Features

Fibromyalgia: A Distinct Disease

Molly T. Vogt, PhD; Amalie Andrew, BA; Terence W. Starz, MD

From its beginnings as an entity on the medical fringe, fibromyalgia has now gained recognition as a distinct disease to the point where the FDA has approved the first drug specifically for its treatment. But while patients can be reassured that they are not “imagining things,” diagnosis and management continue to pose major challenges.

Women experience chronic pain disorders more frequently than men. At any given time, 50% of the population has musculoskeletal pain: 25% report chronic pain (lasting 3 months or more) in specific musculoskeletal regions, and 10% report widespread pain involving multiple locations. Most research indicates that compared with men, women report pain that is more severe, more frequent, and of longer duration. The most severe manifestation of chronic, widespread pain is the fibromyalgia syndrome (FMS), which occurs in 2% to 3% of the general population.1,2

back to top

DEFINITION

Fibromyalgia syndrome is characterized by chronic, generalized musculoskeletal pain, tender points, and a spectrum of multisystem manifestations.3-5 Widespread musculoskeletal pain has been recognized since ancient times, variously labeled as lumbago, psychogenic rheumatism, and fibrositis. Only recently has FMS has been recognized as a discrete syndrome in terms of its manifestations, epidemiology, pathophysiology, management, and socioeconomic impact. Fibromyalgia represents a sensitization of the nervous system with pain amplification. Diagnosing FMS remains a challenge, but the American College of Rheumatology (ACR) developed criteria in 1990 that include:

• Three or more months of widespread musculoskeletal pain above and below the waist, on the right and left sides of the body, and along the midline
• Pain in at least 11 of 18 specific locations (tender points) throughout the body.6

back to top

EPIDEMIOLOGY

Chronic widespread pain occurs in 7% to 10% of the general population. Based on the current ACR criteria, 20% to 50% of those have FMS.1,2 The disorder occurs in more women than men—7:1 in the United States, and 3:1 in Canada.1,2 Prevalence increases sharply with age, ranging from less than 1% in those aged 18 to 24 years to more than 7% by the sixth and seventh decades. The prevalence of FMS is reported to be slightly higher among black women and other nonwhite groups compared with white women, but the data are not definitive.

Data suggest that the incidence of FMS may be rising. For instance, FMS diagnoses in the United Kingdom increased from 1 per 100,000 patients in 1990 to 35 per 100,000 in 2001, but this may be due to publication of the ACR criteria and increased recognition. The disorder now accounts for 33% of all patient visits to rheumatologists, and for 20% to 30% of their referrals.7

Key Points

Advances in understanding pain processing mechanisms have demonstrated that fibromyalgia syndrome (FMS) represents a sensitization of the nervous system with pain amplification. FMS occurs primarily in women, and the prevalence increases markedly with age. Although the ACR developed diagnostic criteria for FMS in 1990, definitive diagnosis continues to be challenging. No confirmatory laboratory or imaging studies are available. Evaluation for FMS begins with a careful history and physical examination, including tender-point evaluation. The Manual Tender Point Survey has been developed for assessing tender points. Targeted interventions to modulate pain processing activities in FMS are not yet available, and nonpharmacologic and pharmacologic measures are still primarily directed at alleviating symptoms.

back to top

PATHOGENESIS

There is no single pain center in the body. Pain processing occurs within a matrix of three separate but highly integrated components: peripheral pain generators, the spinal cord, and the brain. Peripheral pain generators are located in musculoskeletal tissues, and include receptors, nerves, and neuromediators. The activity of the pain matrix is influenced by the intensity and duration of the stimulation and by the character of the microenvironment. For example, repeated stimulation of sensory nerve fibers can sensitize pain receptors, increasing the release of the mediator substance P from nerve endings and lowering the firing threshold of the nerve.

In FMS, there is a central processing disruption with hypersensitization of the pain-generating mechanisms in both the spinal cord and the brain (central sensitization). Second-order neurons in the spinal cord are also affected, reducing their threshold for activation. In addition, neurons not usually involved in pain processing (eg, wide-dynamic-range neurons) are stimulated expanding dispersion of the pain signal. Third-order pain neurons from the medial thalamus may be involved as well, transmitting signals to frontal brain areas, the limbic system, and the hypothalamus, which significantly influences pain perception and response. With a greater understanding of central sensitization, its activation by a variety of stressors, and disturbances of the autonomic nervous system and endocrine function, aberrations of pain processing in FMS are becoming less elusive.

Pain mechanisms in various brain structures differ between women and men, as do hormonal effects and pain modulation. For example, the amygdala functions differently: in women, visceral pain results in activation of the left amygdala, whereas in men the left amygdala seems to be deactivated and their primary response to visceral pain is focused on the fight-or-flight mechanisms. In addition, hormones such as luteinizing hormone, progesterone, and testosterone can influence neurotransmitters and the endogenous opioid pain-control system. Such dissimilarities in pain processing may explain why FMS predominantly affects women.

back to top

RISK FACTORS

The etiology of FMS is probably multifactorial. Most people with FMS have a history of localized or widespread pain prior to onset8: ie, FMS likely represents the final stage of an evolving pain syndrome. Cross-sectional studies suggest that in addition to female gender and increasing age, lower educational level, smoking, and high body mass index are associated with a greater severity of FMS symptoms.3-5 Depression is strongly associated with FMS, even though many patients with FMS are not depressed.4 Other possible risk factors include osteoarthritis (especially cervical or lumbar), rheumatoid arthritis, temporomandibular joint syndrome, various types of trauma, and a history of infections (eg, Epstein-Barr virus, Lyme disease, hepatitis C, human immunodeficiency virus). Relatives of patients with FMS are also more likely to develop FMS and/or regional pain conditions. Increased pain sensitivity and major mood disorders likewise aggregate in relatives. Genotypic analysis of patients with FMS suggests that polymorphisms of genes influencing neurotransmitters involved in pain processing (eg, serotonin) may play a role in the etiology.

back to top

GENDER

In addition to higher prevalence, women report more FMS symptoms (eg, sleep problems, fatigue, and generalized pain). However, patient self-reports of psychological symptoms, pain severity, disability level, and overall severity of illness are similar in US men and women with FMS.9,10 The reasons for these sex-related differences and similarities are unclear, but probably involve genetic, physiologic, and psychosocial factors.

back to top

CLINICAL MANIFESTATIONS

The most characteristic manifestation of FMS is widespread musculoskeletal pain, usually described as deep muscular aching. Concurrent manifestations may include IBS, migraine headache, hand and foot swelling and numbness, morning stiffness, chronic pelvic pain, dysmenorrhea, and restless leg syndrome. A common pathophysiologic mechanism in all of these disorders is dysfunction in the autonomic nervous system. Sleep disturbances with unrefreshed waking occurs in more than 90% of patients with FMS. Brain-wave abnormalities are demonstrated on electroencephalography, with an α-wave intrusion into normal δ-wave sleep. Mood disorders such as anxiety and depression are present in 20% to 40% of patients with FMS. In addition to the disease itself, these affective disorders may be attributable to coping mechanisms, “sick-role” behavior, and life impact. Patients may experience significant fatigue with impaired cognition and memory (“fibro fog”), which often result in considerable distress and interfere with activities of daily living.

back to top

TREATMENT

Given the complexities of FMS, a multi-disciplinary approach is required for evaluation and management. Evaluation begins with a careful history and physical examination, including assessment for tender points. A standardized protocol, the Manual Tender Point Survey (Figure),11 has been developed for this purpose. Concurrent diseases such as other rheumatologic and psychological disorders should be considered, and mimics such as hypothyroidism and polymyalgia rheumatica excluded. There is no laboratory or imaging study that can confirm the presence of FMS, but the 1990 ACR criteria are helpful in establishing the diagnosis. Patients often express relief when they receive a specific diagnosis and other conditions (eg, neurologic, musculoskeletal, neoplastic) are eliminated.

Click to enlarge

FIGURE. Locations of tender points according to the 1990 ACR fibromyalgia criteria (Manual Tender Point Survey).

Treatments with nonpharmacologic and pharmacologic measures are still primarily directed at alleviating symptoms. Targeted interventions to modulate pain processing activity are not yet available. Patient education via discussion and literature is essential. Patients with FMS are often in poor physical condition, and appropriate exercise and functional activity programs with physical and occupational therapists should emphasize pacing and determining pain thresholds. The use of local heat and cold can be beneficial, and patients often describe transient relief with massage therapy. Psychosocial counseling, including cognitive behavior strategies from practitioners with experience in FMS, can help patients and their families cope with symptoms and adjust their lifestyles. Complementary and alternative measures—eg, massage, myofascial release therapy, acupuncture—appear to help some patients, but these treatments have generally not been well studied.

Medications are targeted at different parts of the pain matrix. Nonsteroidal anti-inflammatory agents and acetaminophen can be tried for peripheral pain generators (eg, lower back and neck disorders), and are modestly effective in approximately 40% of patients. Opioids provide only transient benefit in FMS, and in general should be avoided. Tramadol, a centrally acting narcotic analgesic, has demonstrated some efficacy in FMS.

Sleep disorders play a prominent role in FMS, and a trial of nonhabituating agents (eg, amitriptyline, trazodone) is appropriate. If these agents are not effective, more potent, nonbenzodiazepine sleep agents (eg, zolpidem, eszopiclone) can be used. It is important to emphasize proper sleep hygiene as well.

Antidepressants with serotonin and combined serotonin-norepinephrine reuptake inhibition have been studied in FMS, and can be beneficial to some patients. Cyclobenzaprine, a muscle relaxant with structural similarities to the tricyclic antidepressants, has been shown to reduce FMS pain and improve sleep. Recently, pregabalin—a second-generation antiepileptic agent—became the first drug approved specifically for FMS by the FDA. A related agent, gabapentin, has shown some benefit as well. A number of novel agents directed at targeting pain processing mechanisms are currently under investigation for FMS and other pain states.

back to top

PROGNOSIS

The course of FMS is quite variable, but most measures of health status do not change in patients followed for 5 to 7 years.5,8 Generally, the higher the level of pain or distress reported by the patient at baseline, the more likely it is that symptoms will persist or perhaps progress.5

Patients with FMS make extensive use of the health care system. Typically, they visit at least four physicians before they receive a diagnosis, and thereafter make 12 to 14 visits per year. They often have several comorbid conditions (ulcer, depression, hypertension, IBS, severe allergies), and these comorbidities are more prevalent than in patients with rheumatoid arthritis.3 On the average, patients with FMS are hospitalized once every 3 years, and about 50% of these hospitalizations are related to FMS symptoms—eg, pain/musculoskeletal/neurologic (23.2%), genitourinary (11.3%), gastrointestinal (11.2%), cardiovascular (8.6%), and depressive (5.0%).

Patients with FMS are more likely to undergo surgery than patients with other rheumatic diseases, and are more than twice as likely to undergo back, neck, gynecologic, and carpal tunnel surgery and appendectomy. However, although some early studies suggested that FMS might be associated with premature death (particularly cancer death), more recent work indicates that FMS is at most only weakly related to excess mortality.12,13

back to top

CONCLUSION

Fibromyalgia is a complex, multisystemic, chronic condition that is challenging for patients and clinicians alike. With a greater understanding of pain processing mechanisms—including central sensitization—and new insights into clinical manifestations, major advances are underway in the diagnosis and management of FMS.

back to top

Molly T. Vogt, PhD, is Associate Professor of Medicine and Terence W. Starz, MD, is Clinical Professor of Medicine, both in the Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, PA. Amalie Andrew, BA, is a Student in the Occupational Therapy program, School of Health and Rehabilitation Sciences, University of Pittsburgh, PA.

References

1. Wolfe F, Ross K, Anderson J, Russell IJ, Herbert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum. 1995;38(1):19-28.
2. White KP, Speechley M, Harth M, Ostbye T. The London Fibromyalgia Epidemiology Study: the prevalence of fibromyalgia syndrome in London, Ontario. J Rheumatol. 1999;26(7):1570-1576.
3. White KP, Speechley M, Harth M, Ostbye T. The London Fibromyalgia Epidemiology Study: comparing the demographic and clinical characteristics in 100 random community cases of fibromyalgia versus controls. J Rheumatol. 1999;26(7):1577-1585.
4. Uveges JM, Parker JC, Smarr KL, McGowan JF, Lyon MG, Irvin WS, et al. Psychological symptoms in primary fibromyalgia syndrome: relationship to pain, life stress, and sleep disturbance. Arthritis Rheum. 1990;33(8):1279-1283.
5. Wallace DJ, Clauw DJ. eds. Fibromyalgia and Other Central Pain Syndromes. Philadelphia, PA: Lippincott, Williams & Wilkins; 2005:17-28.
6. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia: Report of the Multicenter Committee. Arthritis Rheum. 1990;33(2):160-172.
7. Bennett R. Fibromyalgia: present to future. Curr Pain Headache Rep. 2004;8(5):379-384.
8. Forseth KO, Forre O, Gran JT. A 5.5 year prospective of self-reported musculoskeletal pain and of fibromyalgia in a female population: significance and natural history. Clin Rheumatol. 1999;18(2):114-121.
9. Yunus MB, Inanici F, Aldag JC, Mangold RF. Fibromyalgia in men: comparison of clinical features with women. J Rheumatol. 2000;27(2):485-490.
10. Yunus MB, Celiker R, Aldag JC. Fibromyalgia in men: comparison of psychological features with women. J Rheumatol. 2004;31(12):2464-2467.
11. Okifuji A, Turk DC, Sinclair JD, Starz TW, Marcus DA. A standardized manual tender point survey. I. Development and determination of a threshold point for the identification of positive tender points in fibromyalgia syndrome. J Rheumatol. 1997;24(2):377-383.
12. Macfarlane GJ, Jones GT, Knekt P, Aromaa A, McBeth J, Mikkelsson M, et al. Is the report of widespread body pain associated with long-term increased mortality? Data from the Mini-Finland Health Survey. Rheumatology (Oxford) 2007;46(5):805-807.
13. Dreyer L, Mellemkjaer L, Kendall S, Jensen B, Danneskiold-Samsoe B, Bliddal H. Increased cancer risk in patients referred to hospital with suspected fibromyalgia. J Rheumatol 2007;34(1):201-206.

back to top