PHILIP MEASE
ABSTRACT.
Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population in the USA and other regions in the world where FM is studied. Prevalence rates in some regions have not been ascertained and may be influenced by differences in cultural norms regarding the definition and attribution of chronic pain states. Chronic, widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headache, and mood disorders. Although the etiology of FM is not completely understood, the syndrome is thought to arise from influencing factors such as stress, medical illness, and a variety of pain conditions in some, but not all patients, in conjunction with a variety of neurotransmitter and neuroendocrine disturbances. These include reduced levels of biogenic amines, increased concentrations of excitatory neurotransmitters, including substance P, and dysregulation of the hypothalamic-pituitary-adrenal axis. A unifying hypothesis is that FM results from sensitization of the central nervous system. Establishing diagnosis and evaluating effects of therapy in patients with FM may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. Diagnostic criteria, originally developed for research purposes, have aided our understanding of this patient population in both research and clinical settings, but need further refinement as our knowledge about chronic widespread pain evolves. Outcome measures, borrowed from clinical research in pain, rheumatology, neurology, and psychiatry, are able to distinguish treatment response in specific symptom domains. Further work is necessary to validate these measures in FM. In addition, work is under way to develop composite response criteria, intended to address the multidimensional nature of this syndrome. A range of medical treatments, including antidepressants, opioids, nonsteroidal antiinflammatory drugs, sedatives, muscle relaxants, and antiepileptics, have been used to treat FM. Nonpharmaceutical treatment modalities, including exercise, physical therapy, massage, acupuncture, and cognitive behavioral therapy, can be helpful. Few of these approaches have been demonstrated to have clear-cut benefits in randomized controlled trials. However, there is now increased interest as more effective treatments are developed and our ability to accurately measure effect of treatment has improved. The multifaceted nature of FM suggests that multimodal individualized treatment programs may be necessary to achieve optimal outcomes in patients with this syndrome. (J Rheumatol 2005;32 Suppl 75:6-21)
Fibromyalgia syndrome (FM) is a common chronic pain condition that affects at least 2% of the adult population in the USA and other regions in the world where FM is studied. Prevalence rates in some regions have not been ascertained and may be influenced by differences in cultural norms regarding the definition and attribution of chronic pain states. Chronic, widespread pain is the defining feature of FM, but patients may also exhibit a range of other symptoms, including sleep disturbance, fatigue, irritable bowel syndrome, headache, and mood disorders. Although the etiology of FM is not completely understood, the syndrome is thought to arise from influencing factors such as stress, medical illness, and a variety of pain conditions in some, but not all patients, in conjunction with a variety of neurotransmitter and neuroendocrine disturbances. These include reduced levels of biogenic amines, increased concentrations of excitatory neurotransmitters, including substance P, and dysregulation of the hypothalamic-pituitary-adrenal axis. A unifying hypothesis is that FM results from sensitization of the central nervous system. Establishing diagnosis and evaluating effects of therapy in patients with FM may be difficult because of the multifaceted nature of the syndrome and overlap with other chronically painful conditions. Diagnostic criteria, originally developed for research purposes, have aided our understanding of this patient population in both research and clinical settings, but need further refinement as our knowledge about chronic widespread pain evolves. Outcome measures, borrowed from clinical research in pain, rheumatology, neurology, and psychiatry, are able to distinguish treatment response in specific symptom domains. Further work is necessary to validate these measures in FM. In addition, work is under way to develop composite response criteria, intended to address the multidimensional nature of this syndrome. A range of medical treatments, including antidepressants, opioids, nonsteroidal antiinflammatory drugs, sedatives, muscle relaxants, and antiepileptics, have been used to treat FM. Nonpharmaceutical treatment modalities, including exercise, physical therapy, massage, acupuncture, and cognitive behavioral therapy, can be helpful. Few of these approaches have been demonstrated to have clear-cut benefits in randomized controlled trials. However, there is now increased interest as more effective treatments are developed and our ability to accurately measure effect of treatment has improved. The multifaceted nature of FM suggests that multimodal individualized treatment programs may be necessary to achieve optimal outcomes in patients with this syndrome. (J Rheumatol 2005;32 Suppl 75:6-21)
Key Indexing Terms:
NEUROTRANSMITTER
PAIN
NEUROHORMONE
FIBROMYALGIA
SLEEP
FATIGUE
PAIN
NEUROHORMONE
FIBROMYALGIA
SLEEP
FATIGUE
From the Seattle Rheumatology Associates, Division of Rheumatology Clinical Research, Swedish Hospital Medical Center, University of Washington School of Medicine, Seattle, Washington, USA.
Dr. Mease has received research grant support and is a consultant to Pfizer, Cypress Bioscience, and Lilly, and serves on a speakers bureau for Pfizer and Cypress Bioscience.
P. Mease, MD, Chief, Seattle Rheumatology Associates, Director, Division of Rheumatology Clinical Research, Swedish Hospital Medical Center, and Clinical Professor, University of Washington School of Medicine.
Address reprint requests to Dr. P. Mease, Seattle Rheumatology Associates, 1101 Madison Street, Suite 230, Seattle, WA 98104, USA. E-mail: pmease@nwlink.com
FIBROMYALGIA: THE CLINICAL SYNDROME
Fibromyalgia (FM) is one of several relatively common overlapping syndromes characterized by otherwise unexplained chronic pain and fatigue1,2. The cardinal features of FM are chronic widespread pain in the presence of multiple tender points throughout the body on physical examination. Clinical descriptions of what we now call FM have been reported since the mid-1800s. Various terms, including "neurasthenia" and "muscular rheumatism" had originally been applied. In 1904, Gowers created the term "fibrositis"3, which was used until the 1970s and 1980s, when it was recognized that the etiology of this syndrome lay in the central nervous system (CNS). Pioneering studies by Smythe and Moldofsky4 shed light on associated sleep pathology and opened the door to our current concept of the condition as caused by both central and peripheral pain sensitization mechanisms, which contribute to the constellation of symptoms that define FM5-7.
Diagnosis is made by a combination of patient history, physical examination, laboratory evaluations, and exclusion of other causes for symptoms attributed to FM. In 1990, the American College of Rheumatology (ACR) defined 2 major diagnostic criteria for classifying FM in adults. The first criterion is a history of widespread pain for at least 3 months. The second criterion requires patient report of tenderness in at least 11 of 18 defined tender points when digitally palpated with about 4 kg per unit area of force (Figure 1)8. The diagnostic utility of tender points was supported by reports in the 1980s, including ability to distinguish FM from controls9,10. The pain is often described as a deep, widespread, gnawing or burning ache, frequently radiating and quite variable. Pain self-rating may well be more severe than rheumatoid arthritis (RA)11. Virtually all patients describe severe fatigue, significant in the morning, despite adequate sleep, and worsening again by mid-afternoon. Fatigue may be described as being physically or emotionally draining11. Patients usually describe poor sleep patterns, either difficulty with falling asleep or frequent wakening. Additional features of FM often include stiffness, skin tenderness, postexertional pain, irritable bowel syndrome, cognitive disturbance, irritable bladder syndrome or interstitial cystitis, tension or migraine headaches, dizziness, fluid retention, paresthesias, restless legs, Raynaud's phenomenon, and mood disturbances11,12. Three key features, pain, fatigue, and sleep disturbance, are present in virtually every patient with FM13,14.
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Figure 1. Location of tender points8. * Represents "control" points.
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The ACR tender point criteria for a diagnosis of FM have been accepted as adequate for diagnosis of this condition in the clinical setting15, but have also been criticized. Many patients with chronic widespread pain have less than the 11 of 18 tender points specified in the ACR criteria6. Clauw and Crofford have pointed out that the tender point requirement in the ACR criteria may artificially increase the female predominance of FM, and select for individuals with higher levels of disease-related distress16. It has also been noted that the ACR classification criteria focus only on pain and disregard other important symptoms of FM, including fatigue, cognitive disturbance, sleep disturbance, and psychological distress, and that focusing strictly on pain may fail to capture the "essence" of this syndrome17.
About 10%–11% of the population has chronic widespread pain at any given time and about one-fifth of these individuals have the 11 of 18 tender points specified in the ACR classification criteria16,18. Chronic regional pain is present in 20%–25%. Even when defined according to the highly focused criteria set forth by the ACR, FM is a very common condition that has been estimated to affect about 2% of the adult (≥18 years of age) population in the USA. FM has a prevalence of 3.4% in women versus only 0.5% in men19. It occurs in 5%–6% of adult patients presenting at general medical and family practice clinics and in 10%–20% of adult patients presenting to rheumatologists, making it one of the most common diagnoses in office-based rheumatology practices19,20.
To differentiate symptom characteristics of FM from those present in other patients with chronic pain, it is important that assessments used in the evaluation be sensitive to differences between this condition and other chronic pain states, as they may have similar symptoms21-4. As many as 80% of patients with FM also fulfill criteria for chronic fatigue syndrome, up to 80% have headaches, 75% have temporomandibular disorders, and up to 60% may have irritable bowel syndrome14. The extensive overlap between FM and chronic fatigue syndrome is underscored by results from a recent analysis demonstrating that these 2 syndromes share a large number of symptoms, including muscle pain, sleep disturbance, fatigue, cognitive dysfunction, abdominal pain, muscle weakness, reduced activity, and migratory arthralgias13. The high comorbidity found in patients with FM and the similarity between the cardinal symptoms of this and other closely related diseases make specific assessment of effects of treatment on FM symptoms challenging.
Many patients with FM suffer significant disability and reduced quality of life. Results from one survey carried out in the mid-1990s indicated that 25.3% of patients received disability payments. However, only 25% of these were specifically for the diagnosis of FM25. Results from a small cohort of 127 patients with FM indicated substantially greater disability. Overall, 31% of patients employed prior to onset of their FM reported loss of employment due to their disease26.
The disability associated with FM does not change substantially over time. For example, in a large cohort of 538 patients followed for 7 years and evaluated with the Health Assessment Questionnaire (HAQ) every 6 months, functional disability worsened slightly over this period. Further, measures of pain, global severity, fatigue, sleep disturbance, anxiety, and depression were all abnormal at study entry (an average of 7.8 yrs after disease onset) and were essentially unchanged over the study period27.
The pain, disability, and other symptoms of FM result in significantly reduced quality of life for patients with this disease. Results from one comparison of women with FM versus healthy women and others with RA, osteoarthritis, permanent ostomies, chronic obstructive pulmonary disease, or type 1 diabetes indicated that those with FM had consistently lower scores than all others for nearly all the domains evaluated28. Results from a more focused comparison of 44 women with FM and 41 with RA indicated that the 2 diseases resulted in similar degrees of disability and negative impact on quality of life29.
PATHOPHYSIOLOGY OF FIBROMYALGIA
Our understanding of the pathophysiology of FM has evolved significantly in recent years, but remains incomplete. The following sections briefly summarize information about alterations in neurotransmitters, neurohormones, cytokines, and regional CNS blood flow that have been documented in patients with FM.
Predisposition to FM and Triggering Events
Genetic factors may predispose individuals to FM. Sibship analysis has demonstrated possible genetic linkage of FM to the HLA region9, and a recent analysis of genetic polymorphism for catechol-O-methyltransferase, an enzyme that inactivates catecholamines, indicated that the LL and LH genotypes occurred more often in patients with FM than in controls. In addition, the HH genotype was seen less often in patients with FM than in healthy patients30. Possibly unique autoantibody patterns have been observed in patients with FM, compared to controls, but to date, none have been documented to have diagnostic or clinical relevance. For example, significant differences between serotonin antibodies have been noted between patients with FM and controls31,32, but were not considered diagnostically relevant when correlated with clinical manifestations32.
Environmental factors may play a role in triggering the development of FM, and a number of "stressors" have been temporally correlated with the onset of the syndrome, including trauma, infections (e.g., hepatitis C virus, HIV, and Lyme disease), emotional stress, catastrophic events (e.g., war), autoimmune disease, and other pain conditions16,33.
FM has been reported to coexist in 25% of patients with RA, 30% of patients with lupus, and 50% of patients with Sjögren's syndrome34-36. It is important for the clinician to distinguish the symptoms and signs of a coexistent rheumatic disease from those of FM in order to educate the patient about the potential for these conditions to coexist, and to make proper decisions about therapy. This said, it is not always possible to make these distinctions, and thus observing the results of therapeutic trials helps our understanding of the mechanisms contributing to the symptoms. The possibility exists that pain or immunologic factors contribute to the development of FM in these associations.
Several groups have documented the occurrence of distinct triggering events in patients with FM. Results from one retrospective analysis indicated that 23% of a cohort of 127 patients with FM had a potential precipitating event (trauma, surgery, or medical illness) before onset of disease26. Results from a second prospective trial of 161 patients with trauma indicated that 14.4% developed FM and that it was particularly common after neck injury37. While these results are consistent with the view that there may be a distinct triggering event for many patients with FM, those of Greenfield and colleagues also underscore the point that such an event is not apparent for many patients with this condition. No triggering event was noted for 72% of patients included in their analysis26.
Biochemical, Physiologic, and Psychiatric Abnormalities Underlying FM
Biogenic amines. The biogenic amines 5-HT and norepinephrine (NE) have a significant modulatory effect on peripheral and central pain processing38. Levels of primary metabolites of NE and 5-HT are both reduced in patients with FM39. Serum 5-HT concentrations are also abnormally low in these patients40. The decrease in 5-HT noted for patients with FM is particularly interesting because this amine is involved in several processes and disease states that may contribute to the overall symptomatology in patients with FM. First, 5-HT acts to presynaptically inhibit release of neurotransmitters involved in pain processing (e.g., substance P, excitatory amino acids) from the terminals of primary afferent neurons41. Serotonin also plays an important role in the regulation of mood, and dysregulation of the 5-HT system has been associated with both depression and anxiety42,43. Serotonin is also known to be involved in the regulation of sleep and pain perception, both of which may be altered in patients with FM43.
Substance P and amino acid neurotransmitters. The level of substance P is elevated in the cerebrospinal fluid of patients with FM44,45. Measures of pain intensity in these individuals are positively correlated with levels of the metabolites of the excitatory amino acid neurotransmitters glutamate and aspartate46. Both excitatory amino acids and substance P contribute to the transmission of pain signals via primary afferent neurons, and glutamate is probably the most common excitatory neurotransmitter in the CNS46,47. Concentrations of glycine and taurine were shown to be correlated with pain levels in patients with FM. Glycine is an inhibitory transmitter as well as a positive modulator of the N-methyl-D-aspartate (NMDA) receptor46. The NMDA receptor has been suggested as playing a key role in the nervous system reorganization thought to be involved in the maintenance of chronic pain45,48.
The increased levels of substance P and other excitatory neurotransmitters in patients with FM may be related to reduced 5-HT and the resultant decrease in presynaptic inhibition of pain-related primary afferent neurons. This view is supported by the report that there are significant negative correlations between levels of substance P and 5-HT, its precursor tryptophan, and its primary metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the serum of patients with FM. Moreover, reduced levels of 5-HIAA and tryptophan were associated with increased pain in these patients, and low levels of 5-HIAA and high concentrations of substance P were both positively correlated with more severe sleep disturbance49.
The hypothalamic-pituitary-adrenal axis and autonomic nervous system. A large body of evidence supports the relationship between stress and altered activity in both the sympathetic nervous system and hypothalamic-pituitary-adrenal (HPA) axis50,51, and results from a number of studies have documented significant dysregulation of the HPA axis in patients with FM. Such patients have elevated basal values of adrenocortical trophic hormone (ACTH) and follicle-stimulating hormone and decreased levels of insulin-like growth factor 1 (IGF-1), free triiodothyronine, growth hormone (GH), estrogen, and urinary cortisol52,53. The normal circadian rhythm for plasma cortisol levels is also disrupted in patients with FM due to abnormally elevated plasma concentrations in the evening54. Because the 5-HT system significantly influences the HPA axis, some, if not all, endocrine abnormalities observed in FM may be related to reduced levels of 5-HT observed in these patients52. It has also been suggested that the decreased levels of IGF-1 in patients with FM may be the result of a decrease in stage 4, sleep-dependent release of GH52.
Patients with FM also exhibit marked hypersecretion of ACTH in response to severe acute stressors or insulin-induced hypoglycemia, and this has been suggested to result from chronic hyposecretion of corticotrophin-releasing hormone45,53,55. The abnormal hormonal and autonomic responses in FM appear to reflect impairment in the hypothalamic or CNS response to stimuli rather than a primary defect at the level of the pituitary or peripheral endocrine glands56.
HPA abnormalities reported for patients with FM may be related to depressed autonomic nervous system function. Patients with FM have reduced plasma levels of neuropeptide Y, a peptide colocalized with NE in the sympathetic nervous system57. However, interactions between the autonomic nervous system and the HPA axis have not been clearly delineated in patients with FM45.
Cytokines. Alterations of the cytokine network are correlated with many pain states58, and cytokine abnormalities have been observed in patients with FM. Wallace and colleagues reported that levels of interleukin 1 receptor antibody (IL-1Ra) and IL-8 were significantly higher in the sera of FM patients and that IL-1Ra and IL-6 were significantly elevated in stimulated and unstimulated peripheral blood mononuclear cells from individuals with this disease59. Salemi and colleagues detected IL-1, IL-6, and tumor necrosis factor-a in about 30% of skin biopsies from 53 patients with FM, as compared to none in healthy controls60. The significance of these observations is unknown.
Regional CNS blood flow. A range of abnormalities in regional cerebral blood flow (rCBF) have been reported in patients with FM, including: flow decreases in the dorsolateral frontal cortical areas of both hemispheres61, thalamus and head of the caudate nucleus62, inferior pontine tegmentum63, superior parietal cortex, and the gyrus rectalis64. Although results of these studies support the view that patients with FM have abnormalities in rCBF, it is not clear how they relate to the pain or other symptoms experienced by these patients. Moreover, nearly all the studies that have evaluated rCBF in patients with FM are limited by very small sample sizes, and contradictory results are present in the literature. Nevertheless, neuroimaging studies will likely enhance our understanding of abnormal pain sensitivity in FM and contribute to the development of interventions aimed at altering CNS function in patients with this disease65.
Behavioral and psychologic factors. Behavioral and psychological abnormalities may also contribute to symptom maintenance in patients with FM1. The most common psychiatric conditions observed in patients with FM include depression (22%), dysthymia (10%), panic disorder (7%), and simple phobia (12%)66.
Summary
Despite extensive research, understanding of the etiology and pathophysiology of FM remains incomplete. Results from different studies have implicated a range of biologic abnormalities, including abnormal levels of peripheral and CNS neurotransmitters and dysregulation of the HPA axis. We do not know if these abnormalities play a causal role in the syndrome or are secondary phenomena. We also do not know if there is a specific "common denominator" trigger for the syndrome or multiple triggers, nor do we clearly understand perpetuating factors. No single abnormality or constellation of derangements accurately identifies all patients with FM.
Despite significant gaps in our knowledge, our understanding of pathogenesis has advanced through basic research and deductions from observing patient responses to neurophysiologically targeted therapies. A current unifying hypothesis is that there may be multiple factors that contribute to and perpetuate sensitization of the CNS, so it stands to reason that multiple approaches that lead to improvement of this state may be helpful in treatment6,7,16,17.
ASSESSMENT OF PATIENTS WITH FIBROMYALGIA
The development of specific and sensitive tools for a differential diagnosis or for assessing the effects of treatment in patients with FM is still in its infancy. Tools currently used are dimension-specific and symptom-specific and include both patient-rated and physician-rated measurements of pain, sleep, fatigue, and overall well being that also encompass mood.
Pain Assessment
Chronic generalized pain is a core feature of FM. A number of tools are available for the assessment of pain, including the daily pain diary, the Short Form-McGill Pain Questionnaire (SF-MPQ), the Brief Pain Inventory, and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS). Important issues that may influence assessment of pain in patients with FM include recall bias, use of paper versus electronic diaries to assess pain experiences, and pain scaling methods67.
A daily diary has been used to assess the impact of pain in patients with FM and has been reported to be useful for demonstrating the manner in which pain influences activities of daily living in these individuals68.
The MPQ can provide detailed information on the characteristics of pain in FM. It includes 78 pain adjectives that are divided into 4 major categories (sensory, affective, evaluative, and miscellaneous sensory). This index takes 10 to 15 minutes to complete. The SF-MPQ, consisting of 15 adjectives (11 sensory, 4 affective) taken from the full MPQ, has been validated69. The MPQ did not differentiate pain associated with FM versus that associated with RA, when administered in the standard manner70. However, when patients were allowed to select as many words from an adapted MPQ as they wished, significant differences in word choice emerged. Results from another study that used the MPQ to compare patients with FM, RA, or ankylosing spondylitis indicated significantly higher general pain intensity in FM71.
The Brief Pain Inventory, originally developed for the assessment of cancer pain but now validated in chronic pain states, comprises multiple questions regarding pain intensity, the role of pain in interference in the patient's life, pain relief, pain quality, and patient perception of the cause of pain72.
The LANSS Pain Scale is an instrument developed to diagnose neuropathic pain and to differentiate it from nociceptive pain. It has been employed in a comparison of patients with FM versus those with RA, and study results showed that thermal pain severity was similar in both groups, but that higher percentages of patients with FM reported dysesthetic, evoked, paroxysmal, or thermal sensory disturbances. The LANSS Pain Scale items may be particularly useful for differentiation of FM pain from nociceptive pain present in RA and other arthritic diseases73.
Tender point assessment is a demonstrably useful part of the official ACR criteria for the diagnosis of FM10,74. However, tender points are not unique to the syndrome. Tenderness is widespread in patients with FM rather than being confined to specific anatomic regions, and these individuals may also demonstrate more hypersensitivity to heat, cold, and electrical stimulation. Some methods of assessing tenderness (e.g., dolorimetry) may demonstrate increased pain sensitivity in patients with FM more objectively than palpation, and are relatively independent of biasing factors or patient distress75. In addition to tender point count, assessment of tender point intensity or score has been developed as an assessment tool. The FM Intensity Score (FIS) is obtained by averaging the pain intensity scores (on a 0–10 scale) for the 18 sites assessed in the Manual Tender Point Survey. It has been suggested that the FIS might be helpful when patients are followed through serial examinations over time and for making comparisons among patients76. Whereas clinical trials require tender point assessment as part of the diagnostic criteria for trial entry, there have been variable results utilizing tender point count or score as an outcome measure, thus raising questions about its discriminative ability as a pain assessment tool.
Fatigue
Fatigue is one of the core features of FM, and its measurement is important in both the research and clinical settings. The Multidimensional Assessment of Fatigue index is a 16-item instrument developed to provide information about this symptom69,77. A variety of other measures exist and have proven useful in measuring fatigue in other rheumatic diseases, such as RA and ankylosing spondylitis. These include the Multidimensional Fatigue Index, which measures various types of fatigue including physical and emotional78. Another measure, validated in a number of disease states, is the Functional Assessment of Chronic Illness Therapy system79, which may be customized to certain disease indications. The Fatigue Severity Scale, originally developed for multiple sclerosis and lupus fatigue assessment, may also prove useful80.
Sleep
Sleep quality can be assessed on a 100 mm linear scale with "sleep is no problem" at one extreme and "sleep is a major problem" at the other extreme. Similar scales can be used to rate number of awakenings, and "restedness" on awakening in the morning69. The Medical Outcome Study (MOS) sleep scale is an example of an instrument used in an FM trial81.
Quality of Life and Functional Assessment
Measurement of global sense of well being, quality of life, and functional capacity in multiple dimensions (physical, vocational, social, emotional) is a key area of assessment and is considered essential by regulatory agencies when contemplating approval of medications for chronic pain states82,83. Other than the general knowledge that patients with FM are poorly functional relative to healthy individuals and other rheumatic disease patients, our ability to fully measure all dimensions of this dysfunctionality needs refinement. A newer mandate in this arena of assessment that needs to be addressed is that of "participation," requested by the World Health Organization as a measure of the ability of the individual to participate fully in all aspects of life84.
The Patient Global Impression of Change has been used in evaluations of treatments for FM and is correlated with pain intensity81.
The MOS Short Form-36 (SF-36) Health Survey is a generic instrument with 8 subscales85. Assessment with the SF-36 has shown that patients with FM have reduced physical functioning, physical role functioning, body pain, general health, vitality, and social functioning versus healthy subjects. Results for the SF-36 subscales of physical functioning, body pain, and social functioning in FM patients are highly correlated with functional disability as assessed by the HAQ86.
The FM Impact Questionnaire (FIQ) is a simple instrument specifically designed to reflect changes in the FM patient's general status over time. It includes 10 questions and takes about 5 minutes to complete. The questions are designed to quantify functional disability, pain intensity, sleep disorder, muscular stiffness, anxiety, depression, and overall sense of well being; visual analog scales (VAS) are used to evaluate pain, fatigue, morning stiffness, stiffness severity, depression, and anxiety87.
While the FIQ has been used effectively to assess effects of treatment in patients with FM, it does have significant limitations. It was originally developed to assess the current health status of women with this disease, and its validity in men has not been established. However, results from one study of women and men with FM indicated that both genders had decreased physical functioning as demonstrated by the FIQ physical function subscale88. The FIQ is also limited because respondents may report items on the physical function subscale as "not applicable," and this may result in underestimation of the functional impact of disease89. Finally, the FIQ functional component is aimed at evaluating high levels of disability, and this may limit its ability to detect significant effects of treatment in patients with mild disease. This limitation is supported by the fact that 12% of FM patients in one study scored zero on the FIQ physical function score (i.e., no dysfunction)89.
Assessment of sexual function is important both as an important domain of human function but also because of the potential for adverse effects of medications on sexual function. An instrument used in an FM trial is the Arizona Sexual Experiences Scale90.
Psychological and psychiatric assessment.
Psychological evaluation of the patient can provide useful information about the psychological and behavioral features that may influence their pain and dysfunction as well as provide a sense of the impact of pain, fatigue, and other symptoms on their psychological health. It is often presumed that patients with a greater psychological impairment and/or psychiatric pathology may be more symptomatic or resistant to improvement with therapeutic intervention. However, this assumption may be true only in some cases. Both in clinical practice and in drug trials, it is important to diagnose and effectively treat concomitant depression, anxiety, bipolar states, and especially suicidal tendencies. In addition to a careful history, a number of screening tools are available for both clinical and research purposes, including the Beck Depression Inventory91 and the Mini-International Neuropsychiatric Interview92. In clinical practice, diagnosis of such conditions as depression, anxiety, and bipolar disorder can lead to proper therapy of these comorbid conditions and screen for those with suicidal tendencies. In research trials such instruments can be used to either exclude patients with certain psychiatric diagnoses for safety reasons, or stratify patients, e.g., those with and those without major depression, in order to observe if there are differences in treatment outcomes relative to these comorbid conditions. Turk, et al have provided a recent review of this area93.
What constitutes a clinically meaningful response to treatment in a patient with FM?
The wide variety of tools available for assessment of patients with FM has resulted in significant heterogeneity in the manner in which this disease is assessed, and in how potential treatments for it are evaluated in clinical trials. This heterogeneity has made it difficult to determine the relative effectiveness of different medications being developed for treatment of FM. There is now an effort under way to achieve greater standardization of assessment.
One of the main problems in developing an efficacy claim for FM is the lack of consensus about response criteria that could be used as a primary outcome measure in clinical trials. In June 2003, the US Food and Drug Administration (FDA) Arthritis Advisory Committee met to discuss the development and approval of drugs to treat FM. A transcript of the meeting can be viewed at http://www.fda.gov/ohrms/dockets/ac/03/transcripts/3967T1.htm.
Limitations of current approaches
The primary outcome measure most often used in trials of agents being developed for the treatment of FM is mean reduction in pain intensity. This approach does not adequately address the critical question of whether or not a statistically significant reduction in pain intensity versus placebo with a given treatment is clinically significant or meaningful.
Detection of meaningful change in the condition of patients being treated for FM
Dunkl and colleagues94 assessed the responsiveness of the FIQ, patient ratings of pain intensity, number of tender points, and total tender point pain intensity score to perceived changes in clinical status in patients with FM enrolled in a clinical trial of magnetic therapy. Individual measures were responsive to perceived improvement in health status, but relatively unresponsive to perceived deterioration. The FIQ total score equaled or outperformed all other measures in its ability to detect clinically important change. However, the patients in this trial were predominately women, and the results may not generalize to men with FM.
Hewett and associates95 employed a growth curve model approach to estimate reliability of change for data (46 variables) obtained in a randomized clinical trial comparing biofeedback/relaxation, exercise, a combined program, and education in patients with FM. The variables with the best reliabilities for detecting a change in clinical status were the Myalgic Score, the Tender Point Score, the Tender Point Index, the number of words chosen from the MPQ, and 2 anxiety scales from the Symptom Checklist-90-Revised. These findings suggest that measures of tenderness should be responsive to treatment in clinical trials. However, metaanalyses from studies in which antidepressants were used to treat patients with FM revealed that tenderness only minimally improved with active therapy96. Further, in the trial of pregabalin in FM, the Manual Tender Point Survey did not significantly improve with pregabalin versus placebo despite improvement in pain, sleep, fatigue, global well being, and function scores97.
Responder analysis
An alternative approach to defining efficacy is development of a clinically meaningful criterion for a response to therapy. This approach might permit more meaningful comparison from different studies and perhaps also facilitate definition of factors that predict a positive response to therapy98. The question of what constitutes a meaningful change in pain scores has been addressed in a pooled analysis of results from patients enrolled in 10 studies of pregabalin for the treatment of osteoarthritis, low back pain, FM, and peripheral neuropathy99. In all these trials, pain intensity was measured using an 11-point pain intensity numerical rating scale. Comparison of changes in pain intensity scores with patients' global impression of change over the course of the trial indicated that a reduction of about 2 points or 30% in the pain intensity score represented a clinically important difference, defined as a patient report of "much improved" or "very much improved." A 50% reduction in pain was associated with the highest degree of improvement ("very much improved").
It is not known whether improvement in pain intensity alone should define response to treatment in FM, a syndrome characterized by multiple symptoms, including reduced quality of life, impaired physical, social, and emotional function, sleep disturbance, fatigue, and cognitive impairment.
In an attempt to develop a multicomponent criterion for response to treatment in patients with FM, Simms and colleagues100 proposed that a meaningful response to treatment should be considered to have been achieved if patients met 4 of the 6 following criteria: 50% reduction in pain, sleep, fatigue, patient global assessment, or physician global assessment, and increase of 1 kg in mean total myalgic score. Application of these criteria in a trial that compared amitriptyline, cyclobenzaprine, and placebo in patients with FM indicated that about one-third of patients had at least short-term responses to active treatment101.
Simms and colleagues98 attempted to improve the definition for a response to FM therapy by testing criteria with known effective treatment as a gold standard. A set of preliminary criteria was developed using data from a placebo-controlled clinical trial of amitriptyline versus naproxen102. In this study, only amitriptyline was significantly more effective than placebo, and the proxy for a response was treatment with amitriptyline. The combination of outcome measures with the highest sensitivity in discriminating between patients receiving amitriptyline versus those treated with placebo or naproxen was change in physician global assessment, change in tender point score, and patient sleep assessment. This analysis resulted in the response criteria composed of physician global assessment, patient-assessed sleep score, and tender point score. For details see Simms, et al 98.
These criteria are limited for several reasons. First, reduction in pain, a cardinal feature of FM, did not discriminate between groups and was not included. Second, the trial did not include other possible indicators of response such as functional status or patient global assessment. Third, application of the criteria would require that patients have sufficiently severe symptoms at baseline for entry. Finally, response criteria developed from a trial of amitriptyline might not be applicable in patients receiving other treatments.
More recently, Dunkl, et al94 proposed preliminary criteria for identifying responders in FM clinical trials that were based on a study of magnetic therapy in patients with this disease (Table 1). These preliminary criteria identified responders with a sensitivity of 70.5% and specificity of 87.5%. However, they have not been validated in other clinical trials.
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The studies reviewed in the preceding paragraphs underscore the need for a single generalizable definition for a response to medical therapy in patients with FM. Although responder analysis necessitates dichotomizing continuous outcome variables and might introduce bias103, the benefits of this approach outweigh the potential dangers. A response criterion or index provides the advantage of grouping clinically important results into a metric that defines individual response as the primary outcome. Clinical decisions can then be made on the basis of individual response, rather than inference from the patient's response as part of a group mean. This approach also permits combined evaluation of multiple measures of improvement in the same patient104.
Outcome measures in FM and OMERACT
The large number of instruments briefly reviewed in the preceding sections should make clear that the clinician/researcher is faced with a wide and confusing array of choices for the assessment of disease severity and the effects of interventions in patients with FM. Outcome Measures in Rheumatology Clinical Trials (OMERACT), an informal international network with the goal of improving outcome measurement in rheumatology, has recognized the need to develop consensually approved and validated instruments to assess clinical responses to treatments in patients with FM. An FM working group will be applying the OMERACT "filter" (truth, discrimination, feasability) to develop and refine instruments that yield valid results, are able to discriminate between placebo and treated groups, and are feasible105. There is also increased interest in developing a composite outcome measure of such key domains as pain, global sense of well being, function (considered multidimensionally), fatigue, and sleep disturbance.
The work of the OMERACT FM group is analogous to the work being done by chronic pain researchers, the IMMPACT group (Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials). IMMPACT is a partnership between researchers, industry, and the FDA to determine which key outcomes should be measured in chronic pain trials. Their current consensus is that these domains should include pain, physical and emotional functioning, patient global ratings of satisfaction, negative health states, adverse events, and patient adherence and disposition82,83.
TREATMENT OF FIBROMYALGIA
Many patients with FM benefit from a multidisciplinary approach in clinical practice. Nevertheless, pharmacologic treatment remains the primary approach to management for the majority of patients with FM5. Despite some success with currently used medications, there is a large unmet need for effective pharmacotherapy in FM. Further, there are presently no treatments for this disease approved by the FDA or the European Registry. The complexity of FM and the presence of multiple symptoms makes it challenging for pharmaceutical companies to mount effective clinical trials to assess emerging pharmacotherapies. However, this is changing, as there have been several recent large trials that have successfully distinguished treatment from placebo in multiple domains in a valid and feasible manner.
Pharmacotherapy for Fibromyalgia
A number of classes of medications have been evaluated in patients with FM (Table 2). Nearly all have demonstrated effectiveness in reducing pain, but fewer have demonstrated significant efficacy in improving the other major symptoms of the disease: fatigue, sleep disturbance, and mood abnormalities106.
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Table 2. Efficacy of currently available treatments for fibromyalgia. Adapted from J Rheumatology 1999;26:408-120
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Antidepressants. Given the disturbances in biogenic amines documented for patients with FM, it is not surprising that agents interacting with these aminergic systems have been tested extensively in this disease.
Tricyclics. Amitriptyline, doxepin, and cyclobenzaprine are the most common agents used for FM in the US88,107. A metaanalysis of 9 controlled trials of tricyclics (TCA) in the treatment of FM has demonstrated that agents in this class produced significantly greater effects than placebo in physician and patient overall assessments, pain, stiffness, tenderness, fatigue, and sleep quality (Figure 2). The greatest improvements were in measures of sleep quality, and the smallest were for measures of stiffness and tenderness96.
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Figure 2. Size of effect by type of outcome measure in 9 controlled studies of tricyclic treatment of FM. From Turk, et al. Rheum Dis Clin North Am 2002;28:219-3396, with permission.
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Selective serotonin reuptake inhibitors. Selective serotonin reuptake inhibitors (SSRI) have shown somewhat disappointing results in FM. Wolfe, et al conducted a study with a fixed dose of fluoxetine over 6 weeks, which showed improvement in depression scores but no benefit in other aspects of FM, including pain108. On the other hand, Arnold, et al showed that by using a flexible dose of fluoxetine, benefit could be achieved. In a 12-week trial with 51 patients, patients could upwardly titrate their dose of study drug. Statistically significant improvements in FIQ total and MPQ were achieved with a mean dose of 45 mg/day109. The combination of fluoxetine and amitriptyline was shown to be more efficacious in FM than either agent alone or placebo110. In one randomized, double-blind, placebo-controlled, 4-month trial study of citalopram (2040 mg/day), 40 female patients, 21 in the citalopram and 19 in the placebo group, who fulfilled ACR criteria were enrolled. VAS, the Montgomery Asberg Depression Rating Scale, and FIQ were used to assess pain, depressive symptoms, and physical functioning. The results indicated no significant advantage of active treatment over placebo with respect to pain or well being. However, among those who completed the study, there was a tendency for more patients in the citalopram group (52.9%) to have improved well being versus placebo (22.2%). Citalopram was also significantly superior to placebo in improving depression111. A second trial with citalopram also did not show improvement in the pain of FM112. Thus, SSRI may play a role in improvement of mood and possibly fatigue, but appear to have little impact on pain or other manifestations of FM.
Serotonin/norepinephrine reuptake inhibitors. Newer medicines are capable, as seen in TCA, of inhibiting reuptake of both serotonin and norepinephrine (SNRI), but with fewer side effects. SNRI milnacipran, currently licensed for treatment of depression in Europe and Asia, was used in a placebo-controlled trial based on the postulate that the greater ratio of norepinephrine to serotonin reuptake inhibition effect would render it superior for pain treatment. In this 12-week trial, 125 patients were randomly prompted to record, on an electronic hand-held device, their level of pain, fatigue, and sleep, as well as quality of life information. Patients using the medication twice a day achieved statistically significant improvement in weekly average daily pain scores as well as patient global impression of change, fatigue, and function as measured by components of the FIQ and SF-MPQ. Thirty-seven percent were responders, achieving a 50% Gracely scale improvement in pain. The drug was generally well tolerated113.
Duloxetine, another new SNRI, was tested at a 60 mg bid dose in a placebo-controlled trial in 207 subjects with FM over 13 weeks. The co-primary outcome measures were the total FIQ and the FIQ pain score. Although treated patients had statistically significant improvements on the total score, they did not improve on the FIQ pain score. However, they did improve on the Brief Pain Inventory score, a secondary outcome measure. Other measures showing improvement included: tender point number and pain threshold, global impression of change, and several quality of life measures. Among the small number of male patients no significant improvement was observed. There were no significant tolerability issues114.
Venlafaxine, also an SNRI, has been assessed at 75 mg/day in a 12-week study of 15 patients with FM. The primary outcome measures were the FIQ total score and pain score. Anxiety and depression were measured with Beck Depression, Beck Anxiety, Hamilton Anxiety, and Hamilton Depression scales. Venlafaxine treatment significantly reduced pain (F = 14.3; p = 0.0001) and disability caused by FM (F = 42.7; p = 0.0001). It also significantly decreased both physician and patient-rated depression and anxiety115.
Monoamine oxidase inhibitors. Monoamine oxidase inhibitors (MAO-I) block the catabolism of 5-HT and thus increase its level in the brain. Preliminary studies with moclobemide, a second-generation MAO-I, failed to demonstrate significant analgesic activity in patients with FM when compared with amitriptyline. Results from a recent study with another MAO-I, pirlindole, indicated that there were significant beneficial effects on sleep, fatigue, and mood in FM patients106.
5-HT3 receptor antagonists. Clinical trials have shown that a 5-HT3 receptor antagonist has significant clinical efficacy in patients with FM. Tropisetron, a selective, competitive 5-HT3 receptor antagonist, was tested in a short-term study of 418 patients with FM. Patients were randomly assigned to receive placebo or 5 mg, 10 mg, or 15 mg/day of tropisetron. Clinical response was measured by changes in pain score, VAS, tender point count, and ancillary symptoms. Responders were prospectively defined as patients showing a 35% or higher reduction in pain score. Treatment with the 5 mg dose of tropisetron resulted in a significantly higher response rate (39.2%) than placebo (26.2%) with a mean reduction in pain score of 55.4%. Higher tropisetron doses were not effective116, which is consistent with the observation that 5-HT3 receptor antagonists may have nociceptive and antinociceptive effects under different circumstances. The mechanism by which 5-HT3 receptor antagonism reduces FM-associated pain and other symptoms is not understood; it has been suggested that these benefits may be secondary to reduced release of substance P117.
Antiepileptic drugs. Antiepileptic drugs (AED) have been demonstrated to be effective in a variety of different types of neuropathic pain118 and are widely used as analgesics. It has been suggested that the pain of FM has a neuropathic origin119. Gabapentin has been used clinically, and a placebo-controlled trial in FM is being conducted (Arnold LM, personal communication). A newly developed AED, pregabalin, was shown to be effective for treatment of FM97. Pregabalin (up to 150 mg tid) was evaluated in an 8-week, randomized, double-blind, placebo-controlled, parallel-group trial that included 529 patients. Pregabalin was superior to placebo in reducing scores for pain, SF-MPQ, MOS Sleep Index, fatigue, Patient Global Impression of Change, Clinician Global Impression of Change, and 4 of the 8 domains on the SF-36. Twenty-seven percent of patients achieved a responder status of 50% improvement. The most common adverse events were dizziness and somnolence, and overall tolerability was good97. Pregabalin is also effective for postherpetic neuralgia and painful diabetic neuropathy, for epilepsy, and for generalized anxiety disorder120-123.
Opioids. Opioids have analgesic activity and are used in some patients with FM. However, their use is generally limited because of concern about addictive potential and other adverse effects106.
Tramadol. Tramadol, a weak µ-opioid receptor agonist that also inhibits reuptake of 5-HT and NE, is effective for treatment of FM-associated pain112. In a 6-week, randomized, double-blind, placebo-controlled study to evaluate efficacy of tramadol 50–400 mg/day dose in the treatment of pain of FM, 35 patients were randomized to the tramadol group and 34 to a placebo group. Kaplan-Meier estimate of cumulative probability of discontinuing the double-blind treatment period because of inadequate pain relief was significantly lower in the tramadol group compared to placebo group (p = 0.001). Twenty (57.1%) patients in the tramadol group successfully completed the study compared with 9 (27%) in the placebo group124. In a more recent trial with the combination of tramadol and acetaminophen, 315 patients were studied in a placebo-controlled fashion for 91 days. The primary endpoint was length of time until discontinuation due to lack of efficacy. This occurred significantly less frequently in the tramadol group, 29 patients as compared to 51, and the overall discontinuation due to any reason was also less in the treated group: 48 versus 62125.
Muscle relaxants. Muscle relaxant medications are used both chronically for FM as well as on a short-term basis for symptom flares. However, there has been little systematic study of their effectiveness. Cyclobenzaprine, considered to be a muscle relaxant but with significant similarity to tricyclics in chemical structure, has been assessed in 4 randomized trials, 2 of which were positive101,126-128. Other muscle relaxants have been used, but have not been subjected to controlled trials in FM.
N-methyl-D-aspartate receptor antagonists. The NMDA receptor may play a key role in nervous system reorganization thought to be involved in maintenance of chronic pain48, and it has been shown that NMDA receptor blockade can relieve pain in patients with FM129,130. However, the cognitive side effects of NMDA receptor blockade may limit use of NMDA as FM therapy106.
Dopamine agonists. A new dopamine agonist, pramipexole, used for Parkinson's disease and restless leg syndrome, is being tested in a placebo controlled trial in FM, following positive results in a single open-label trial131.
Sedative hypnotics. Sedative hypnotic agents, including zopiclone and zolpidem, have been used in patients with FM, and have been shown to improve sleep and relieve fatigue. Other agents include gamma hydroxybutyrate (a precursor of gamma-aminobutyric acid with powerful sedative properties), melatonin, and pramipexole, have also been shown to act on symptoms of FM106. Several antidepressant agents, such as amitriptyline and trazodone, are used in low dosage for their sedative properties.
Growth hormone. A number of studies have demonstrated that growth hormone or insulin-like growth factor-1 (IGF-1) levels are reduced in patients with FM53. Bennett, et al employed growth hormone supplementation subcutaneously in a placebo-controlled trial in 45 FM patients for 9 months132. The treatment group showed improvement of overall symptoms and tender points. Carpal tunnel syndrome occurred in 7 patients, possibly as an adverse drug event. Despite these positive efficacy results, Geenen, et al suggest caution in utilizing this approach in consideration of potential side effects and the potential for hindering endogenous growth hormone production53. GH analogs are being studied in FM.
Nonsteroidal antiinflammatory drugs. NSAID (including cyclooxygenase-2 selective agents) and acetaminophen are used in the treatment of FM for their analgesic properties, but there is limited evidence to support their effectiveness in patients with this condition106.
Pharmacotherapy of associated symptoms. Patients with FM will benefit from selective attention to associated symptoms, which often results in overall improvement by reduction of symptom burden. Fatigue may be improved with the use of SSRI (see above) or modafinil. A small open trial with the latter demonstrated improvement in fatigue but not in pain129. A variety of approaches are used to treat irritable bowel syndrome, including dietary fiber, antispasmodics, both laxatives and antidiarrheal agents, and more recently, the 5-HT3 antagonists5. Irritable bladder syndrome may be treated with antispasmodics, biofeedback, and forms of physical therapy, as well as urethral dilatation5. Various analgesic medications, beta blockers, calcium channel blockers, and other agents may improve headache, and migraine-specific medications aid migraine5. It is important not to overmedicate this problem, which may lead to medication-induced chronic headache. Temporomandibular joint dysfunction may be treated with dental prostheses, biofeedback, and treatment of associated trigger points5. Restless leg syndrome may be treated with clonazepam or antiparkinsonian medications at bedtime. These are but a few of the examples of treatment of associated symptoms.
Summary
A wide range of agents have been employed in the treatment of patients with FM. However, only a small number of these medications have demonstrated effectiveness in controlled clinical trials. Antidepressants, primarily tricyclics, are effective, but they have a relatively narrow therapeutic index, and their use may be limited by poor tolerability133. SSRI have better tolerability than TCA, but do not appear to be as effective in relieving the wide range of FM-associated symptoms106. Medications that inhibit reuptake of both norepinephrine and serotonin (SNRI), such as milnacipran and duloxetine, show promise in treating both pain of FM and associated symptoms of sleep disturbance and fatigue, yet with fewer side effects than traditional TCA67,114. The new antiepileptic pregabalin has been shown to be effective for reducing many of the symptoms associated with FM and is well tolerated97. This agent appears to work through binding to the a2g subunit of voltage-gated calcium channels. Its efficacy for this indication, as well as for neuropathic pain, may shed further light on the pathophysiology of FM120. There also is interest in a related compound, gabapentin, which is currently being tested in FM (Arnold LM, personal communication).
Nonpharmacologic Treatment
A variety of nonpharmacologic treatments have been demonstrated to have at least modest efficacy in patients with FM.
Cognitive behavioral therapy. Psychological and behavioral therapies are being used in the treatment of FM with increasing frequency. The rationale for including psychological therapies is improved management of psychological and social factors that may influence perception and maintenance of chronic pain in these patients134. It has been suggested that patients with FM experience significantly greater daily stress than individuals without this disease, and it has been shown that inclusion of cognitive behavioral therapy as part of the treatment regimen for patients with FM can improve physical functioning135.
Exercise. Exercise programs, including strength and flexibility training, have been shown to have positive effects in patients with FM, improving both mood and physical function136. A controlled trial of graded aerobic exercises versus relaxation and flexibility training indicated that the former treatment resulted in a significantly greater percentage of participants rating themselves as much or very much better at 3 months. Exercise also resulted in a reduction in the number of patients fulfilling the ACR criteria for FM, decreased tender point counts, and improved FIQ scores137. Review of randomized controlled trials has resulted in the recommendation that low intensity aerobic exercise, such as walking, can improve function and symptoms in patients with FM. This exercise should be performed twice weekly at moderate intensity. Because of the highly variable levels of functioning and symptom severity in patients with FM, exercise prescriptions should be individualized138.
Sleep hygiene. A variety of approaches can be used to improve sleep in patients with FM in addition to pharmacotherapeutic approaches discussed previously. These include behavioral approaches, fitness, and regular proper nutrition that may reduce disturbances in circadian sleep-wake rhythms. Diagnosis and treatment of comorbid conditions such as sleep apnea can be helpful. These and other issues related to sleep physiology have been recently reviewed139.
Alternative therapies. Complementary and alternative medicine (CAM) has gained increasing popularity, particularly among individuals with FM, for whom traditional medicine has generally provided inadequate benefits. Alternative therapies, including osteopathic manipulation, acupuncture, low-power laser therapy, balneotherapy (20-minute bathing, once a day, 5 times per week, for a 3-week period), and sulfur baths, have all demonstrated beneficial effects in relieving at least some symptoms of FM136. In general, there are only very limited data from well controlled trials to support any alternative therapies in patients with FM140.
Summary
The range of pharmacologic therapies that have efficacy in relieving at least some symptoms in subsets of patients with FM and the fact that no single treatment is completely effective in all patients suggest that multiple pathogenic mechanisms may contribute to FM and that their influence may differ from one patient to another. The multifaceted nature of FM suggests that multimodal, individualized treatment programs that combine pharmacologic and nonpharmacologic therapies may be necessary to achieve optimal outcomes in patients with this syndrome.
CONCLUSION
FM is a relatively common disorder that encompasses symptoms of chronic, widespread pain, often in association with other clinical manifestations such as sleep disturbance, fatigue, and mood disorders. Our understanding of the pathophysiology of this condition is increasingly focused on neurotransmitter and neurohormone dysregulation and central sensitization of the nervous system. It is anticipated that increased understanding may lead to more targeted therapies. Currently available effective treatments for FM appear to share common mechanisms of modulating neurotransmitters related to perception and pathogenesis of pain. Nevertheless, no single agent is likely to be completely effective in relieving all FM-associated symptoms, and a multifaceted, integrated approach to treatment will continue to be needed to achieve good treatment outcomes in patients with this syndrome. Recent FM-specific studies with emerging medications demonstrate the ability of the medications to be partially effective in multiple symptom domains such as pain, fatigue, sleep disturbance, quality of life, and function. The outcome measures used in these trials have been able to discriminate treatment response. Further refinement of these measures, including development of a composite response measure, is desirable to most accurately assess treatment effect.
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