Fibromyalgia

Gregory Kaltsas, MD, FRCP,Assistant Professor of Medicine, Dept of Pathophysiology, Laikon University Hospital, Athens 115 27, Greece. email: GKaltsas@endo.gr

Konstantinos Tsiveriotis, MD

Revised: 9 Feb 2009

Introduction

Although the term fibromyalgia is relatively new, throughout the history of the medical literature there have been a variety of semantic terms applied to persons suffering from widespread musculoskeletal pain. The most recent term prior to fibromyalgia, fibrositis, implied that there was an inflammatory process within the connective tissues. This term was abandoned when research showed that this condition is not due to inflammation in the tissues. The currently preferred label, fibromyalgia, is a descriptive term that connotes the presence of pain within the tissues, without attempting to define the pathogenesis of the pain.

Classification criteria

A number of classification criteria have been proposed for fibromyalgia. In 1990 the American College of Rheumatology (ACR) committee established the criteria which are most widely used today for the classification of fibromyalgia. According to these criteria fibromyalgia is defined as chronic widespread pain involving both sides of the body, above and below the waist, as well as the whole length of the spine, and excessive tenderness in the pressure of 11 of 18 specific muscle-tendon sites (9 pairs of tender points). The locations of the tender points are described in Figure 1 and Table 1. Pressure equivalent of 4 kg/cm must be applied to these points using the pulp of the thumb or the first two or three fingers. This can be accurately measured with a dolorimeter or estimated, since applying enough pressure to whiten the examiner`s fingernail bed generates approximately 4kg/cm of pressure. These criteria specifically state that fibromyalgia is not an exclusionary diagnosis (1).

Figure 1: Fibromyalgia tender points

Table 1: Description of the location of fibromyalgia tender points

Prevalence

The prevalence of fibromyalgia as defined by the 1990 ACR criteria is reported to be in the U.S.A. 3.4% in women and 0.5% in men (2). It increases with age from 2% at age 20 to 8% at age 70, declining thereafter. Fibromyalgia appears more often in relatives of patients suffering from fibromyalgia (3).

Clinical features

The presenting complains of patients with fibromyalgia include chronic widespread pain, fatigue and poor sleep. The pain, although initially localized, eventually involves many muscle groups and it is characterized as persistent with varying intensity, while it can often be described as a sensation of burning, gnawing soreness, stiffness, or aching. Excessive sensitivity to normally painful stimuli, such as pressure or heat (hyperalgesia) and painful sensation to normally non-painful stimuli, such as touch (allodynia) are significant features of fibromyalgia. Often patients complain of swollen joints and paresthesias without any objective clinical findings during physical examination. Pain is often aggravated by cold and humid weather, poor sleep, physical and mental stress. Additionally the patients may have a variety of less well understood pain symptoms, including abdominal pain, chest wall pain, symptoms suggestive of irritable bowel syndrome, pelvic pain and bladder symptoms of frequency and of urgency suggestive of interstitial cystitis (4-9).

Fatigue is present in almost all patients with fibromyalgia. Many patients complain of unrefreshing sleep, while others awaken frequently during the night and have difficulty falling back to sleep. Sleep apnea and nocturnal myoclonus can also be present. A sensation of light-headedness, dizziness, and faintness is common. Some patients complain of cognitive difficulties such as short term memory loss, groping for words and poor vocabulary, while mood disturbances, including depression, anxiety and heightened somatic concern, often occur. Headaches, either muscular or migraine type, are also often (6, 7).

Multiple chemical sensitivity and “allergic” symptoms, ocular dryness, palpitations, dyspnea, vulvodynia, dysmenorrhoea, premenstrual syndrome, sexual dysfunction, weight fluctuations, night sweats, dysphagia, restless leg syndrome, temporomandibular joint pain, chronic fatigue syndrome, Raynaud`s phenomenon, autonomic dysfunction and dysgeusia are additional conditions that can co-exist (6, 8, 9). Approximately 25% of fibromyalgia patients have major depression at the time of diagnosis, while 50-75% have a lifetime history of depression. The lifetime prevalence of an anxiety disorder in fibromyalgia patients is approximately 60% (10-12). Up to about 25% of patients correctly diagnosed with a systemic rheumatic disease (e.g. rheumatoid arthritis, systemic lupus erythematosus) will also fulfill the classification criteria for fibromyalgia (13). The most commonly encountered comorbid conditions in fibromyalgia patients are displayed in Table 2.

Table 2: The most commonly encountered co-morbid conditions in fibromyalgia

Relevant social, personal and family history can be helpful in establishing the diagnosis of fibromyalgia, since there is evidence that the symptoms of fibromyalgia can appear after a physical or emotional trauma, a medical illness or surgery, while a family history of fibromyalgia, increases the possibility of diagnosis of fibromyalgia (14).

Fibromyalgia assessment

Fibromyalgia is a chronic illness. Consequently the current pain level, fatigue, sleep disorders and well-being should be regularly assessed. Pain perception can be divided in location, intensity and affect. Pain intensity and the affective dimension of pain can be assessed using visual analog scales or verbal analog scales. Pain location can be assessed by shading on body maps or pain diagrams. Fatigue and sleep disorders can also be assessed with visual analog scales. Overall functional ability can be evaluated using the fibromyalgia impact questionnaire (FIQ). This represents a useful tool in assessing functional abilities in daily life and measures patient status, progress and outcomes. FIQ is self-administered and is highly sensitive to changes during the course of the disease. Other tools for assessing overall function and quality of life include the Health Assessment Questionnaire, the Symptom Interpretation Questionnaire, the Western Ontario and McMaster Universities Osteoarthritis Index, the Patient Global Impression of Change scale (PGIC), and psychometric scales (15).

Fibromyalgia subgroups

Fibromyalgia patients do not form a homogenous group. Based on the coexistence of depression and anxiety, they can be divided into 2 major groups. The first group comprises of fibromyalgia patients without coexisting mood disorders, while the second of patients with concomitant depressive mood, often in combination with anxiety. According to the results of a study that intended to subgroup fibromyalgia patients based on: 1) mood status (evaluated by the Center for Epidemiologic Studies Depression Scale [for depression] and the State-Trait Personality Inventory [for symptoms of trait-related anxiety]), 2) cognition (by the catastrophizing and control of pain subscales of the Coping Strategies Questionnaire), and 3) hyperalgesia/tenderness (by dolorimetry and random pressure-pain applied at suprathreshold values), fibromyalgia patients with depressive mood and anxiety are also catastrophizing. This means that they have a very negative, pessimistic view of what their pain is and what is causing, while they have no sense that they can control their pain. On the contrary fibromyalgia patients who are neither depressed nor anxious do not catastrophize and have a moderate sense that they can control their pain. These patients can be further divided into 2 subgroups based on the hyperalgesia/tenderness. The first subgroup consists of patients with low levels of tenderness (although they fulfill the ACR classification criteria for fibromyalgia), and the second of patients with high levels of tenderness (16). It has been proposed that depressed fibromyalgia patients can be divided into 2 subgroups. In the first subgroup depression is a co-morbid condition, while in the second depression is the cause of fibromyalgia (17). All these fibromyalgia subgroups are illustrated in Figure 2.

Figure 2: Subgroups of fibromyalgia patients

In another study fibromyalgia patients were classified as dysfunctional, interpersonally distressed or adaptive copers, based on their responses to the Multidimensional Pain Inventory. The dysfunctional patients had more pain behaviors (overt expressions of pain, distress, and suffering, such as slowed movement, bracing, limping, and grimacing) than either the interpersonally distressed or the adaptive copers (18).

Controversy over classification criteria

The use of the 1990 ACR classification criteria in clinical practice is surrounded by substantial controversy. The tender points, which are examined in fibromyalgia, are not just areas that the patient feels pain. They are points that fibromyalgia patients are more tender, compared to normal individuals, when pressure is applied on them. But fibromyalgia patients are more tender wherever you apply pressure, not only to some of these 18 specific tender points, including areas previously considered to be “control points” (19). There is evidence that these tender points are areas that everyone is generally more tender. Fibromyalgia patients are more tender not only when pressure is applied. They are also more tender for heat, cold and other sensory stimuli, most probably due to decreased pain threshold. The number of tender points an individual has is highly correlated with distress, as defined by anxiety, depression, sleep disturbance, fatigue and global severity. Tender points have been described as “a sedimentation rate of distress”. Consequently tender points measure the combination of tenderness and distress an individual has (20). Other more sophisticated measures of tenderness, such as applying stimuli randomly, when the individual can’t anticipate what the next stimulus is going to be, are equally abnormal in fibromyalgia patients, but do not correlate with distress (19). However they require special training and are more time consuming than the trigger point count. Other alternative assessment methods include functional magnetic resonance imaging (fMRI) and nociceptive flexion reflex (NFR) testing, which documents abnormal pain processing in fibromyalgia. fMRI demonstrates similar brain activation in regions involved in pain processing in fibromyalgia patients and normal individuals. However fibromyalgia patients have increased pain sensitivity and brain activation during comparable stimulus (21). Nociceptive flexion reflexes are sensory-motor responseselicited by electrical noxious stimuli, which involve activationof spinal and supraspinal neuronal circuits, providing an objectiveand quantitative assessment of the function of the pain-controlsystem. It has been demonstrated that the NFR threshold in patients with fibromyalgia is significantly decreased compared with that in controls (22). Of these methods fMRI is expensive and complex. On the other hand the nociceptive flexion reflex testing may be more easily accessible and convenient, since standard elecromyographic equipment can be used. This test also appears to eliminate subjective bias and dissimulation (23).

The 1990 ACR classification criteria, define fibromyalgia in terms of pain rather than its other features.However patients with fibromyalgia apart from tenderness and pain, also have a number of other somatic symptoms. Although non pain symptoms are important, there is no evidence to support the notion that they are more important than hyperalgesia and allodynia, which are key symptoms of fibromyalgia (23). Some clinicians with experience in fibromyalgia do not feel that the ACR criteria are sufficiently reliable for the diagnosis of fibromyalgia in clinical practice and have started to consider other aspects of the disease. These additional criteria seem to identify a larger number of patients as having fibromyalgia, many of whom would not have been diagnosed with the ACR criteria. However no consensus has yet been reached regarding the validity of these additional criteria (14). It should be noted that the ACR criteria are classification and not diagnostic criteria, and they were intended to standardize research studies. However until new, more accurate, widely accepted criteria for the diagnosis of fibromyalgia emerge, it would not be prudent to abolish the ACR criteria.

Differential diagnosis

Several conditions can mimic or overlap with fibromyalgia. In order to reach a differential diagnosis, careful history taking should be followed by a thorough physical examination. Careful neurologic and musculoskeletal examination needs to be performed in all fibromyalgia patients in order to excludethe presence of such conditions. Mood and functional impairment should also be evaluated. This can be easily performed using simple self-administered questionnaires. Patients with obvious mood disturbances should have a formal evaluation by a mental health professional. Baseline blood tests should be limited to a complete blood count, erythrocyte sedimentation rate, a comprehensive metabolic panel, and thyroid function tests. These tests are usually normal in fibromyalgia patients. Consequently the identification of abnormalities in any of these examinations might suggest that a different condition is present. Additional tests are not recommended for a diagnosis, unless they are clinically indicated. The disorders that can mimic and/or overlap with fibromyalgia and characteristic clinical features which differentiate them from fibromyalgia are displayed in Table 3. The clinical features of fibromyalgia, chronic fatigue syndrome, depression, migraine and irritable bowel syndrome often overlap. They can be so interchangeable that some authors consider that these conditions should be approached as a “spectrum” of associated disorders (10). They are also considered as part of the spectrum of post-traumatic stress disorder (24,25).

Table 3: Disorders that can mimic and/or overlap with fibromyalgia and characteristic clinical features which differentiate them from fibromyalgia.

HIV: human immunodeficiency virus, HTLV: human T-lymphotropic virus

Pathophysiological mechanisms

Pain sensitivity in the population occurs over a wide continuum, forming a classic bell shaped curve, just like any other physiologic variable. Genetic predisposition in combination with environmental factors, are responsible for the place an individual takes in this continuum. People who are placed in the right end of this curve are very sensitive to pain and they probably can develop pain even without having any inflammation or damage in the peripheral tissues. This pain can be either regional or widespread (19).

In the past fibromyalgia was thought to be a primary muscle disease. However, controlled studies found no evidence of significant pathologic or biochemical muscle abnormalities that can be the cause of chronic widespread pain and tenderness. Most investigators believe that any muscle pathology is secondary to chronic pain and inactivity, rather than primary in nature (26-29). Current research suggests that altered central nervous system (CNS) physiology might underlie the symptoms of fibromyalgia. Abnormal central sensory processing of pain signals seems to play a significant role in the pathogenesis of fibromyalgia. This dysregulation of the nociceptive system can arise from a combination of interactions between neurotransmitters, cytokines, hormones, the autonomic nervous system, behavioral constructs and external stressors.

Abnormalities in sensory processing

As it has already be mentioned above fibromyalgia overlaps, and is associated with, several other similar syndromes including chronic fatigue syndrome and myophasial pain syndrome (Table 4). It has been proposed that these disorders should be considered as members of the central sensitivity syndromes. These similar and overlapping syndromes are bound by the common mechanism of central sensitization that involves hyper-excitement of the second-order neurons, especially the wide-dynamic-range neurons (WDR) in the dorsal horns of the spinal cord, by various synaptic and neurotransmitter/neuromodulator activities (30). Central sensitization is clinically and physiologically characterized by hyperalgesia, allodynia, expansion of the receptive field (pain expanding beyond the area of the peripheral nerve supply, after the application of a nociceptive stimulus), prolonged electrophysiological discharge, and an after-stimulus unpleasant quality of the pain (e.g. burning, throbbing, tingling or numbness). Parallel to central sensitization, temporal summation takes place in the second-order neurons. It is characterized by a progressive increase in electrical discharges (and consequently increase in the perceived intensity of pain) in response to repetitive short noxious stimuli. Temporal summation involves the production of second pain, which is described as dull or burning, and leaves an after-stimulus unpleasant sensation (31).

Table 4: Central sensitivity syndromes

N-methyl-D-aspartate (NMDA) receptors are mostly responsible for escalation of hyperexcitability of the second-order nociceptive neurons. The role of the major neurotransmitters of the nociceptive system that participate in signal conduction at the level of the spinal cord is briefly illustrated in Figure 3 (30).

Figure 3: The role of the major neurotransmitters of the nociceptive system that participate in signal conduction at the level of the spinal cord

NGF: nerve growth factor, NMDA: N-methyl-D-aspartate, D: dopamine

The second-order neurons have ascending projections to the thalamus, hypothalamus, the limbic system and the somatosensory cortex. These supraspinal structures are involved in the sensory, evaluative and affective dimensions of pain (e.g. unpleasantness, emotional reaction). Several descending pathways from the cortico-reticular system, locus ceruleus, hypothalamus, brain stem, and local spinal cord interneurons terminate to the dorsal horn cells. These pathways utilize neurotransmitters that include serotonin (5-HT), norepinephrine, γ-amino-butyric acid (GABA), enkephalines and adenosine (30). This descending system, once thought to be predominantly inhibitory, is now known to have a facilitatory potential (32). Evidence suggests that the 5-HT₃receptor has a facilitatory function, while the 5H-T_1Areceptor is inhibitory. The ascending and descending pathways should not be considered as dichotomus in function. They are interactive and their functions are bidirectional. Both pathways can either facilitate or inhibit pain, depending on the site of action and the neurotransmitters that are used (30).

The dysregulation of the nociceptive system, either at the level of the dorsal horns of the spinal cord, or at the level of the ascending and descending pathways, can lead to its hyperexcitability. In other words it can lead to central sensitization. Several factors may amplify and sustain central sensitization through interactive and synergistic actions. These factors are summarized in Table 5 (31). Central sensitization can become self-sustained, even when the event that triggered it no longer exists, due to long-term CNS plasticity.

Table 5: Factors that may amplify and sustain central sensitization

Although nearly all of the research on sensory processing in fibromyalgia has focused on the processing of pain, there are some data suggesting a more generalized disturbance in sensory processing. There is evidence that fibromyalgia patients have a hypersensitivity to unpleasant stimuli of other sensory systems. For example, many patients experience reduced tolerance to loud noises, bright lights, odors, drugs, and chemicals (33).

Neurotransmitters

The levels of SP in the cerebrospinal fluid (CSF) in patients with fibromyalgia are significantly increased compared to normal individuals. Whereas CSF levels of serotonin metabolites are decreased in fibromyalgia patients, as are metabolites of dopamine and norepinephrine (34). The first direct evidence that fibromyalgia patients may have abnormal dopamine response to pain came from positron emission tomography(PET) competitive binding studies using the D₂/D₃receptor antagonist [¹¹C] raclopride. It was shown that dopamine is released in response to tonic toxic noxious muscle stimulation, but not after non-painful muscle stimulation in healthy human subjects. In contrast the dopamine response in fibromyalgia patients did not differ between painful and non-painful muscle stimulation (33). There are indications that disturbances of the opioidergic system occur in fibromyalgia patients, as there is an upregulation of opioid receptors in the periphery, with a reduction of the brain opioid receptors (35,36).

Cytokines

Although fibromyalgia is not considered an inflammatory disorder, the interaction of immunological mechanisms with pain physiology, has led to the identification of alterations in the levels of various cytokines in fibromyalgia patients. The serum levels of interleukin 1 receptor antibody (IL-1Ra) and IL-8 are higher in fibromyalgia patients, compared to controls. Although serum IL-6 levels in patients with fibromyalgia are similar to those of normal individuals, the production of both IL-6 and IL-1Ra by peripheral blood mononuclear cells (PBMC) is higher in fibromyalgia patients (37). Additionally inflammatory cytokines such as IL-1β, IL-6 and tumor necrosis factor alpha (TNFα) have been detected in skin biopsies taken from fibromyalgia patients, possibly indicating an element of neurogenic inflammation (38).

Inflammatory cytokines like IL-1β, IL-6 and TNFαcan elicit pain, induce hyperalgesia and they are associated with neuropathic pain (39), although they do not appear to be involved in “normal” pain. Serum cytokines cannot pass the blood brain barrier. However the release of proinflammatory cytokines by immune cells in the body leads, in turn, to release of proinflammatory cytokines by glial cells within the brain and spinal cord (40).

Inflammatory cytokines like IL-1β, IL-6 and TNFαcan cause stimulation of the hypothalamo-pituitary-adrenal (HPA) axis alone, or in synergy with each other. There is evidence to suggest that IL-6, which is the main endocrine cytokine, plays the most significant role in the immune stimulation of the axis, especially in chronic inflammatory stress (41). IL-6 can stimulate the hypothalamic secretion of corticotropin-releasing hormone(CRH) and arginine vasopressin(AVP), leading to the increase of serum adrenocorticotropic hormone(ACTH) and cortisol levels (42).

Hypothalamo-pituitary-adrenal axis

There is substantial data indicating that the HPA axis functions abnormally in fibromyalgia. However the results on the HPA axis function in fibromyalgia patients are heterogenous. The 24-hour urinary free cortisol has been found to be reduced or normal (43). Findings regarding alterations in diurnal variation of cortisol secretion are also inconsistent. Although normal diurnal patterns of ACTH and cortisol have been reported, there is data demonstrating flattened cortisol diurnal rhythm with normal morning peak and higher evening cortisol, levels (44). A significant decrease in the rate of decline from acrophase (peak) to nadir for diurnal cortisol levels in fibromyalgia patients, compared to controls, has been shown, while there is no change in the ACTH to cortisol ratio (43). This can imply a decreased ability of the HPA axis to return to baseline after a physiologic stimulation by meals, several other activities or even pain (43). Decreased morning cortisol release and reduced frequency of cortisol pulses over 24 hours have also been reported. It is worth mentioning that the reduced cortisol release in fibromyalgia patients is associated with depressive symptoms and experiences of childhood trauma (44).

In line with studies suggesting reduced adrenal output in fibromyalgia patients, reduced cortisol secretion has been reported in response to pharmacological challenge with ACTH_1-24and to insulin tolerance test (44). Fibromyalgia patients exhibit increased ACTH, but normal cortisol response to CRH stimulation test, compared to controls. This finding suggests a sensitization of the pituitary in combination with adrenal insufficiency (44). Arginine vasopressin (AVP), an ACTH secretagoghe, has been found to be more increased in response to the postural challenge test in fibromyalgia patients, compared with controls (45).

Alterations in the feedback regulation of HPA axis have also been reported in fibromyalgia patients, using the overnight dexamethasone suppression test (DST). Increased rates of nonsuppressiveness following the standard (1 mg) DST have been reported in fibromyalgia patients, compared to controls, but it was associated with depression. Interestingly, other studies have revealed lower rates of nonsuppressiveness in fibromyalgia patients. It has been shown that the low-dose (0.5 mg) DST causes normal ACTH but increased cortisol suppression in fibromyalgia patients when compared to controls (46), suggesting reduced adrenal output.

There are indications that a dissociation between total and free cortisol occurs in fibromyalgia patients, with normal salivary and plasma free cortisol despite diminished total cortisol levels. One possible explanation is a reduced concentration of glucocorticoid binding globulin (CBG). Reduced levels of CBG have been reported in fibromyalgia patients compared to controlls. It is of particular interest that chronic social stress might result in reduced CBG levels. Furthermore IL-6 and IL-1βcan inhibit the production of CBG (44).

Apart from HPA axis abnormalities in fibromyalgia patients, abnormal levels of growth hormone have also been found in some, but not all reports (47). On the other hand the levels of sex hormons have not been clearly shown to differ between female fibromyalgia patients and controls (48).

Autonomic nervous system

Sympathetic hyperactivity, often associated with sympathetic hypoactivity in response to stressors, or parasympathetic underactivityhas been described in fibromyalgia. Orthostatic hypotension and increased pain in response to tilt table test have been found in fibromyalgia patients. Moreover increased resting supine heart rate and decreased heart rate variability have been reported (49,50) . IL-6 administration causes exaggerated norepinephrine responses and increases in heart rate, as well as delayed ACTH release, suggesting an incapacitated stress-regulating system (51). In-vitro testing of beta adrenergic receptor mediated cyclic AMP generation has revealed decreased responsiveness to beta-adrenergic stimulation (52). It has been suggested that sympathetic dysfunction can not only cause diffuse pain, but also contribute to other symptoms like sleep disturbances, due to sustained nocturnal sympathetic activity, and fatigue, due to deranged sympathetic response to stress (30).

Psychological, cognitive and behavioral factors

Pain apart from a sensory-discriminative dimension, which includes the location and the intensity of pain, has a very significant psychological component. This includes the affective dimension of pain, the emotional valance of pain in other words, as well as attentional and cognitive aspects, which are based on CNS mechanisms. Emotion and selective attention can enhance pain perception, whith the involvement of the descending pathways that have a facilitatory effect on the spinal cord dorsal horn neurons (31). Catastrophizing has been shown to be related to decreased pain threshold and tolerance to heat stimuli in fibromyalgia patients. However there is a subgroup of fibromyalgia patients that is very tender, despite the fact that they do not catastrophize and they have a moderate control over their pain (16). In a fMRI study it was shown that although depression is associated with the magnitude of neuronal activation in brain regions that process the affective-motivational dimension of pain, neither the extent of depression nor the presence of comorbid major depression modulated the sensory-discriminative aspects of pain processing in fibromyalgia patients (53). Catastrophizing, has been associated with increased activity in brain areas related to anticipation, attention and the emotional aspects of pain, as shown by fMRI in response to pressure stimuli. This study also revealed an association between catastrophizing and increased activity in the secondary somatosensory cortex, indicating that the way patients think about their pain might actually influence its sensory processing (31).

Genetic predisposition

It is currently well established that familial aggregation is a characteristic o fibromyalgia. First degree relatives of fibromyalgia patients are 8.5 times more likely to have fibromyalgia than relatives of patients with rheumatoid arthritis (12). As with other complex and multifactorial syndromes, the occurrence of familial aggregation in the case of fibromyalgia does not necessarily imply a genetic basis. Shared environmental factors and learned patterns of behavior that may evolve within families are equally valid targets of investigation.

The following genes have been associated with fibromyalgia:

Serotonin transporter (5-HTT) gene:an increased frequency of the S/S genotype of the 5-HTT gene has been demonstrated in fibromyalgia patients compared to controls (54,55). However this putative association may be limited to patients with concomitant affective disorders, since it was not confirmed in fibromyalgia patients without depression or anxiety (56).

D₄receptor gene: polymorphisms affecting the number of repeats in the third cytoplasmic loop of the dopamine D₄receptor gene have been shown to be significantly decreased in frequency in fibromyalgia patients (57).

Catechol-O-methyl transferase (COMT) gene:the homozygous low activity (LL) and the heterozygous low activity (LH) COMPT genotypes occur more often in fibromyalgia patients than in controls, whereas the homozygous high activity (HH) genotype was less frequent (58).

External stressors

Nearly all illnesses are caused by a combination of genetic predisposition and environmental factors. We are now beginning to better understand the environmental factors that seem to be important in triggering fibromyalgia. Most of them act as “stressors” that in the basis of a deranged stress-response system can lead to the dysregulation of the nociceptive system.

Peripheral pain syndrome

Pain due to damage or inflammation of peripheral tissues may trigger fibromyalgia. Chronic localized – regional pain can lead to central sensitization and pain disinhibition, causing widespread pain hypersensitivity and widespread pain. Systematic autoimmune diseases can be associated with fibromyalgia. Approximately 20-25% of patients with rheumatoid arthritis, systematic lupus erythematosus and ankylosing spondylitis, have co-morbid fibromyalgia (13). In such cases, it is important to realize that many symptoms may be attributed to fibromyalgia rather than the underlying disorder. This recognition has significant clinical implications.

Infections

Various infections have been linked to the development of fibromyalgia and chronic fatigue syndrome. Epstein-Barr virus, parvovirus, Lyme disease, Q fever, HIV and hepatitis C virus (HCV), have been suggested as triggers of fibromyalgia or chronic fatigue syndrome, but more robust evidence is needed. The role of vaccination in precipitating fibromyalgia and related syndromes still remains to be established (59,60).

Physical trauma

Various forms of physical trauma have been considered culprits of triggering the pathogenesis of fibromyalgia. Many patients report the initiation or the exacerbation of their symptoms after a traumatic event such as whiplash injury, while increased rates of fibromyalgia have been demonstrated among patients undergoing cervical trauma during motor vehicle accidents (61,62).

Psychological distress

It has been considered that psychological factors that give rise to chronic stress may initiate the chain of events that leads to fibromyalgia. The chronic stress can be a result of the cumulative events of day-to-day stresses. Emotional stress, catastrophic events, such as war, job loss, marital discord and excess family responsibilities, such as caring for sick elders, have been implicated as triggers of fibromyalgia (63). However the data that supports the notion that psychological stress and distress directly causes fibromyalgia is rather weak (19).

Management

The treatment of fibromyalgia patients is challenging, because of our limited understanding of the pathogenesis of fibromyalgia and the poor response of the patients to conventional pain treatments. The aim of the therapy is to decrease pain and increase function using a multimodal therapeutic strategy which, in most cases, includes pharmacologic and nonpharmacologic interventions. Current clinical-based evidence advocates the use of a multifaceted program that emphasizes patient education, medications for improving symptoms, exercise and cognitive-behavioral approaches to retain or restore function (64).

Nonpharmacological management

Patient education

The first step should be the education of the patient. The patients with fibromyalgia need to understand their illness before any treatment modality is used (65). Providing a diagnosis, “labeling” the patient with fibromyalgia, may have beneficial effects. It has been shown that fewer symptoms and an improvement in health status were noted after the patients were informed of the diagnosis (66,67). The physician should clarify that fibromyalgia is a real illness and the symptoms the patient experiences are not imaginary. The role of neurotransmitters and neuromodulators in pain perception, fatigue, abnormal sleep and mood disturbancies should be discussed, so as the patient to understand the rationale of the pharmacologic therapy, especially when antidepressant drugs are used.

Exercise

Another potent nonpharmacological treatment for fibromyalgia is exercise. It has been reported that an exercise program incorporating aerobic, strengthening and flexibility elements led to greater benefits than a relaxation program. Exercise in fibromyalgia patients should have 2 major components: strengthening to increase soft-tissue length and joint mobility, and aerobic conditioning to increase fitness (64). Exercise should be of low impact and of sufficient intensity so as to be able to change aerobic capacity (15). It has been suggested that if exercise-induced pain does occur, the intensity and duration of exercise should be reduced, while its frequency should be maintained, so as to avoid any further decrease in exercise tolerance (64).

Cognitive-behavioral approaches

One of the goals of the management should be to help them understand the effect of thoughts, beliefs and expectations on their symptoms. In this way patients will be able abolish the perception of helplessness and the catastrophising thoughts that can deteriorate their condition. Patients with greater self-efficacy are more likely to respond favorably to treatment programs and experience better outcomes. It is worth mentioning that psychologically based interventions, have been proven to be useful when combined with exercise as part of a multimodal program, but not when used alone (64).

Complementary and alternative therapy

The effectiveness of acupuncture and biofeedback has been supported by some studies (68,69). A number of other modalities has been utilized in the treatment of fibromyalgia including chiropractic therapy, yoga, tai chi, massage therapy, magnetic therapy and tender point injections. However there are no well-designed studies to advocate their general use (64).

Pharmacologic treatment

A wide range of drugs has been used in the treatment of fibromyalgia including antidepressants, sedatives, muscle relaxants and antiepileptic drugs. Nonsteroidal anti-inflammatory drugs and opioids, although often prescribed for fibromyalgia, are not an effective form of treatment (19,70). Patients should be informed that for most pharmacologic therapies several weeks may be needed until the appearance of beneficial effects. Initially a single drug should be administered. However in the case of non-responsiveness combination therapy should be considered. Since therapeutic responses are rarely durable, physicians should not be surprised when the initial efficacy of a medication is abolished. Successful treatment of fibromyalgia may require regular reassessment and possible rotation of medications (71). The doses of the most commonly used medications with strong and moderate evidence of effectiveness are shown in Table 6.

Antidepressants

Tricyclic antidepressants(TCAs) are often used as initial treatment for fibromyalgia. Their analgetic effect is independent of their antidepressant action and is thought to be mediated by inhibition of norepinephrine (rather than serotonin) reuptake at spinal dorsal horn synapses, with secondary activity at the sodium channels. The most widely studied drugs of this group are amitryptiline and cyclobenzamine. They should be administered at lower doses than those required to treat depression, a few hours before bedtime, and their dose should be escalated very slowly. However their use is limited by the fact that they are ineffective or intolerable in 60-70% of patients (64). The combination of 20 mg of fluoxetine in the morning with 25 mg of amitryptiline at bedtime has been shown to be more effective than either medication used alone (72). Desipramine is less well studied for fibromyalgia, but remains a possible alternative because of its fewer andicholinergic side effects.

Monoamine oxidase inhibitorsblock the catabolism of serotonin, increasing its levels in the brain. It has been indicated that pirlindole has significant beneficial effects on sleep, fatigue and mood (64).

Serotonin-norepinephrine reuptake inhibitors(SNRIs) are similar to TCAs in their ability to inhibit the reuptake of both serotonin and norepinephrine, but they differ from TCAs in being devoid of significant activity at other receptor systems, resulting in diminished side effects and increased tolerance. Venlafaxine and duloxetine have been shown to be efficacious in diminishing fibromyalgia symptoms (64).

Anticonvulsants

Gabapentinhas been shown to be efficient in treating fibromyalgia associated pain, while it was well tolerated.

Pregabalinhas been demonstrated to be efficient against pain, sleep disturbances and fatigue in fibromyalgia. Side effects such as somnolence and dizziness have been reported (19).

Muscle relaxants

Cyclobenzamineis structurally a tricyclic muscle relaxant. A meta-analysis of five placebo-conrolled trials has revealed improvement of the global functioning, with a similar effect size as this reported for amitriptiline. The group that received cyclobenzamine had a significant decrease in pain for 4 weeks, compared to those treated with placebo, but the decrease in pain was not significantly different after 8 and 12 weeks (73-75).

Carisoprodolin combination with acetaminophen and caffeine has been shown to improve pain, sleep quality and the overall feeling of well being in fibromyalgia patients (76).

Sedative hypnotic agents

Zopicloneand zolpidemhave been used in fibrobyalgia. It has been suggested that they can improve the sleep and perhaps fatigue, without any significant effects on pain (64).

Sodium oxibate, a precursor of GABA with powerfull sedative properties has been shown to improve pain, fatigue and sleep architecture in fibromyalgia (19).

Tramadol

Tramadol has multiple analgesic effects, since it inhibits norepinephrine and serotonin reuptake, and its major metabolite bind weakly to opioid mu receptors (64). The use of tramadol (with or without acetaminophen) is both effective and well tolerated in fibromyalgia. There is some concern regarding the long term potential of abuse of tramadol, although the risk is less than that of more potent narcotic analgesics that have also been used in fibromyalgia.

Table 6: The doses of the most commonly used medications with strong and moderate evidence of effectiveness in fibromyalgia

Conclusion

Fibromyalgia is a common disease that is often underdiagnosed. Genetic predespisition, in combination with exposure to external stressors may lead to dysregulation of the nociceciptive system and to the appearance of clinical symptoms. Fibromyalgia patients do not form a homogenous group. Some patients respond adequately to current therapeutic modalities, while some others do not seem to have any long term benefit. Patients treated by primary care physicians in the community have a much better prognosis, compared to patients of tertiary referral canters. Certain psychological factors, such as an increased sense of control over pain, a belief that one is not disabled, that pain is not a sign of damage, and behaviors like seeking help from others, decreased guarding during examination, exercising more and having pacing activities are associated with better prognosis. Conversely, catastrophizing is associated with increased awareness of pain and with worsening symptoms.