Fibromyalgia Syndrome: A Guide for the Perplexed

February 1, 2009
Dennis C. Turk, PhD

Volume 26, Issue 2

Fibromyalgia syndrome is a chronic condition that consists of a pervasive set of unexplained physical symptoms with widespread pain (involving at least 3 of 4 body quadrants and axials) of at least 3 months duration and point tenderness at 9 bilateral locations (Figure) as the cardinal features.1 Patients with FM report a set of symptoms, functional limitations, and psychological dysfunctions, including persistent fatigue (78.2%), sleep disturbance (75.6%), feelings of stiffness (76.2%), headaches (54.3%), depression and anxiety (44.9%), and irritable bowel disorders (35.7%).1 Patients also report cognitive impairment and general malaise, “fibro fog.” This pattern of symptoms has been reported under various names (such as tension myalgia, psychogenic rheumatism, and fibro­myositis) since the early 19th century.

[Editor's Note: This article was originally presented as an independent educational activity under the direction of CME LLC. The testing period to receive CME credits has expired. The article is now presented here for your reference. CME LLC does not review this content to ensure its continued relevance.]

Educational Objectives-After reading this article, you will be familiar with:

• The symptoms that constitute fibromyalgia.
• The proposed pathophysiology of fibromyalgia.
• The affective, behavioral, and cognitive factors that contribute to fibromyalgia.
• The available options for treating symptoms of fibromyalgia.

Who will benefit from reading this article?
Psychiatrists, neurologists, primary care physicians, geriatricians, nurse practitioners, and other health care professionals. Continuing medical education credit is available for most specialists. To determine whether this article meets the continuing education requirements of your specialty, please contact your state licensing board.

Fibromyalgia syndrome (FM) is a chronic condition that consists of a pervasive set of unexplained physical symptoms with widespread pain (involving at least 3 of 4 body quadrants and axials) of at least 3 months duration and point tenderness at 9 bilateral locations (Figure) as the cardinal features.1 Patients with FM report a set of symptoms, functional limitations, and psychological dysfunctions, including persistent fatigue (78.2%), sleep disturbance (75.6%), feelings of stiffness (76.2%), headaches (54.3%), depression and anxiety (44.9%), and irritable bowel disorders (35.7%).1 Patients also report cognitive impairment and general malaise, “fibro fog.” This pattern of symptoms has been reported under various names (such as tension myalgia, psychogenic rheumatism, and fibro­myositis) since the early 19th century.

In the United States, there are an estimated 3 to 6 million people who have FM.2 The condition is more common in women: the ratio of women to men who seek treatment is approximately 7 to 1. Community samples are closer to 3 to 1. The number of diagnoses of FM tends to increase from the second through the sixth decade of life.

FM may have an insidious onset without an identifiable cause, may develop following a flu-like illness, or may rapidly develop following a physical trauma (such as a motor vehicle accident).3 The natural course of FM symptoms seems to be chronic and nonprogressive; symptoms fluctuate in severity and are often exacerbated by stress. Patients with FM report a diminished sense of physical well-being; they have significant health concerns and are high users of the health care system.4

PATHOPHYSIOLOGY

The pathophysiological mechanisms that underlie FM are poorly understood. There is no accepted biological marker, and the results of radiographic and laboratory studies tend to be normal. A number of different peripheral and central mechanism have been proposed, which may not be mutually exclusive.

Peripheral: muscular involvement
The earliest efforts to understand FM assumed that reported pain was caused by abnormalities related to the muscle anatomy, physiological processes (eg, oxygen availability and depletion), or tension myalgia. Research suggests that the involvement of the peripheral pathology is, however, nonspecific, cannot account for the diverse symptoms, and is unlikely to be primary.5

Central: neurotransmitter dysregulation
Various neurochemical factors have been studied in patients with FM. These include dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and serotonin imbalance.4,6 However, no definitive neurochemical features have been consistently identified. What is most notable in studies that have examined various neuroendocrine substances in FM is the large intragroup variability observed in the substances tested. Thus, although persons with FM may differ statistically from those without FM, the large individual differences within patients with FM make it difficult to interpret the results.

Stress
A number of investigators have proposed that chronic emotional stress plays a causal role in FM.7 This hypothesis is consistent with evidence that people with FM have high rates of disorders characterized by chronic stress, including depression, posttraumatic stress disorder, and other anxiety disorders.8,9 The importance of stress is supported by research that indicates that high proportions (more than 75%) of people with FM report that stress aggravates the symptoms.10 Moreover, a significant percentage of people with FM report that the symptoms began following physical or emotional stress.10

Longitudinal data also support the hypothesis that psychological dysfunction and distress increase the risk for FM.11 On the other hand, there is little doubt that living with FM and its associated symptoms serves as an ongoing stressor. Thus, high levels of emotional distress among people with FM might be construed as a consequence of the difficulties they face in adapting to the condition.

Investigators of the HPA axis function have generally found that people with FM are in a state of physiological exhaustion or “burnout.” Studies of autonomic nervous system function report blunting of phasic responses to acute stressors but argue that these responses are by-products of chronic hyperarousal.12 Therefore, stress may be both a causal and maintaining factor.

Hypervigilance
Research investigating sensory processing in FM has consistently demonstrated that patients have a lower pain threshold than do age- and sex-matched healthy persons.13 Based on these results, a hypervigilance model of FM in which increased attention to somatosensory stimuli is a predisposing factor for developing the syndrome has been proposed.14 Vigilance to sensory information in FM may not be limited to pain. Some data indicate that patients with FM are more sensitive to cold, noise, and environmental irritants.15

Dysfunction of sensory modulation
There is growing agreement that FM is characterized by an augmentation of central processing of sensory stimuli, to the extent that there is disordered pain regulation and a lowered threshold for noxious stimulation of unknown cause.5 This might account for the widespread pain and myriad symptoms.

There is increasing evidence for a genetic predisposition for FM, including the possible role of polymorphisms in the serotonergic, dopaminergic, and catecholaminergic systems.16 The abnormal sensitivity to pain may be the result of heightened generalized sensitivity from pathological nociceptive processing within the CNS-central sensitization.17 The genetic predisposition may be expressed following instigation by a physical or emotional trauma-a diathesis-stress model.18

AFFECTIVE FACTORS

There has been ongoing debate in the FM literature about whether psychological factors are causal or a reaction to the presence of a large number of symptoms with unknown cause and no cure. Some have suggested that FM is one of a set of depression-spectrum disorders.19 Others note that the lifetime prevalence of psychiatric disorders is high in FM, yet not all patients have a significant psychiatric history.20-22 Anxiety, depression, and anger have each been shown to be important in the etiology, maintenance, and exacerbation of symptoms, adaptation, and response to treatments by patients with FM.

Anxiety
A large, multicenter study reported that between 44% and 51% of patients with FM acknowledged that they were anxious.22 A recent epidemiological study found that patients with FM were 4 times more likely to have an anxiety-related claim than health care users who did not have FM.23

Depression
The prevalence of depression among patients with FM has been reported to be as high as 70% in clinic samples.2,24 In community samples, the prevalence exceeds 30%.25 Whether depression causes pain or the converse has been of some theoretical interest. However, practically, once a person receives a diagnosis of FM, it no longer matters which is the cause and which is the consequence-pain or depression. Both need to be treated.

Anger
Chronic angry emotional reactions are maladaptive because they lead to pervasive interpersonal disruption and conflict with significant others, including health care providers. Such reactions also alter descending and central pain modulation systems and can lead to chronic sympathetic activation that may exacerbate symptoms.26 Furthermore, anger has been associated with more severe pain in patients with FM.27,28 In an anonymous Internet survey, more than 85% of people with FM acknowledged some degree of anger.10

Be aware of the significant role that negative mood plays in patients with FM because it is likely to influence a patient’s motivation and willingness to adhere to treatment recommendations. Clinicians who treat patients with FM must focus on mood states, as well as physical pathology and somatic fac­tors. Patients with FM cannot be treated successfully without attention to their emotional state along with behavioral, cognitive, and physical contributors.

BEHAVIORAL FACTORS

Operant conditioning is an important principle of behavioral learning that helps us understand acquisition of adaptive as well as dysfunctional behaviors associated with symptoms. Its cardinal premise is that if the consequence of the given behavior is rewarding, the likelihood of its occurrence increases; if the consequence is aversive, the likelihood of its occurrence decreases (Table 1).

Behaviors associated with symptoms, such as distorted ambulation and rubbing painful body parts, are labeled “pain or symptom behaviors.” When a person is exposed to a stimulus that causes tissue damage, the immediate behavior is withdrawal in an attempt to escape from noxious sensations. Such symptom behaviors are adaptive and appropriate. However, Fordyce29 reported that these these behaviors are subjected to the principles of operant conditioning and may not be adaptive in the long term. For example, such symptom behaviors as avoidance of activity effectively prevent or withdraw aversive results (eg, pain, fatigue); these effects increase the likelihood that the behaviors will be repeated and that they may evolve into a chronic problem.

Consider one of my patients, a woman with FM who reported that when her symptoms flared up, she lay down to rest. She noted, and her husband confirmed, that his typical responses were to bring her some medication, to take the children out to the park to give her some quiet time, and to assume some household chores. Such responses positively rewarded my patient’s behavior so that she increased the amount of time she spent reclining, despite no change in her symptoms. In other words, her symptom behaviors were being maintained by the learned positive consequences-attention and avoidance of household chores.

People with FM may not be consciously communicating their symptoms to obtain attention or to avoid undesirable activities. In my patient’s case, her behaviors were likely to have been shaped gradually in a way that neither she nor her husband recognized.

Health care professionals may also positively and inadvertently reinforce symptoms by their responses. The physician who prescribes medication when the patient complains of symptoms may be reinforcing the symptom reporting. That is, the patient learns that his or her behavior elicits a response from the physician, and if the response provides some relief, the patient may learn to report pain to obtain the desired outcome.

This is the case when pain medication is prescribed on a take-as-needed (PRN) basis. With PRN dosing, the patient must recognize that the pain has increased before she can take the medication. If the medication provides some reduction of symptoms then the attention to and self-rating of symptoms may be maintained by the anticipated outcome of relief.30,31 The combination of reinforced pain behaviors and neglected well behaviors is common in patients who have FM (Table 1).

COGNITIVE FACTORS

Much research has been directed toward identifying cognitive factors that contribute to pain and disability.31,32 These studies have consistently demonstrated that patients’ attitudes, beliefs, and expectancies about their plight, themselves, their coping resources, the future, and their health care system affect their reports of pain, activity, disability, and response to treatment.33-35

Clearly, it is essential for people who have chronic pain to develop adaptive beliefs about impairment, pain, suffering, and disability, and to de-emphasize the role of the symptoms in their everyday functioning. In fact, results from numerous treatment outcome studies have shown that changes in pain level do not parallel changes in other variables of interest, including a patient’s activity level, medication use, return to work, rated ability to cope with pain, and pursuit of further treatment.36

Self-efficacy expectations-a personal conviction that one can successfully execute a course of action to produce a desired outcome in a given situation-appear to be particularly important. Lower self-efficacy beliefs are related to greater pain, disability, and depressive mood in FM.32,37 Patients with relatively low self-efficacy beliefs who underwent physical training and exercise had lower posttreatment physical activity than those with higher self-efficacy beliefs. Furthermore, improvements in self-efficacy beliefs during treatment were associated with lower tender point scores and pain intensity.37

TREATMENT

There is no known cure for FM, and treatments are most often focused on relieving pain and on improving sleep and physical and emotional functioning. The lack of identification of a specific mechanism for FM has resulted in a wide array of interventions. Those with the greatest efficacy are briefly reviewed below.

Medications
Oral medications are often prescribed for patients with FM, but the effectiveness of any specific agent is not uniform. Various trials have investigated the efficacy of many pharmacological prep­arations. Table 2 outlines drug classes that have been evaluated as potential treatments for FM.

Although many studies indicate that treatments provide statistically significant effects, absolute improvements in the most recently investigated drugs were often modest, averaging about 34%. For example, a significant clinical response for antidepressant medication showed a 25% to 37% reduction in symptoms, and overall efficacy was modest.38,39 Moreover, the clinical trials included in the meta-analyses of antidepressants were mostly of short duration (6 to 12 weeks). The longest study of tricyclic medications followed 208 patients treated with amitriptyline, cycloben­z­aprine, or placebo for 6 months. Initial improvements were not sustained at 26 weeks.40

Medication that targets key symptoms (fatigue, sleep, and depression) should be considered as a component of FM treatment.2,41,42Table 3 provides information about medications studied in randomized controlled trials with data about benefit, mode of action, dosage, and adverse effects. Providing symptomatic relief may enable patients to sleep better and to engage in physical activities. In particular, antidepressant medication may work because it not only addresses depression itself but may also help improve sleep quality or reduce pain severity, even at dosages lower than those used for clinical depression.

Low-dose tricyclic antidepressants (TCAs) and selective serotonin-norepinephrine reuptake inhibitors (SNRIs) can be effective in reducing pain in FM. The SSRIs have a less consistent positive outcome. TCAs and SNRIs may reduce pain independent of their antidepressant actions as a result of their serotonin- and norepinephrine-mediated effects on the descending pain-inhibitory pathways in the brain and spinal cord.

Recently, the antiepileptic drug pregabalin that acts by disrupting neuronal signaling by binding to the alpha-2-delta subunit of voltage-gated calcium channels in the CNS has been approved by the FDA for the treatment of FM. Pregabalin, which has anxiolytic, sedative, and pain-alleviating properties, has also been approved by the FDA for the treatment of generalized anxiety disorders. Sleep problems are extremely prevalent in FM patients. One strategy that has been effective in FM is the combination of an antidepressant and an antiepileptic medication, such as gabapentin or pregabalin, although this has not been studied in randomized controlled trials.

In addition to pharmacological agents, treatments include a diverse array of modalities. Table 4 presents some of the most recent approaches.43,44

Physical modalities
Heat and cold, massage, stretching, and a range of motion exercises can be helpful. Systematic reviews and meta-analyses have supported the benefits of exercise and spa therapies.45,46 Supervised exercise programs (eg, aerobic conditioning, muscle strengthening, flexibility training) may be helpful as long as care is taken not to overfatigue patients.

A host of other treatments, such as acupuncture and chiropractic manipulations, have been evaluated. The results of these trials are mixed and even the positive results are modest, and the trials have been of short duration.45

Psychological treatments
Hypnosis, biofeedback, relaxation, behavior therapy, and cognitive-behavioral therapy (CBT) have all been evaluated as treatments for FM. CBT has been the most extensively investigated.47 Two recent clinical practice guidelines reviewed the literature and recommended CBT in combination with other treatments for FM.2,41

Multicomponent treatment
Although no single intervention has been shown to be highly effective for most patients with FM, there is reasonably good evidence that multicomponent approaches, which include education, exercise, and CBT, delivered to groups of patients by a multidisciplinary team may be helpful.43,47,48

Based on the available research through 2003, the American Pain Society (APS) proposed an evidence-based clinical practice guideline that recommended a stepwise or a combination approach to treating FM2:

• Education
• TCAs
• Exercise
• CBT

The APS guideline was published before the approval of the SSRIs duloxetine and pregabalin. Two evidence-based guidelines have since recommended these 2 medications for treating FM symptoms.41,42Table 5 provides an integration of these 3 treatment guidelines.2,41,42 

PATIENT HETEROGENEITY

A number of investigators have suggested that patients who have FM may not be a homogeneous group. Rather, there may be subgroups of people with FM. Studies have focused on differences based on symptom onset (eg, idiopathic vs traumatic), symptom presentation,

and psychological distress.49,50 Delineation of the relevant subgroups may facilitate the identification of the mechanisms that underly the symptoms of FM and the development of treatments customized to address the specific needs of patients.

CONCLUSIONS
FM is a perplexing condition of unknown cause that has no cure. Many treatments have some beneficial effects, but the syndrome remains a chronic problem. Research is needed to determine the type of treatment for each subset of patients. The failure to achieve and maintain positive outcomes in many patients indicates, most assuredly, that one size does not fit all.

Health care providers need to consider not only the physical basis of symptoms (the nociceptive, sensory component) but also patients’ moods, fears, expectancies, coping resources, coping efforts, and the responses of significant others (including themselves). Regardless of whether there is an identifiable physical basis for the reported symptoms, psychosocial and behavioral factors interact to influence the nature, severity, and persistence of pain and disability. In particular, behavioral, emotional, and cognitive variables should be addressed.

An integrative treatment model for FM needs to incorporate the interrelationships among physical, psychological, and social factors-and the changes that occur among these relationships over time.51,52 Treatment approaches that focus on only one set of factors will inevitably be incomplete. Because there is no cure for FM, patients need to be given realistic expectations. They need to understand that, at least for the foreseeable future, they will need to learn to self-manage their symptoms for an extended period.

Drugs Mentioned in This Article
Amitriptyline (Elavil, Endep)
Cyclobenzapine (Flexeril)
Duloxetine (Cymbalta)
Gabapentin (Neurontin)
Milnacipran
Pregabalin (Lyrica)
Tramadol (Ultram)

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Evidence-Based References
Burckhardt CS, Goldenberg D, Crofford L, et al. Guidelines for the Management of Fibromyalgia Syndrome Pain in Adults and Children. APS Clinical Practice Guidelines Series, No 4. Glenview, IL: American Pain Society; 2005.
Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum. 1990;36:160-172.