromyalgia in patients with inflammatory rheumatic disorders. In a study of patients presenting for treatment of rheumatoid arthritis, spondyloarthritis, or connective tissue disease, and whose pain had persisted for at least 3 months, FiRST screening detected concomitant fibromyalgia in 143 of 586 patients (24.4%).[98, 99]

By comparison, use of American College of Rheumatology 1990 criteria detected only 52 cases of fibromyalgia (8.6%), and assessment by a rheumatologist, 93 cases (15.4%). The study authors conclude that FiRST can be used by rheumatologists in clinical practice to rule out fibromyalgia as a possible explanation for apparent treatment failure in other rheumatologic disorders.[98, 99]

Differential Diagnoses

 

Workup

Approach Considerations

Patients with fibromyalgia do not have characteristic or consistent abnormalities on laboratory testing. However, routine laboratory and imaging studies are important to help rule out diseases with similar manifestations and to assist in diagnosis of certain inflammatory diseases that frequently coexist with fibromyalgia. In addition to complete blood cell (CBC) count and differential count, basic metabolic panel, and urinalysis, the following limited evaluation is reasonable.

  • Thyroid-stimulating hormone: Hypothyroidism shares many clinical features with fibromyalgia, especially diffuse muscle pain and fatigue.

  • 25-Hydroxy vitamin D level: Low levels can cause muscle pain and tenderness.

  • Vitamin B-12 level: Very low levels can cause pain and fatigue.

  • Iron studies, including serum iron, total iron-binding capacity, percent saturation, and serum ferritin: Iron deficiency is very common in fibromyalgia patients and can cause or worsen fatigue, poor sleep, and depressive symptoms.For patients with restless legs syndrome, percent saturation should be maintained above 20% and serum ferritin should be kept above 50 ng/mL.

  • Magnesium: Low levels can lead to muscle spasms, which are common in fibromyalgia patients; magnesium supplementation can also improve symptoms in some fibromyalgia patients; recommended magnesium levels in fibromyalgia patients are at least 2 mEq/L.

The erythrocyte sedimentation rate (ESR) is often recommended as a routine laboratory test in fibromyalgia patients to rule out the presence of inflammatory disorders that may mimic symptoms. The upper limit of normal for the ESR in women is half their age (eg, a level of 40 in an 80-year-old women is normal), and in men is half their age minus 10.

While the ESR is usually normal in patients with fibromyalgia, it is a nonspecific measure of inflammation and mild elevations may not be meaningful. For example, the ESR can be mildly elevated in obese patients. However, a high ESR may be indicative of an inflammatory disorder or occult malignancy that should be thoroughly evaluated.

Routine antinuclear antibody (ANA) or rheumatoid factor (RF) testing in not recommended unless patients have signs or symptoms concerning for systemic lupus erythematosus (SLE) or rheumatoid arthritis. A low-titer positive ANA or RF level is common in the general population, so these findings may be of no clinical significance in a fibromyalgia patient.

Formal sleep studies may be useful in patients whose sleep does not improve with the usual conservative measures (eg, elimination of caffeine, prescription of hypnotics or nighttime tricyclics). These studies can be performed as part of a formal assessment by a neurologist or pulmonologist experienced in sleep disorders.

Serum transferrin saturation and serum ferritin screening can be useful for detecting the unusual cases of hemochromatosis in which patients present with diffuse arthralgias and myalgias. Consider screening with a serum transferrin saturation and a serum ferritin concentration in patients aged 40-60 years, especially those with small-joint arthropathy in the hands and/or calcium pyrophosphate dihydrate deposition disease (CPPD).

The antipolymer antibody assay is a blood test. Antipolymer antibodies are present in approximately 50% of patients with fibromyalgia. This biologic marker may provide conclusive evidence for a subgroup of people with fibromyalgia.

There are no histologic abnormalities seen in fibromyalgia syndrome. Earlier belief that fibromyalgia was associated with inflammation in muscle fascia has been disproved.

Carefully assess all possible causal or perpetuating factors. Investigate psychological and sociocultural factors and identify any specific regional sources of ongoing nociceptive pain (eg, degenerative spondylosis, bursitis).

Self-Report Forms

While waiting to see the physician, the patient, in a few minutes, can complete a simple self-report form[100] that incorporates visual analogue scales for pain and fatigue and a global self-assessment of overall status, along with validated scales for physical and psychological health status such as the following:

  • Modified Health Assessment Questionnaire
  • Fibromyalgia Impact Questionnaire
  • Checklist of current symptoms
  • Scales for helplessness and cognitive performance
  • The Physician Health Questionnaire–9 for depression
  • The Generalized Anxiety Disorder–7 questionnaire for anxiety
  • The Mood Disorder Questionnaire to screen for bipolar disease

Easily adaptable to a busy practice, the use of self-report forms provides information that is invaluable for the psychosocial assessment of pain, both for aiding with diagnosis and monitoring response to therapy.

Psychometric Testing

Psychometric testing includes the following:

  • Minnesota Multiphasic Personality Inventory
  • Social Support Questionnaire
  • Sickness Impact Profile
  • Multidimensional Pain Inventory (MPI)

In multidisciplinary settings, information obtained from these tests is useful for a more comprehensive assessment. For example, subgroups of patients with chronic pain can be identified based on MPI responses that appear to predict response to interdisciplinary therapeutic interventions.

 

Treatment

Approach Considerations

The physician should inform the patient that no cure exists for fibromyalgia but that education, lifestyle changes including regular physical activity, and proper medications can help the individual to regain control and achieve significant improvement.[101] When patients with fibromyalgia fully understand the nature of the disease, they are more likely to comply with treatment and to take an active role in managing the disease.

European League Against Rheumatism (EULAR) 2016 guidelines recommend that initial management of fibromyalgia involve patient education and focus on nonpharmacological therapies. Patients whose condition fails to respond should receive treatment tailored to their specific needs, such as psychological therapies for mood disorders and unhelpful coping strategies, pharmacotherapy for severe pain or sleep disturbance, and/or a multimodal rehabilitation program for severe disability. EULAR noted that most treatments have only a relatively modest effect.[102]

At the initial visit, give patients educational materials about fibromyalgia, including a list of resources, such as Web sites, books, videotapes, newsletters, and brochures, related to the disease. Some authors recommend encouraging patients to attend their local fibromyalgia support group. Provide education and support to the patient's significant family members.

Therapeutic recommendations for fibromyalgia can now be based almost entirely on evidence from well-designed randomized controlled trials. Models of pain behavior that interrelate biologic, cognitive, emotional, and behavioral variables form the basis for cognitive-behavioral and operant-behavioral approaches to pain management. Wood published a useful summary of therapeutic approaches to central sensitivity syndrome (CSS) comorbidities in fibromyalgia.[103]

The first crucial element in the treatment of pain, fatigue, and other diverse symptoms in patients with fibromyalgia is for the clinician to validate the patient’s illness through empathetic listening and acknowledgment that the patient is indeed experiencing pain.[27, 34, 104, 105, 106, 107, 108, 109, 110] Comments such as "it’s all in your mind" or "I cannot find anything wrong with you" only add to the patient's frustration.

Avoid excessive use of physical therapy modalities after minor trauma, excessive activity limitation, and overly liberal work release. Be aware of confounders to recovery, such as pending litigation or compensation claims.

The overall approach for chronic pain in fibromyalgia involves a multifaceted treatment plan that incorporates various adjuvant medicines, aerobic and resistance exercise, and psychological and behavioral approaches to reduce distress and promote self-efficacy and self-management (eg, relaxation training, activity pacing, visual imagery, distraction).

If significant nociceptive pain coexists with the diffuse chronic pain of fibromyalgia, manage it pharmacologically with non-narcotic medications such as antidepressants, anticonvulsants, or muscle relaxers. For associated regional chronic pain syndromes (eg, temporomandibular disorder), referral to an experienced specialist who advocates nonsurgical approaches is recommended.

In a systematic review by Häuser of 1119 patients in 9 randomized controlled trials, multicomponent treatment (at least 1 form of educational or other psychological therapy plus at least 1 form of exercise therapy) yielded short-term benefits for the symptoms of pain, fatigue, depression, and quality of life. They found no evidence that these symptomatic benefits were durable in the long term, but strong evidence suggested that multicomponent therapy conferred a long-term benefit to maintenance of physical fitness.[111]

Poor sleep is virtually universal in fibromyalgia and contributes importantly to pain, depression, and fatigue. Accurate diagnosis and pharmacologic and nonpharmacologic management are essential.[112, 113, 114]

Trigger point injections, acupuncture, chiropractic manipulation, and myofascial release are usually well received by patients and can be beneficial, but results are not long lasting. In addition, patients may not be able to afford long-term therapy since these are sometimes not covered by insurance.

A possible etiologic link between Chiari malformation and fibromyalgia has been suggested. However, no generally accepted evidence indicates that skull surgery for correction of Chiari malformation is of benefit in patients with fibromyalgia, and screening all fibromyalgia patients for Chiari formation is not recommended.

Treatment of Children

Fibromyalgia in children responds to a combination of psychotherapy, exercise, relaxation techniques, and education. Pharmacotherapy is generally not indicated or recommended. Stephens et al conducted a 12-week randomized controlled trial of exercise intervention in children with fibromyalgia and found that both aerobics and qigong yielded benefits in terms of fibromyalgia symptoms, pain, and quality of life in this population. Aerobics were found to be advantageous in several measures.[115]

Juvenile-onset fibromyalgia in adolescents is unlikely to resolve spontaneously. A prospective longitudinal study found that more than 80% of adolescents with juvenile-onset fibromyalgia continued to have symptoms into adulthood. At a mean age of 21 years, approximately half met American College of Rheumatology criteria for adult fibromyalgia.[116, 117]

For more information, see Juvenile Primary Fibromyalgia Syndrome.

Managing Flare-ups

Patients should learn to identify the factors that trigger flare-ups (although, on occasion, no trigger can be identified) and what measures to take to decrease their symptoms.[109] Tips for avoiding and managing flare-ups include the following:

  • Treat infections quickly

  • Avoid changes in diet

  • Exercise as prescribed (ask patients not to increase their routine without consulting a physician)

  • Moderate changes in activity

  • Avoid unnecessary life changes

  • Treat changes in mood or sleep early and aggressively

  • Always start new medications at the lowest possible dose

  • Prepare for unavoidable situations that have caused flare-ups in the past (eg, arrange for an increase in sleep medication or for help with housework and child care)

  • Encourage patients to pace their activities and know their limits

Psychological and Behavioral Therapy

Depression, anxiety, stress, sleep disturbance, pain beliefs and coping strategies, and self-efficacy all are central to the pain experience in many patients and frequently determine the outcome of chronic pain. Depression must be treated aggressively.

Unless psychosocial and behavioral variables are recognized and approached, strictly pharmacologic interventions are of limited benefit. Cognitive-behavioral therapy (CBT) and operant-behavioral therapy (OBT) both effect clinically meaningful improvements in pain intensity and physical impairment in approximately one third to one half of patients with fibromyalgia.[118]

Pretreatment patient characteristics are important predictors of response to nonpharmacologic therapies.[119] High levels of affective distress, poor coping skills, few pain behaviors, and unsolicitous spouse behavior predict response to CBT. Prominent pain behaviors, high levels of physical impairment, catastrophizing, and solicitous spouse behavior predict response to OBT.

Other useful strategies include the following:

  • Relaxation training
  • Activity pacing
  • Guided imagery
  • Written emotional disclosure
  • Distraction strategies
  • Instruction in proper sleep hygiene

Depression in fibromyalgia may be treated with a regimen that includes nonpharmaceutical therapies. Treating depression alone does not cure fibromyalgia. Antidepressants may help, but the clinician also should address other symptoms, such as fatigue or pain. Modifying diet and practicing good sleep hygiene are crucial. Starting a rehabilitation exercise program is important. Behavioral modification techniques and stress management may also be used.

A meta-analysis by Häuser et al of randomized controlled clinical trials found strong evidence that antidepressants reduced pain, fatigue, depressed mood, and sleep disturbances and improved health-related quality of life in patients with fibromyalgia.[120] The study included analysis of tricyclic and tetracyclic antidepressants, selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors in 1427 participants.

In a study of patients with fibromyalgia who were taking an SSRI or an SNRI for comorbid depression, Arnold et al reported that the addition of pregabalin significantly improved pain, anxiety, and depression and improved sleep quality, compared with placebo.[121]

Physical Therapy/Physical Modalities

Because many patients with chronic pain fear that activity will worsen their pain and fatigue, they become deconditioned. In fact, limitations on activity, including work release, should generally be avoided. Graded aerobic exercise (eg, low-impact aerobics, walking, water aerobics, stationary bicycle) is an integral part of optimum treatment in patients with fibromyalgia.

However, exercise programs should start gently and progress gradually to endurance and strength training. Patients should avoid prolonged, overly strenuous physical exercise before reconditioning is established.

The benefits of exercise for patients with fibromyalgia include improvement in subjective and objective measures of pain and in an overall sense of well-being.[110, 122, 123]

In a randomized controlled trial, Munguía-Izquierdo and Legaz-Arrese found that unfit women with severe fibromyalgia symptoms benefitted from aquatic therapy (in a warm pool) 3 times per week for 16 weeks. This approach also resulted in greatly improved adherence to exercise in the study participants.[124]

Qigong, a traditional Chinese practice that is currently characterized as meditative movement, has demonstrated benefit in fibromyalgia. However, the best outcomes require diligent practice. Four trials in 201 subjects who practiced qigong for 30-45 minutes daily over 6-8 weeks found significant and consistent benefits in pain, sleep, impact, and physical and mental function, with benefits maintained at 4-6 months.[125]

Tai chi resulted in greater improvement in fibromyalgia symptom scores than did aerobic exercise, in a randomized controlled trial by Wang et al in 226 patients. Patients randomized to tai chi were enrolled in one of four regimens: supervised sessions once or twice weekly for 12 or 24 weeks. Aerobic exercise comprised supervised sessions twice weekly for 24 weeks. Participants were also advised to perform tai chi or aerobic exercise on their own for 30 minutes daily.[126]

At 24 weeks, the change in fibromyalgia severity score was significantly greater in the four tai chi groups combined than in the aerobic exercise group, but the difference was not clinically meaningful. However, tai chi twice weekly for 24 weeks provided substantial clinical benefit compared with aerobic exercise.[126]

Heat, massage, and other treatments are useful. Diffuse and regional pain is improved by strategies such as saunas, hot baths and showers, hot mud, and massage. However, excessive dependence on administration of physical therapy and modalities by another person may confound the patient's efforts to achieve self-efficacy for pain control.

Encouragement and positive reinforcement can improve compliance. Obesity, poor posture, and overloading activities at work and at home should be addressed.

Pharmacologic Therapy

The treatment of fibromyalgia (FM) should always combine pharmacologic approaches with nonpharmacologic therapy, especially stress management, aerobic exercise, and, in some cases, psychological counseling. Aggressively treat comorbid depression and anxiety.

Patients with fibromyalgia have difficulty tolerating regular doses of most medications and supplements. They are sensitive to medications, and often experience adverse effects. To avoid those problems, use the lowest dose available or perhaps one half to one quarter of the lowest recommended dose.

Many fibromyalgia patients have cognitive dysfunction that limits their ability to understand and process verbal information. Avoid complications and confusion by providing easily understandable written instructions on medication use. Patients should be instructed to consult their physician before starting any over-the-counter (OTC) medications or supplements to avoid potentially harmful drug interactions.

The US Food and Drug Administration (FDA) has approved three drugs for use in fibromyalgia: pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella).[127]  Pregabalin is used to reduce pain and improve sleep. The antidepressants duloxetine and milnacipran, which are used to relieve pain, fatigue, and sleep problems, are generally prescribed at lower doses than for treatment of depression.

In randomized, controlled trials, a significantly higher proportion of patients have experienced > 30% improvement from baseline in pain with pregabalin, duloxetine, or milnacipran, compared with placebo. However, a meta-analysis found no significant difference in the efficacy and tolerability of the three drugs, when given at the recommended doses.[128]

Other anticonvulsants and antidepressants are often used off-label to treat fibromyalgia and there is evidence that many can decrease pain sensitivity. In particular, tricyclic antidepressants (TCAs) have proven benefit but anticholinergic side effects often limit their use. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are useful only for management of coexisting inflammatory processes and are not recommended as first-line therapies. Pharmacologic and nonpharmacologic treatment of poor sleep is crucial for improving the patient's overall sense of well-being.

Anecdotally, dextromethorphan, an N-methyl-D-aspartate (NMDA) receptor antagonist available as an over-the-counter (OTC) antitussive, and naltrexone, an opioid receptor antagonist, have been used to treat fibromyalgia, but placebo-controlled trial data is lacking. Topical capsaicin, obtained from red chili peppers, is essentially free of toxicity, other than mild burning at the site of application, and can be a useful adjunct in combination with gentle massage.

Beta-blockers and/or increased fluid and sodium/potassium intake may benefit a subset of patients with fibromyalgia who have orthostatic hypotension, palpitation, and vasomotor instability. Growth hormone and cytokine therapies are still experimental.[129]

Several medications should be avoided or used carefully. Opioids, hypnotics, anxiolytics, and certain skeletal-muscle relaxants must be used with caution because of the potential for abuse and the risk of worsening fatigue and cognitive dysfunction.

Analgesics

NSAIDs and acetaminophen are of limited efficacy in reducing pain due to fibromyalgia but are important adjuncts for nociceptive pain generators, such as osteoarthritis and degenerative spondylosis.[130]  Topical anesthesia with lidocaine (5% Lidoderm patch) can also be helpful in this regard.

Tramadol, a weak opioid agonist with additional effects on serotonin and norepinephrine receptors, improves pain associated with fibromyalgia. A trial of tramadol may be considered for second-line therapy in patients with moderate to severe pain that is unresponsive to other treatments. [101]  [131]   In a 12-month observational study of opioid use in 1700 adult patients with fibromyalgia, tramadol proved superior to other opioids for improving pain-related interference with daily living, functioning, depression, and insomnia. [132]   

Opioid analgesics with more potency (eg, hydrocodone, oxycodone, fentanyl, morphine), although frequently prescribed in patients with fibromyalgia, appear to be of limited efficacy in most patients with this disorder and are generally not recommended. However, in addition to utility in the treatment of severe nociceptive pain (eg, radicular pain, advanced osteoarthritis of the knee), opioid analgesics may reduce pain, improve quality of life, and occasionally restore function in a patient with fibromyalgia who has severe allodynia and who has not responded to other approaches.

More often, rheumatologists discover that patients with fibromyalgia are already taking very high doses of opioids prescribed by their family physician. The task is then to gradually withdraw opioids, if possible, or perhaps switch therapy to reasonable doses of methadone (eg, 5-10 mg tid). Tapering takes 2-3 weeks; clonidine, 0.2-0.4 mg/day, is helpful for controlling withdrawal symptoms. Remember that opioid-induced hyperalgesia can be a paradoxical complication of high-dose opioid therapy.

Monitoring of patients receiving opioid medications requires frequent reevaluation for efficacy, improvement in daily functioning, and adverse effects during initiation, titration, and maintenance therapy, especially in older patients. The patient should sign a "narcotics contract" that specifies the following:

  • One prescribing physician
  • One dispensing pharmacy
  • Acceptance of no new prescription of opioids if the medication runs out early or is lost or stolen
  • Agreement for random urine testing

Antianxiety agents

Agents of varying durations of action are used frequently for anxiety and panic and as sleep aids (poor sleep is nearly universal in fibromyalgia).[114]  Antianxiety agents are often used in combination with antidepressants and anticonvulsant drugs (both of which also have efficacy for anxiety and insomnia) and include benzodiazepines (eg, alprazolam [Xanax, Niravam; half-life, < 12 h], temazepam [Restoril; half-life, 10-15 h], clonazepam [Klonopin; half-life, 25-100 h], buspirone, trazodone [Oleptro]).

In considering the choice of an anxiolytic drug, remember that many antidepressants also have indications for anxiety. The short-acting nonbenzodiazepine hypnotics zolpidem (Ambien) and zaleplon (Sonata), along with careful attention to optimum sleep hygiene, are useful in the treatment of insomnia but have no effect on pain in fibromyalgia.

An effective combination is zolpidem at bedtime as needed, plus zaleplon (5 mg)—which has a very short half-life—for awakenings in the middle of the night. Patients who do not experience improved sleep with the above and with careful attention to good sleep hygiene should be referred for polysomnography.

Sodium oxybate (Xyrem),[133]  a sedative hypnotic, prolongs stage III/IV restorative sleep, which is essential to feeling rested and refreshed on awakening. Such deep sleep is usually disrupted in patients with fibromyalgia, leaving the patient stiff, sore, and exhausted upon awakening.

Sodium oxybate is currently approved by the FDA for narcolepsy-associated cataplexy and excessive daytime sleepiness. In phase III trials, it has proved effective for relief of pain and fatigue and for sleep quality and patient global improvement.[134]  Because of its potential for abuse, dependence, and diversion (date rape), it is available only through a centralized pharmacy (1-866-997-3688). 

Antidepressants

Low-dose TCAs have proved to have short-term efficacy for pain control, improved sleep, and improved sense of well-being in patients with fibromyalgia. However, adverse anticholinergic effects (eg, dry mouth, drowsiness, weight gain) often limit patient acceptance/tolerance. 

First-generation selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac) and paroxetine (Paxil, Pexeva), improve symptoms in fibromyalgia but the high doses required often cause adverse effects that are poorly tolerated. For this reason, the SSRIs have largely been replaced as a treatment for fibromyalgia by dual serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine (Effexor), desvenlafaxine (Pristiq), levomilnacipran (Fetzima), milnacipran (Savella),[135] or duloxetine (Cymbalta).[136, 137, 138]

Milnacipran has been approved for use in fibromyalgia by the FDA. Duloxetine has been shown to improve pain in fibromyalgia irrespective of comorbid depression[139] and is currently approved by the FDA for pain in fibromyalgia. SNRIs can cause nausea, so they should be taken with food.

A useful combination is a TCA (eg, amitriptyline, nortriptyline) in low dosage at bedtime plus a first-generation SSRI (eg, fluoxetine, paroxetine), which allows for improved efficacy with lower dosing that can help prevent adverse effects.[140] However, patients taking combinations of serotonin-active drugs should be closely monitored for the development of serotonin syndrome,[141] and all patients taking antidepressants should be carefully monitored for worsening depression or the emergence of suicidal thoughts.

While many patients find relief with the above-mentioned antidepressants, some fail to tolerate them. For those patients, antidepressants that work via alternative mechanisms are reasonable options. Animal studies have shown that 5-HT1A receptor activation can induce analgesia.[142, 143]

Currently available drugs with 5-HT1a receptor agonist activity include buspirone (Buspar), vilazodone (Viibryd), and vortioxetine (Brintellix). Buspirone is indicated as an anti-anxiety agent and is also used off-label to augment antidepressant activity, while vilazodone and vortioxetine are both indicated only for the treatment of depression. The most common side effect of both vilazodone and vortioxetine is nausea, so both should be taken with food. All three medications should be started in the morning, since they can cause activation.

Bupropion is structurally different from other antidepressants and its ability to reduce pain is due to its inhibition of the neuronal reuptake of norepinephrine and dopamine.[142, 143] While bupropion is available in an extended release (ER) preparation that allows for once daily dosing, it is activating and can cause or worsen insomnia, so patients should start with immediate-release tablets in the morning with gradual up-titration, or switch to the ER preparation as tolerated. The activating aspect of bupropion can be particularly helpful for fatigue, which is common in fibromyalgia.

Anticonvulsants

Anticonvulsants are useful for chronic pain states, including fibromyalgia and related syndromes and various types of neuropathic pain, and serve as adjunctive medications for disturbed sleep and anxiety. While multiple choices are available, the most studied options for fibromyalgia are gabapentin[144] and pregabalin (Lyrica).[145, 146, 121]  Other options include the following:

  • Tiagabine
  • Levetiracetam 
  • Topiramate 
  • Zonisamide
  • Oxcarbazepine 

Anticonvulsants often cause sedation, so they should be started using low doses at night with gradual up-titration and/or use during the day. One option for improving tolerability and efficacy of anticonvulsants is by combining them with antidepressants. Studies have shown benefits from combining pregabalin with milnacipran[147]  as well as gabapentin with venlafaxine,[148]  and the author's personal experience has shown that other combinations of anticonvulsants and antidepressants can result in augmentation.

Other medications

The selective estrogen receptor modulator raloxifene (Evista), 60 mg every other day, is effective in improving pain, improving fatigue, reducing tender-point count, and improving daily functioning in postmenopausal women with fibromyalgia.[149]  Modafinil (Provigil), approved for narcolepsy and shift-work sleep disorder, 100-200 mg in the morning, can improve fatigue and cognitive disturbances.[150, 151]

A review of medical cannabis for the treatment of fibromyalgia by Habib and Artul concluded that the treatment had a significant favorable effect, with few adverse effects. The study included 26 patients, who used a mean dosage of 26 g per month, for a mean duration of 10.4 months. All the patients reported experiencing a significant improvement in every parameter on the Revised Fibromyalgia Impact Questionnaire after starting medical cannabis treatment, and 13 patients stopped taking any other medications for fibromyalgia. Eight patients experienced very mild adverse effects.[152]

Preliminary data suggest that the synthetic cannabinoid nabilone (Cesamet), in doses escalating from 0.5 mg daily to 1 mg twice daily, improves pain and anxiety in fibromyalgia.[153]  Beta-adrenergic antagonists such as pindolol or propranolol (Inderal), given in low doses at bedtime, can also improve pain and agitation.[154]

Sleep

Poor sleep worsens and perpetuates symptoms, so intensive treatment is indicated. Most patients understand little about the nature of sleep; therefore, instruct them on the basics of sleep and proper sleep hygiene. Providing this education is one of the most helpful interventions.[155]

Dietary and behavioral changes that may be helpful include avoiding caffeine and large evening meals; avoiding alcohol is also helpful. Teach the patient basic relaxation techniques to use before bed. If urinary frequency is problematic, restrict fluids in the evenings.

It may be helpful for the patient to keep a sleep diary for 2 weeks before starting any new medications. The sleep diary provides useful information for choosing medications. The diary should include the following:

  • Medications taken
  • Time at which the patient went to bed
  • Approximate time of falling asleep
  • Number of awakenings
  • Number of times the patient got out of bed
  • General description of how rested the patient felt

Consider comorbid illnesses that may be present, such as restless legs syndrome, periodic limb-movement disorder, or sleep apnea. If these disorders are suspected, a sleep study may be needed.

Medications to improve sleep

If proper education and instruction on sleep hygiene and dietary changes fail to provide adequate improvement in the patient’s sleep, consider using appropriate medications. Sleep problems may be treated with the following:

  • Antidepressants (eg, trazodone, SSRIs, SNRIs, tricyclic antidepressants)
  • Anticonvulsants (eg, clonazepam, gabapentin, tiagabine, pregabalin)
  • Nonbenzodiazepine hypnotics (eg, zolpidem, zaleplon, eszopiclone)
  • Muscle relaxants (eg, cyclobenzaprine, tizanidine)
  • Dopamine agonists (eg, pramipexole, ropinirole)

Sleep-maintenance disorders are more difficult to manage than are sleep-onset problems. In general, antidepressants are most commonly used because of their effect on serotonin. Tricyclic antidepressants have the strongest evidence for efficacy. The criterion standard is amitriptyline, but many patients cannot tolerate this drug.

Trazodone is inexpensive, well-tolerated, and effective. It should be taken at 8 pm. The starting dose is 25 mg, If necessary, the dose can be slowly titrated upward. If the patient is not staying asleep, adding an SSRI may be helpful.

If the patient has concomitant restless legs syndrome or mitral valve prolapse, clonazepam may be the drug of choice. The starting dose is 0.125 or 0.25 mg taken at 8 pm. Titrate the dose to the lowest effective dose.

Tiagabine increases sleep efficiency with a marked increase in slow-wave sleep in healthy elderly patients. Tiagabine titrated from 2 mg to 12 mg may improve sleep maintenance in some patients.

Gabapentin may also aid in sleep maintenance.[144] Evidence suggests that pregabalin, which is approved for use in fibromyalgia by the US Food and Drug Administration (FDA), is effective for improving sleep.[156]

The dopamine agonist pramipexole (Mirapex) is FDA approved for the treatment of moderate to severe restless legs syndrome. This medication may aid in sleep maintenance in patients with fibromyalgia and restless legs syndrome. It is also under investigation as a treatment for fibromyalgia pain.[157, 154]

Dietary Recommendations

Patients with fibromyalgia are generally interested in diet and are influenced heavily by information that promotes complementary and alternative approaches to this disorder; therefore, promote sound general nutrition, appropriate vitamin supplementation, bone health, and weight reduction, if needed.[158, 159]

Physicians must acquaint themselves with the available research on diet and metabolism. Investigate the trend diets and make informed recommendations to each patient on an individual basis. Help patients set attainable goals for dietary modification.

Poor diet worsens the symptoms of fibromyalgia, possibly as a result of impaired glycolysis and carbohydrate metabolism. Dietary changes are essential to improving symptoms in such patients, but they are challenging to achieve.

Although many dietary choices can be made, some may be no healthier than the patient's existing diet. While no dietary or nutritional approach is universally accepted, increasing evidence reveals that some nutritional changes may improve the symptoms of fibromyalgia. Choose an approach that is nutritionally balanced and safe. Help the patient to set reasonable and attainable goals.[158]

Have the patient keep a food journal for 2 weeks. Determine what foods the patient normally eats.

Slowly wean the patient off caffeine, because abruptly stopping caffeine will increase fatigue and pain, headaches, anxiety, and sleep disturbance. Some suggest that all alcohol must be avoided for at least 6 months; however, a patient with stable symptoms may consume no more than two alcoholic drinks a day.

Tobacco use should cease, as should the consumption of chemical-laden foods, aspartame, and monosodium glutamate (MSG). In some, but not all, cases, elimination of aspartame and MSG from the diet has resulted in patient improvement.[160, 161, 162]

Most patients with fibromyalgia consume enormous amounts of carbohydrate-rich foods, suchas refined sugars and white flour, which may contribute to their symptoms. Some suggest a diet high in fresh vegetables, fish, and fiber. Green, leafy, and yellow vegetables are preferred because of their low carbohydrate content.

Choose fruits carefully; some are more glycemic than others. Fruits such as citrus fruits, apples, berries, cantaloupe, and peaches may be preferred.

The rate of carbohydrate absorption decreases if the patient combines starchy food with a food containing fiber or fat. Advise patients to avoid junk foods or processed snack foods, which usually contain large amounts of sugar or salt.

Patients with fibromyalgia produce more damaging free radicals than do healthy people, and they have a reduced antioxidant capacity. Normal cellular respiration produces free radicals that lead to oxidative stress. The antioxidant defense system normally keeps these free radicals in check. Dietary antioxidants consumed in foods are essential to increasing our antioxidant status and maintaining our antioxidant systems.

Vitamins (eg, C, E), minerals (eg, selenium, zinc), and phytochemicals are important dietary antioxidants. Vegetarian diets improve some symptoms, in association with an increased intestinal bacterial profile and increased antioxidant status; however, they may be difficult to maintain long term. A vegetarian diet rich in a variety of fruits, vegetables, and nuts may be of some benefit. Moderation may be the key to long-term compliance.

Deficiency of 25-hydroxyvitamin D is very common in patients with rheumatologic conditions and chronic pain and should be routinely sought. Low levels of vitamin D are not associated with chronic pain, however, and treatment with vitamin D does not reduce pain.

Other dietary measures used in fibromyalgia include the following:

  • Malic acid and magnesium combination
  • Antioxidants
  • Amino acids
  • Herbs and supplements

Consultations

Consultation with a rheumatologist experienced in the diagnosis and treatment of fibromyalgia is appropriate. In addition, a rheumatologist can assist in the differential diagnoses of chronic pain and fatigue syndromes and in the assessment of comorbid rheumatologic disorders.

Referral to a neurologist, dentist, or other specialist may be beneficial in patients with prominent regional pain disorders that coexist with fibromyalgia. Psychological counseling is useful. If a psychiatric disorder is suggested, consult a psychiatrist.

Long-Term Monitoring

Follow-up care in patients with fibromyalgia is greatly facilitated by the following:

  • Maintaining rapport

  • Encouraging compliance with exercise regimens

  • Paying attention to current psychological and physical stressors

  • Obtaining ongoing self-report questionnaire information that provides semiquantitative data concerning the patient's function, levels of pain and fatigue, and global self-assessment of how the patient is doing

Integrative Medicine

Integrative medicine (complementary and altenative medicine [CAM]) is popular in patients with fibromyalgia, in part due to medical skepticism (ie, doubt in the ability of conventional medical care to appreciably alter health status).[163] Many physicians are ignorant of, if not overtly hostile toward, integrative medicine, and patients are often reluctant to inform their physician about their use of it. This can be dangerous because of unsuspected drug-to-drug interactions.

A practical approach includes the following:

  • Inquire about integrative medicine usage.
  • Refrain from expressing negative opinions if a particular integrative treatment is relatively inexpensive and appears to be safe.
  • Encourage whatever works in the context of the power of the placebo effect and promotion of self-efficacy for pain control.
 

Guidelines

Guidelines Summary

Guidelines on fibromyalgia have been issued by the following organizations:

  • Japan Pediatric Society [164]
  • German Pain Society (three guidelines: pediatric fibromyalgia, [165] drug therapy, [166] and multimodal therapy [167] )
  • European League Against Rheumatism (EULAR) [102]
  • Canadian Pain Society and Canadian Rheumatology Association [168]  
  • Association of the Scientific Medical Societies in Germany [169]
  • Israeli Rheumatology Association [170]

The Japanese and German guidelines on juvenile fibromyalgia recommend exclusively using nonpharmacologic treatments in pediatric patients. While the guidelines on adult fibromyalgia differ in specifics, all of them stress the importance of individualized treatment consisting of both nonpharmacologic (specifically patient education, aerobic exercise, and psychologic counseling if necessary) and pharmacologic therapies.  

 

 

Medication

Medication Summary

Medication use in patients with fibromyalgia should always be combined with nonpharmacologic therapy. Japanese and German guidelines recommend that pediatric patients receive nonpharmacologic treatment exclusively.[164, 165]

The US Food and Drug Administration (FDA) has approved three drugs for use in fibromyalgia: pregabalin (Lyrica), duloxetine (Cymbalta), and milnacipran (Savella).[127] Pregabalin is used to reduce pain and improve sleep. The antidepressants duloxetine and milnacipran, which are used to relieve pain, fatigue, and sleep problems, are generally used at lower doses than for treatment of depression.

Other anticonvulsants and antidepressants are often used off-label to treat fibromyalgia and there is evidence that many can decrease pain sensitivity. Corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) are useful only for management of coexisting inflammatory processes and are not recommended as first-line therapies. Pharmacologic and nonpharmacologic treatment of poor sleep is crucial for improving the patient's overall sense of well-being.

Several medications should be avoided or used carefully. Opioids, hypnotics, anxiolytics, and certain skeletal-muscle relaxants must be used with caution because of the potential for abuse and the risk of worsening fatigue and cognitive dysfunction.

Analgesics

Class Summary

Pain control is essential to quality patient care. Analgesics ensure patient comfort, promote pulmonary toilet, and have sedating properties, which are beneficial for patients who experience pain.

Tramadol (Ultram, Ryzolt, Rybix)

Tramadol is a centrally acting analgesic indicated for moderately severe pain. This agent inhibits ascending pain pathways, altering the perception of and response to pain. Tramadol also inhibits reuptake of norepinephrine and serotonin.

Antianxiety Agents

Class Summary

Agents of varying durations of action are used frequently for anxiety and panic and as sleep aids (poor sleep is nearly universal in fibromyalgia).[114] Antianxiety agents are often used in combination with antidepressants and anticonvulsant drugs.

Alprazolam (Xanax, Niravam)

Alprazolam binds receptors at several sites within the central nervous system (CNS), including the limbic system and reticular formation. Effects may be mediated through the gamma-aminobutyric acid (GABA) receptor system. It has a short half-life (< 12 h).

Clonazepam (Klonopin)

Clonazepam suppresses muscle contractions by facilitating inhibitory GABA neurotransmission and other inhibitory transmitters. It has a long half-life (25-100 h).

Zolpidem (Ambien)

Zolpidem is indicated for insomnia. It is structurally dissimilar to benzodiazepines but similar in activity, with the exception of having reduced effects on skeletal muscle and seizure threshold.

Zaleplon (Sonata)

Zaleplon interacts selectively with the GABA receptor. It binds to the omega-1 receptor situated on the alpha subunit of the GABA-A receptor complex in the brain.

Trazodone (Oleptro)

Trazodone is useful as an alternative to improve sleep and to treat anxiety and panic disorders that may be associated with fibromyalgia. It is an antagonist at the 5-HT2 receptor and inhibits the reuptake of 5-HT. It also has negligible affinity for cholinergic and histaminergic receptors. In animals, trazodone selectively inhibits serotonin uptake by brain synaptosomes and potentiates behavioral changes induced by the serotonin precursor 5-hydroxytryptophan.

Buspirone

This agent is a 5-HT1 agonist with serotonergic neurotransmission and some dopaminergic effects in the CNS. It has an anxiolytic effect but may take as long as 2-3 wk for full efficacy.

Temazepam (Restoril)

Temazepam is indicated for insomnia. It depresses all levels of the CNS (eg, limbic and reticular formation), possibly by increasing activity of GABA.

Sodium Oxybate (Xyrem)

Sodium oxybate acts as an inhibitory chemical transmitter in the brain through specific receptors for gamma hydroxybutyrate (GHB) and GABA.

Skeletal Muscle Relaxants

Class Summary

These agents have modest short-term benefit as adjunctive therapy for nociceptive pain associated with muscle strains and, used intermittently, for diffuse and certain regional chronic pain syndromes. With the exception of cyclobenzaprine, long-term improvement over placebo has not been established for muscle relaxants in fibromyalgia, and they are not recommended. Cyclobenzaprine can be helpful for sleep and pain control as a single nighttime dose in combination with an anxiolytic/hypnotic agent.

Cyclobenzaprine (Flexeril, Flexmid)

Cyclobenzaprine acts centrally and reduces motor activity of tonic somatic origins, influencing both alpha and gamma motor neurons. This agent is structurally related to tricyclic antidepressants (TCAs) and, thus, carries some of the same liabilities.

Antidepressants

Class Summary

Low-dose TCAs have proven to have short-term efficacy for pain control, improved sleep, and improved sense of well-being in patients with fibromyalgia. However, adverse effects (eg, dry mouth, drowsiness, weight gain) limit patient acceptance.

Selective serotonin reuptake inhibitors (SSRIs), including fluoxetine (Prozac), citalopram (Celexa), escitalopram (Lexapro), fluvoxamine, paroxetine (Paxil, Pexeva), and sertraline (Zoloft), improve symptoms in fibromyalgia but have largely been replaced as a treatment for pain by dual serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine (Effexor), desvenlafaxine (Pristiq), milnacipram (Savella),[135] or duloxetine (Cymbalta).[136, 137, 138]

Milnacipram has been approved for use in fibromyalgia by the FDA. Duloxetine has been shown to improve pain in fibromyalgia irrespective of comorbid depression[139] and is currently approved by the FDA for pain in fibromyalgia.

A useful combination is a TCA (eg, amitriptyline or cyclobenzaprine in low dosage at bedtime) and an SNRI. Patients taking either SSRIs or SNRIs should be carefully monitored for worsening depression or emergence of suicidal thoughts.

Amitriptyline

Amitriptyline inhibits the reuptake of serotonin and/or norepinephrine at presynaptic neuronal membrane, which increases their concentration in the CNS.

Duloxetine (Cymbalta)

Duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake. Its antidepressive action is theorized to be due to serotonergic and noradrenergic potentiation in CNS.

Milnacipran (Savella)

Milnacipran is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Its exact mechanism of central pain inhibitory action and ability to improve symptoms of fibromyalgia remain unknown. It is indicated for fibromyalgia.

Venlafaxine (Effexor, Effexor XR)

Vanlafaxine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake.

Desvenlafaxine (Pristiq)

Desvenlafaxine inhibits neuronal serotonin and norepinephrine reuptake.

Levomilnacipran (Fetzima)

A potent inhibitor of neuronal serotonin and norepinephrine reuptake, levomilnacipran inhibits norepinephrine uptake with ~3-fold higher potency in vitro than serotonin, without directly affecting the uptake of dopamine or other neurotransmitters

Anticonvulsants

Class Summary

These agents are useful for chronic pain states, including fibromyalgia and related syndromes and various types of neuropathic pain, and serve as adjunctive medications for disturbed sleep and depression. Multiple choices are available, including gabapentin (Neurontin),[144] tiagabine (Gabitril), and the more recently released pregabalin (Lyrica),[145, 171, 146, 121] which has been particularly well-studied in fibromyalgia.

Pregabalin (Lyrica)

Pregabalin is a structural derivative of GABA. Its mechanism of action is unknown. Pregabalin binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, it reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. This agent is FDA approved for neuropathic pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, or fibromyalgia. It is also indicated as adjunctive therapy in partial-onset seizures.

Gabapentin (Neurontin)

Gabapentin is effective for pain and associated depressed mood and anxiety. It has anticonvulsant properties and antineuralgic effects; however, its exact mechanism of action is unknown. Gabapentin is structurally related to GABA but does not interact with GABA receptors. Titration to effect can take place over several days to weeks.

Tiagabine (Gabitril)

This drug enhances GABA activity by inhibiting uptake in neurons and astrocytes.

Alpha2 Agonists

Class Summary

Clonidine is helpful in controlling withdrawal symptoms during tapering of opioids, which may take 2-3 weeks or longer.

Clonidine (Catapres, Kapvay)

Clonidine stimulates alpha-2 adrenoreceptors in the brain stem, activating an inhibitory neuron, which, in turn, results in reduced sympathetic outflow. These effects result in a decrease in vasomotor tone and heart rate.

 

Questions & Answers

Overview

What is fibromyalgia?

What are the signs and symptoms of fibromyalgia?

What are the diagnostic considerations in fibromyalgia?

Which lab tests are used in the workup of fibromyalgia?

Which patient questionnaires are used in the diagnosis of fibromyalgia?

Which psychometric tests are used in the diagnosis of fibromyalgia?

How is fibromyalgia managed?

Which nonpharmacologic techniques are used in the management of fibromyalgia?

Which medications are used in the treatment of fibromyalgia?

Which medications may help sleep problems in fibromyalgia that does not respond to other treatments?

Which OTC drugs are used to treat fibromyalgia?

How is fibromyalgia characterized?

Which syndromes overlap with fibromyalgia?

What is required to successfully care for patients with fibromyalgia?

What is involved in the management of fibromyalgia?

What is the historical background on fibromyalgia?

How often is fibromyalgia correctly diagnosed?

What is the nomenclature for fibromyalgia?

What is the pathophysiology of fibromyalgia?

How is pain defined in the pathophysiology of fibromyalgia?

Which factors influence how pain is perceived in patients with fibromyalgia?

What is the role of negative emotions in the intensity of pain experienced in fibromyalgia?

What are the biological elements in the pathophysiology of pain in fibromyalgia?

Where does pain derive from in the pathophysiology of fibromyalgia?

What abnormalities in pain processing have been demonstrated in fibromyalgia?

What is the role of single-nucleotide polymorphism (SNP) haplotypes in the pathophysiology of pain in fibromyalgia?

How do drugs reduce pain in fibromyalgia?

What is the role of biochemical changes in the CNS in the pathophysiology of fibromyalgia?

Why does increased pain sensitivity occur in women with fibromyalgia?

Which central processes play a role in the pathophysiology of fibromyalgia?

What is the role of serotonin in the pathophysiology of fibromyalgia?

What is the role of substance P in the pathophysiology of fibromyalgia?

What is the role of adenosine triphosphate (ATP) in the pathophysiology of fibromyalgia?

What is the importance of the hypothalamic-pituitary-adrenal (HPA) axis in the pathophysiology of fibromyalgia?

Which neuroendocrine abnormalities are associated with hypothalamic-pituitary-adrenal (HPA) axis dysfunction in fibromyalgia?

What is the role of serotonin in the hypothalamic-pituitary-adrenal (HPA) axis dysfunction in fibromyalgia?

What is the role of growth hormone in the pathophysiology of fibromyalgia?

What is the role of the nerve growth factor in the pathophysiology of fibromyalgia?

What is the cognitive impact of fibromyalgia?

What does fMRI reveal about the pathophysiology of fibromyalgia?

What causes cognitive dysfunction in fibromyalgia?

How is sleep dysfunction characterized in patients with fibromyalgia?

What are the basic patterns of normal sleep relative to understanding abnormal sleep architecture in fibromyalgia?

What occurs during the REM stage of sleep relative to understanding abnormal sleep patterns in fibromyalgia?

What is the role of altered NREM sleep in the pathophysiology of fibromyalgia?

What is the role of sleep dysfunction in the pathophysiology of fibromyalgia?

Which primary sleep disorders may affect sleep quality in patients with fibromyalgia?

What causes fibromyalgia?

What biologic variables contribute to the development of fibromyalgia?

What is the role of genetics in the development of fibromyalgia?

What are the sex-related effects in fibromyalgia?

What is the role of abnormal sleep in the development of fibromyalgia?

What is the role of trauma in the development of fibromyalgia?

What is the role of stress response system dysregulation in the etiology of fibromyalgia?

What other variables play a role in the etiology of fibromyalgia?

Which variables have an uncertain relationship to the development of fibromyalgia?

Which psychological variables are implicated in the etiology of fibromyalgia?

What is the role of meaning structures in the etiology of fibromyalgia?

What are the consequences of negative beliefs associated with fibromyalgia?

What is the role of negative beliefs in the etiology of fibromyalgia?

What is the role of hypervigilance in the etiology of fibromyalgia?

What is the role of perceived self-efficacy in the etiology of fibromyalgia?

Which areas of the brain are involved in pain perception in fibromyalgia?

Which psychiatric comorbidities are associated with fibromyalgia?

How do pressure-pain thresholds correlate with psychological comorbidity in patients with fibromyalgia?

What is the role of depression in the etiology of fibromyalgia?

What is the role of personality traits in the etiology of fibromyalgia?

What is the role of pain behaviors in the etiology of fibromyalgia?

What is the role of environmental and sociocultural variables in the etiology of fibromyalgia?

What is the role of developmental variables in the etiology of fibromyalgia?

What is the role of family and work variables in the etiology of fibromyalgia?

What sociocultural factors play a role in the etiology of fibromyalgia?

What is the prevalence of fibromyalgia?

What is the prevalence of fibromyalgia in the US?

What is the international prevalence of fibromyalgia?

What are the race-related differences in the incidence of fibromyalgia?

What are the sex-related differences in the incidence of fibromyalgia?

Which mechanisms may contribute to increased pain sensitivity in women with fibromyalgia?

What are the age-related differences in the incidence of fibromyalgia?

What is the prognosis of fibromyalgia?

How are patients with fibromyalgia categorized?

Which patient characteristics are associated with a guarded prognosis in fibromyalgia?

What is the prognosis of fibromyalgia without proper and diagnosis and treatment?

How does fibromyalgia affect the quality of social and economic life?

What are the risks of death from suicide in patients with fibromyalgia?

What is involved in patient education for fibromyalgia?

What educational resources are available on fibromyalgia?

Presentation

How is fibromyalgia characterized and diagnosed?

What are the diagnostic criteria for fibromyalgia?

Which scales are used in the ACR diagnostic criteria for fibromyalgia?

What is the widespread pain index (WPI) in the diagnostic criteria for fibromyalgia?

What is the symptom severity (SS) scale in the diagnostic criteria for fibromyalgia?

Which conditions meet the criteria for a definitive diagnosis of fibromyalgia?

How is symptom severity determined in fibromyalgia?

What does a self-administered patient questionnaire on fibromyalgia assess?

How are self-administered patient questionnaires on fibromyalgia scored?

What are the goals of the physical exam for fibromyalgia?

What is the manual tender-point survey (MTPS) method in the physical exam of fibromyalgia?

How is the manual tender-point survey (MTPS) performed in the physical exam for fibromyalgia?

How is the manual tender-point survey (MTPS) scored in the physical exam of fibromyalgia?

What are the standard fibromyalgia tender points?

What are the specific locations of tender points on the anterior body in fibromyalgia?

What are the specific locations of tender points on the posterior body in fibromyalgia?

What are the benefits of using pressure algometry in fibromyalgia?

What evaluations other than tender point assessment are indicated in the physical exam for fibromyalgia?

What are the potential complications of fibromyalgia?

DDX

What are the diagnostic considerations for fibromyalgia?

What other problems should be considered in the differential diagnosis of fibromyalgia?

What is the Fibromyalgia Rapid Screening Tool (FiRST)?

What are the differential diagnoses for Fibromyalgia?

Workup

What are the approach considerations in the workup of fibromyalgia?

When is erythrocyte sedimentation rate (ESR) testing indicated in the workup of fibromyalgia?

When is antinuclear antibody (ANA) or rheumatoid factor (RF) testing indicated in the workup of fibromyalgia?

What are the benefits of formal sleep studies in the workup of fibromyalgia?

What are the benefits of serum transferrin saturation and serum ferritin screening in the workup of fibromyalgia?

How is the antipolymer antibody assay used in the workup of fibromyalgia?

What is the role of histology in the workup of fibromyalgia?

What is the recommended approach to the workup for fibromyalgia?

What are the benefits of self-assessments in the workup of fibromyalgia?

What is involved in psychometric testing in the workup of fibromyalgia?

Treatment

How should physicians inform patients with fibromyalgia regarding treatment?

What are the EULAR guidelines for the initial management of fibromyalgia?

What are the therapeutic recommendations for the management of fibromyalgia?

How should physicians approach the discussion of a fibromyalgia diagnosis with a patient?

What should be avoided in the treatment of fibromyalgia?

How is chronic pain managed in fibromyalgia?

When is medication indicated in the management of fibromyalgia?

What is the efficacy of multicomponent treatment of fibromyalgia?

How does poor sleep affect fibromyalgia?

What medical therapies can be effective for pain management in fibromyalgia?

What is the relationship between Chiari malformation and fibromyalgia?

What is involved in the treatment of children with fibromyalgia?

What are some tips for avoiding and managing flare-ups in fibromyalgia?

What is involved in psychological and behavioral therapy for the treatment of fibromyalgia?

What are the treatment options for depression in fibromyalgia?

What is the role of physical exercise in the management of fibromyalgia?

What are the benefits of exercise in patients with fibromyalgia?

Which physical modalities in addition to exercise may be beneficial to patients with fibromyalgia?

What is involved in the treatment of fibromyalgia?

What are considerations regarding pharmacologic therapy for fibromyalgia?

Which drugs have been approved for use in fibromyalgia?

How effective is drug treatment for fibromyalgia?

What pharmacologic options are available for fibromyalgia?

Which medications should be avoided or used with caution in the treatment of fibromyalgia?

How effective are analgesics in the treatment of fibromyalgia?

How are patients with fibromyalgia tapered off opioid medications?

Which antianxiety drugs are used in the treatment of fibromyalgia?

What are the benefits of antidepressants in the treatment of fibromyalgia?

Which antidepressants have been approved for use in fibromyalgia?

Which combination of antidepressants are effective for the treatment of fibromyalgia?

Which antidepressants with 5-HT1 receptor agonist activity are available for the treatment of fibromyalgia?

How are anticonvulsants used for the treatment of fibromyalgia?

What second-line medications are used in the treatment of fibromyalgia?

How are sleep problems addressed in the management of fibromyalgia?

Which medications are available to improve sleep in patients with fibromyalgia?

What dietary recommendations are indicated in the management of fibromyalgia?

How does a poor diet affect patients with fibromyalgia?

What are the dietary recommendations for patients with fibromyalgia?

What is the role of dietary antioxidants in the treatment of fibromyalgia?

What other dietary measures are used in fibromyalgia?

Which specialist consultations are indicated in the treatment of fibromyalgia?

What is involved in the follow-up care of patients with fibromyalgia?

What is the role of integrative medicine in the treatment of fibromyalgia?

Guidelines

What are the guidelines on the treatment of fibromyalgia?

Medications

What are the goals of drug treatment for fibromyalgia?

Which medications in the drug class Analgesics are used in the treatment of Fibromyalgia?

Which medications in the drug class Antianxiety Agents are used in the treatment of Fibromyalgia?

Which medications in the drug class Skeletal Muscle Relaxants are used in the treatment of Fibromyalgia?

Which medications in the drug class Antidepressants are used in the treatment of Fibromyalgia?

Which medications in the drug class Anticonvulsants are used in the treatment of Fibromyalgia?

Which medications in the drug class Alpha2 Agonists are used in the treatment of Fibromyalgia?