An In-Depth Topic Review of Fibromyalgia Syndrome

For Physicians


Lisa R. Sammaritano, MD

Associate Attending Physician, Hospital for Special Surgery
Associate Professor of Clinical Medicine, Weill Cornell Medical College

  1. Definition
  2. Pathogenesis
  3. Clinical Presentation
  4. Laboratory Findings
  5. Differential Diagnosis
  6. Treatment
  7. Long term management Issues
  8. Prognosis
  9. When to Refer
  10. Annotated References

 

I.  Definition

Fibromyalgia syndrome causes chronic widespread musculoskeletal pain, often associated with fatigue and other symptoms. The pain of fibromyalgia is often defined by the presence of particular areas of increased sensitivity called tender points.

Pain is difficult for anyone to describe or quantify. An accepted definition, from the International Association for the Study of Pain (IASP), is "...an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage." The important point the IASP definition makes is that pain has both affective and sensory components and may occur in the absence of obvious pathology. In chronic pain, as opposed to acute pain, the intensity of the pain response may seem out of proportion to the painful stimulus.

Fibromyalgia is a well-described clinical syndrome, but little is notable on the physical exam other than the characteristic tender points. It represents a distinct part of the broader spectrum of chronic widespread pain that affects an estimated 11 - 13% of the population. Approximately 2% of the U.S. population meet the specific American College of Rheumatology (ACR) criteria for fibromyalgia syndrome (FMS). (see Fig. 1 and Table 1)

Table 1

1990 American College of Rheumatology Fibromyalgia Guidelines

  • Widespread pain of greater than three months
  • Pain in an axial distribution with pain on both right and left sides of the body and pain above and below the waist
  • Pain in = 11 of 18 specified tender points on digital palpation
    TENDER POINT: Anatomic sites where application of 4 kg of pressure - enough to blanch the examiner's fingernail - upon physical examination elicits pain at the site.
  • Tender points: pain is at the site of pressure, without radiation or referral. (This is not a trigger point.)

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 criteria committee. Arthritis Rheum 1990;33:160-72.
©1990 American College of Rheumatology. Reproduced with permission of John Wiley & Sons, Inc.

Created for research purposes, these criteria require patients to have widespread pain of at least three months duration in combination with a minimum of 11 of 18 specified anatomic tender points. Widespread pain as defined here is pain in an axial distribution, on both sides of the body and above and below the waist. 

Figure 1


The 18 Tender Point Locations for FMS based on "The Three Graces" Masterpiece.

The ACR criteria define a group of patients with "definite fibromyalgia," and this ensures comparability of patient groups throughout different clinical studies. In clinical practice, however, patients with FMS may not meet the rather rigid criteria of 11 or more tender points, but instead will often show a generalized lowering of the pain threshold along with other typical characteristics. Similarly, tenderness at "control points" does not necessarily exclude the diagnosis of fibromyalgia in clinical practice as it might for a research study. Control points are points that are expected to be non-tender, located at the thumbnail and the anterior mid-tibia.

Despite the current poor understanding of its cause, fibromyalgia is usually easily recognized in medical practice. An estimated four to seven million Americans are affected. FMS is more frequent and more severe in women, and its prevalence increases with increasing age. Median age of onset is from 29 to 37 years; prevalence in the general population is about 3.4% in women and 0.5% in men.

Until recently, FMS was often viewed as a predominantly psychiatric or affective disorder. Broad-based clinical studies confirm that the diagnosis of fibromyalgia syndrome in the general population is not a manifestation of psychiatric morbidity. However, many physicians and other health care workers still do not agree on the validity of classifying fibromyalgia as a discrete clinical syndrome.

II. Pathogenesis

The fact that the etiology of fibromyalgia is unclear contributes greatly to continued misunderstanding and frustration on the part of patients and physicians. A yet-to-be-defined interplay of genetic and environmental factors leads to the end result of "central sensitization" in fibromyalgia -- a sensitization of the central nervous system that is the proposed mechanism for pain amplification. While onset of symptoms is often gradual, up to one-quarter of patients cite a precipitant of physical or emotional trauma. Suggested (but not documented) environmental triggers include physical trauma, hypermobility (with repeated minor musculoskeletal trauma), infections, acute or chronic emotional distress, chronic underlying autoimmune disease, and others.

The contribution of psychological factors to development of FMS is still debated. A history of significant psychiatric disease correlates with more severe fibromyalgia. Concurrent depression is most common in patients treated at tertiary care referral centers and may reflect a cognitive response to the effects of fibromyalgia symptoms on daily life. Interestingly, post-traumatic stress disorder (PTSD) symptoms occur in one-half of patients with FMS, and these particular patients report greater pain, emotional distress and disability than those without PTSD.

Causative genetic factors have not been identified in FMS syndrome, although research is directed at defining possible susceptibility factors. For example, one particular genotype of the promoter region of the serotonin transporter gene (S/S) is more common in FMS patients than in controls. The significance of this is unproven.

Since muscle pain is by far the most common complaint, initial work focused on studying muscle structure and physiology, especially at tender points. Early biopsies suggested tissue anoxia (lack of blood supply), but more definitive studies have found no abnormalities and attribute structural changes to disuse atrophy. Localized muscle pathology does not seem to be an underlying etiologic factor in fibromyalgia.

Current Theories
A significant number of biochemical and hormonal abnormalities have been identified which, in conjunction with electrophysiologic and functional neuro-imaging studies, point toward fundamental neuro-endocrine abnormalities in patients with FMS. While used in the study of disease pathophysiology, these findings are not currently useful clinically in diagnosis or care of the fibromyalgia patient.

Sleep abnormalities: Insomnia is a frequent complaint of patients with fibromyalgia, and abnormalities are commonly documented on sleep electroencephalograpy (EEG). Up to 80% of patients show a characteristic alpha wave intrusion into normal delta rhythm of stage 4 (non-REM) sleep. Although not specific for fibromyalgia, this irregular sleep pattern may be an important factor contributing to the severity of disease manifestations. Muscle symptoms have been shown to develop in healthy subjects with experimentally interrupted sleep, and may relate to a resulting serotonin deficiency.

Endocrine factors: Endocrine abnormalities of the hypothalamic - pituitary - adrenal (HPA) axis result in a blunted adrenal cortisol response to ACTH with lowered 24-hour free cortisol levels in many patients with fibromyalgia. Low insulin-like growth factor (IGF) is seen in one-third of patients, resulting in decreased nocturnal growth hormone (GH) secretion. As with sleep studies, measurements of these hormones are important in the study of the disease process but are not indicated for clinical use in patient care.

Metabolic abnormalities: Central nervous system fluid (CSF) abnormalities include increased levels of substance P and nerve growth factor, and a lowered level of serotonin. Evidence points to activation of NMDA (N-Methyl-D-Aspartate) receptors, which interact specifically with excitatory amino acids to increase chronic (but not acute) pain. Activation of NMDA receptors seems critical in the maintenance of the pain state; the pain of fibromyalgia is blocked by intravenous ketamine (a short acting, noncompetitive blocker of the NMDA receptor).

Central Sensitization: Fibromyalgia patients have qualitative differences in pain perception due to central sensitization, which causes a generalized disturbance in the processing of sensory information within the CNS. (see Fig.2)

Figure 2

Nocioceptive nerve fibers are those that normally carry painful signals to the brain. Repetitive stimulation of the pain-carrying peripheral nerve can lead to central sensitization through a mechanism called "wind-up." All afferent or ongoing nerve fibers, both nociceptive (painful sensation) and non-nociceptive (non-painful sensation) converge on the same "wide dynamic range" second-order neuron in the dorsal ganglia of the spinal cord. Repetitive stimulation leads to "wind-up," a generalized up-regulation of the CNS, in which non-painful stimuli become perceived as pain. In fibromyalgia, patients develop "non-nociceptive pain" (NNP) as a consequence of this mechanism.

Neurophysiology studies support an enhanced pain response in patients with fibromyalgia, with increased EEG somatosensory responses to pain and spread of the impulse to the contralateral cerebral cortex.

Functional abnormalities in regional cerebral blood flow in the thalamus and caudate nucleus (shown on SPECT brain imaging studies) are associated with low pain-threshold levels in fibromyalgia (in contrast to depression, for example). These areas of the brain are important in integration of nociceptive stimuli and perception of pain and in generation of signals to the HPA axis (Figure 3).

Figure 3

III. Clinical Presentation

Diffuse musculoskeletal pain and tenderness are the clinical hallmarks of fibromyalgia. In general, muscle and skin symptoms predominate. While the sensation of joint swelling and pain is not uncommon, clinical exam does not reveal objective evidence of synovitis. Typical tender points in defined anatomic locations are expected.

Table 3

Clinical Syndromes Associated with Fibromyalgia

Migraine
Premenstrual syndrome
Irritable bladder syndrome
Restless leg syndrome
Raynaud's syndrome
Irritable bowel syndrome

Associated clinical symptoms are diverse and include fatigue, stiffness, paresthesia, skin tenderness, post-exertional pain, lightheadedness, fluid retention, and insomnia. Stress or anxiety, lack of sleep, or cold exposure may exacerbate symptoms. Cognitive complaints (particularly memory and vocabulary problems) are frequent and have been documented with formal testing in several studies.

While precipitating factors have been suggested, no decisive data support a specific factor as a trigger for disease onset. Within the spectrum of physical and emotional trauma, prior abuse has been associated with greater likelihood of chronic pain in adulthood. There is no evidence of an association of fibromyalgia with Gulf War service or silicone breast implants. Musculoskeletal injury as a precipitant is controversial. Fibromyalgia has been reported to follow numerous infections, including viral (hepatitis C, parvovirus) and bacterial (Lyme).

Associated syndromes represent disorders which, while recognized as primary syndromes themselves, overlap clinically with fibromyalgia and may reflect some manifestation of the same central sensitization process (Table 3). The degree of overlap may be significant; for example, one-third of patients with fibromyalgia fulfill criteria for irritable bowel syndrome (IBS).

Despite the broad range of symptoms that patients may experience, the physical exam - except for tender points or other allodynia - is generally remarkably normal. (Allodynia is the term for pain evoked by ordinarily non-painful stimuli.)

IV. Laboratory Findings

Laboratory findings in fibromyalgia are classically normal, and routine laboratory tests are not helpful in diagnosing or following FMS. Complete blood count, chemistries (including CPK and aldolase), thyroid function tests, urinalysis, and erythrocyte sedimentation rate are normal in FMS, but they are reasonable screening tests to exclude other disorders. No serologic marker has been identified. Antinuclear antibody (ANA) and rheumatoid factor (RF) tests are typically negative.

V. Differential Diagnosis

Fibromyalgia is a clinical diagnosis and one of exclusion. Before committing to a definite diagnosis of FMS, other diagnoses, as suggested by history, physical exam or serologic work-up must be excluded.

The differential diagnosis for FMS is broad, and patients commonly present to a wide variety of clinical specialists, including internists, neurologists, gynecologists, orthopaedists, and rheumatologists.

Patients with fibromyalgia - as with a small proportion of the general population - may occasionally have a low positive ANA or an elevated ESR. This does not mean that the patient has systemic lupus or that his or her illness will develop into lupus. One guide to the diagnosis of fibromyalgia is duration of symptoms; it is less likely to be another disorder if symptoms are present for many years.

Fibromyalgia syndrome may occur in the setting of established connective tissue disorders. FMS shares overlapping symptoms with some autoimmune disorders - particularly systemic lupus erythematosus and rheumatoid arthritis - that include fatigue, arthralgia, myalgia, morning stiffness, perception of joint swelling, malar flush, and Raynaud's syndrome. Identification of the correct underlying etiology for particular symptoms in these patients may be difficult. Fibromyalgia may coexist with autoimmune disease in up to one-quarter of patients with systemic lupus and other connective tissue disorders. Diagnosis is critical to prevent aggressive therapy that is not helpful for FMS.

VI. Treatment

Treatment of fibromyalgia is management of a chronic illness. No cure exists. A combination of therapeutic modalities, however, may control symptoms for many patients. Therapies are best tailored to the needs and response of the individual patient as the patient population is heterogenous.

A. Pharmacotherapy
Pharmacotherapy is commonly prescribed; unfortunately, only a limited number of medications have been shown to be effective for fibromyalgia in placebo-controlled trials. Traditional pain medications are often ineffective, and use of narcotic analgesics is discouraged. Data is strongest for the use of certain antidepressants, specifically tricyclic antidepressant agents (TCAs), serotonin or serotonin/norepinephrine re-uptake inhibitors, and certain anticonvulsant drugs. Most studies, even with these agents, have been limited by a relatively short duration of follow-up. Only Lyrica (pregabalin) is currently FDA-approved for use in fibromyalgia; patients should be made aware of this.

It is likely that there are differences in pain processing between subgroups of patients with FMS which may influence response to pharmacologic therapy. One research group treated FMS patients with separate intravenous infusions of morphine, lidocaine and ketamine, with wide variation in clinical response between patients.

1. Tricyclic antidepressants (TCAs), specifically amitriptyline (Elavil), are probably the best supported pharmacotherapy, and they are often considered as first-line treatment. Use is limited, however, due to the common side effects of dry eyes or mouth, drowsiness, and weight gain. The response rate for amitriptyline is about 30 to 50%. Improvement may be noted in pain relief, fatigue, and sleep quality. Usual dosage range is 10 to 50 mg, started at the lowest dose with incremental dose adjustment to minimize side effects. Amytripyline may be effectively used in combination with either fluoxetine or cyclobenzaprine (see below).

2. Serotonin re-uptake inhibitors (SSRIs) are a more attractive therapy than the TCAs due to the increased tolerability of these drugs. Very recently, fluoxetine (Prozac) has been shown to be of benefit in 60 patients with FMS in a 12-week placebo-controlled study. Improvement was independent of any effect on depressive symptoms. Study dose was flexible, from 10 to 80 mg per day; mean daily dose was 45 mg. Longer-term follow-up (beyond 12 weeks) was not reported.

3. Serotonin/norepinephrine reuptake inhibitors include the antidepressants venlafaxine (Effexor), duloxetine (Cymbalta), and milnacipran; these may be more effective than SSRI’s. Duloxetine 60 mg BID improves pain and global function irrespective of underlying depression. Milnacipran also binds N-methyl-D-aspartate receptors, which are thought to be important in chronic pain.

4. Cyclobenzaprine (Flexoril), which reduces brainstem noradrenergic function and motor neuron efferent activity, is another commonly used medication with some proven benefit in fibromyalgia. Efficacy appears to decline with increasing duration of use, however, and sedating effects (even with the commonly used dose of 10 mg) often limit use to bedtime.

5. The anticonvulsants pregabalin (Lyrica) and gabapentin (Neurontin) have both been recently shown to be effective in randomized controlled trials, and pregabalin is now FDA-approved for treatment of firbromyalgia. Both are generally well-tolerated by most patients; pregabalin is most effective at a total daily dose of 450 mg (usually in three doses), while gabapentin dose ranges from 1200 – 2400 mg daily (divided into 3 or 4 doses). Sedation is a concern with higher doses of both medications, and relatively larger doses are usually reserved for just prior to sleep. Alprazolam (Xanax) is the only benzodiazepine studied so far that has shown limited usefulness in fibromyalgia.

6. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are of debatable benefit in FMS patients, although most patients have been on NSAIDs at some point in their disease course. NSAIDs may have modest benefit in reducing pain in patients with FMS through analgesic rather than anti-inflammatory mechanisms.

7. Tramadol (Ultram) is a mu-opioid receptor antagonist felt to have lower addictive potential than traditional narcotic drugs. It has been suggested for patients who have had incomplete relief with or who have not tolerated other medications. Dosages range from 50 mg prn up to 100 to 150 mg several times per day. Traditional opioids are avoided unless other measures have failed.

Prednisone is not indicated for therapy of fibromyalgia. It has been shown to be of no benefit in a double-blind crossover study.

Other promising pharmacologic agents include dopamine agonists (e.g. pramipexole), tizanidine, and even gamma-hydroxybutyrate (sodium oxabate); the latter is infrequently used as it is a scheduled substance with significant abuse potential. Other research agents currently under investigation include intravenous lidocaine and growth hormone. S-adenosyl-methionine (SAMe), a supplement available in health food stores, has been evaluated in several double-blind, randomized, controlled trials that have shown mixed results. Limitations include lack of conclusive benefit and the current limited availability of standardized preparations.

B. Non-pharmacologic therapies
The following non-pharmacologic therapies have been shown to be of benefit in several placebo-controlled trials.

1. A regular exercise program is considered essential in the treatment of FMS. Aerobic exercise several times a week has clear benefit. Pool exercise may be particularly beneficial. Although pain may limit initial efforts, patients are encouraged to progress slowly through a program of increasing difficulty. Cardiovascular fitness training is superior to flexibility/stretching alone. The major problem encountered is poor compliance due to post-exertional pain. A recent study confirmed the benefit of graded aerobic exercise by comparing one such 3 month program with a program of relaxation and flexibility exercises. More patients in the graded aerobic exercise group reported themselves much or very much better at three months (35% vs. 18%); most importantly, benefits were maintained at one year follow-up. Another study compared muscle strengthening with stretching alone, tailoring the individual program to the patient's baseline fibromyalgia status. While no statistically significant differences emerged between the two groups, there was a trend toward superiority of the muscle-strengthening protocol, and most patients in both groups completed the program without the post-exertional pain that often leads to high drop-out rates in exercise studies.

2. Cognitive-behavioral therapy (CBT) is of proven benefit for patients with FMS. CBT teaches patients coping mechanisms to better deal with their chronic pain, and results in improved functional status. FMS patients may also respond to adjunctive psychological therapy, particularly those who clearly have depression as part of (or as a result of) their disorder.

3. Acupuncture is increasingly being used in pain management of many rheumatic diseases. A number of smaller studies previously suggested usefulness in FMS patients, and a recent blinded, controlled trial of FMS patients found that those receiving acupuncture improved in five out of eight outcome measures. A recent systematic review of acupuncture trials, however, concluded that there was inadequate evidence to support a recommendation for use in fibromyalgia.

4. Massage therapy is anecdotally helpful for many patients with fibromyalgia. One randomized trial comparing massage therapy with relaxation techniques found improvements in sleep and pain, and decreased levels of substance P. Comprehensive programs, available at a limited number of sites, include a combination of educational techniques, cognitive therapies, aerobic exercise, stretching, pacing, enhancement of pain tolerance, and family education. Significant improvement with any individual technique or combination of techniques, however, will not occur without the active participation of the patient.

C. Other alternative treatments
There are a number of less conventional approaches to treatment such as hypnotherapy, meditation, magnetic fields, EEG-driven stimulation, and dietary changes/manipulations. These have not been proven effective in reasonable clinical trials to date.

VII. Long term management Issues

Long-term management issues in patients with fibromyalgia are difficult. As in most chronic illnesses for which no good therapy is yet available, frustration on the part of patient, family, and health care providers is common. Medications initially helpful may lose efficacy over time, and persistent adherence to exercise programs may be difficult. The most rational approach is to use a multi-faceted protocol including pharmacologic treatment, exercise, and behavioral therapies, along with education for the patient and his/her family.

One cannot underestimate the importance of reassurance and support for patients with fibromyalgia. Many patients fear a severe or fatal outcome due to the often frightening nature of symptoms. Reassurance involves emphasizing that fibromyalgia, even with severe pain, does not cause internal or "organ" involvement, and that the disease is unlikely to evolve into other illnesses whose symptoms FMS may mimic such as lupus, rheumatoid arthritis, or even multiple sclerosis. The goal is to help patients and family understand that fibromyalgia is a "real" clinical diagnosis, but one that is usually manageable and rarely leads to severe disability. Patient effort and social support are important in maintaining quality of life.

VIII. Prognosis

Studies of long-term follow-up support the clinical impression that fibromyalgia is a chronic disease. In one study of patients with an average disease duration of 15 years, while most patients at follow-up still had fibromyalgia complaints, two-thirds of patients felt they were better than when first diagnosed. Less than 10% of patients reported doing poorly (see Kennedy below). Another longitudinal prospective study of shorter duration (see Fitzcharles et al. below) evaluated prognosis and specifically tried to identify factors predictive of favorable outcome. While almost half the patients reported improvement in FMS status at 40 months follow-up, the only baseline predictors were younger age at onset and less disturbed sleep. Still, this adds impetus to the effort to diagnose patients as early as possible and is a reminder of the need to target sleep disturbance as part of overall disease management.

Periods of increased pain symptoms often alternate with periods of stable, less intense pain. It is uncommon for a patient to experience a complete, long-lasting remission of symptoms. When identified early, however, as many as a quarter of FMS patients in the community are reported to be in remission two years after diagnosis. Most patients with FMS who want to work are able to do so, although a proportion of patients change or modify their jobs as a result of their illness.

IX. When to Refer

The two most common reasons for referral of patients to a specialist are difficulty or uncertainty in establishing the diagnosis, and an inadequate response to usual therapy. Often the primary care provider is the medical professional best suited to care for FMS patients, since he or she already knows the patients and may have an established relationship with them.

Referrals may vary, depending on patient symptoms, and specialists may play a role only in diagnosis. Paresthesias or complaints of muscle weakness may warrant evaluation of a patient by a neurologist to rule out a primary neurologic diagnosis. A rheumatologist will often be able to confidently rule out the diagnosis of lupus, RA or other rheumatic disease.

If usual treatment fails, referral to a rheumatologist or other specialist for management is appropriate. The best care, however, will likely be with a team of specialists, including rheumatologists, physical therapists, psychologists, pain specialists, and others.

X. Annotated References

A. Arnold LM, Hess EV, Hudson JI, Welge, Berno SE, Keck PE Jr. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med 2002;112(3):191-7. Sixty women with fibromyalgia were randomly assigned to treatment with either fluoxetine (Prozac) or placebo in this 12-week study. The primary outcome measures were scores on well-established questionnaires (such as the Fibromyalgia Impact Questionnaire, or FIQ). Patients treated with fluoxetine showed significant improvement in most measures. Two points of significance for clinical practice: the pain benefit of fluoxetine was independent of its effect on depression, and the dosage range of 10 to 80mg/day (mean daily dose of 45 + 25 mg) is higher than doses used in prior studies for fibromyalgia or depression.

B. Crofford LJ, Rowbotham MD, Mease PJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005 Apr;52(4):1264-73. This multi-center trial randomized 529 patients to placebo or one of three doses of pregabalin (150, 300, or 450 mg/day) for a treatment period of 8 weeks. Pregabalin at 450 mg/day reduced pain, fatigue, and improved sleep quality and several domains of health-related quality of life. Pregabalin is the first FDA-approved treatment for fibromyalgia.

C. Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia: a randomized, double-blind, placebo-controlled multicenter trial. Arthritis Rheum 2007 Apr;56(4):1336-44. This 12-week trial involved 150 patients randomized to gabapentin or placebo; gabapentin-treated patients showed a significant improvement in BPI average pain severity score compared to placebo. Gabapentin dosage range was 1200 – 2400 mg per day.

D. Sarzi-Puttini P, Buskila D, Carrabba M, Doria A, Atzeni F. Treatment study in fibromyalgia syndrome: where are we now? Semin Arthritis Rheum 2007 (in press; available online October 31, 2007). The authors review major developments in various areas of fibromyalgia research, including updates in clinical manifestations, pathophysiology and treatment. A limited number of well-controlled treatment trials of single agents were available for this review, but there are few trials of combination therapy (pharmacologic agent and either exercise or cognitive-behavioral therapy).

E. Kennedy M, Felson DT. A prospective long-term study of fibromyalgia syndrome. Arthritis Rheum. 1996 Apr;39(4):682-5. The authors reevaluated patients involved in a previous research study 10 years earlier. All patients had persistence of fibromyalgia symptoms, although one-half had not seen a doctor in the last year for them. Over two-thirds of patients were still taking medications for fibromyalgia. Two-thirds felt their fibromyalgia symptoms were a little or a lot better than at the time of diagnosis. With long-term follow-up, most patients were doing well 15 years out; only 7% felt they were doing poorly. A low rate of work disability was noted. One worrisome finding: two of the original 39 patients had since committed suicide. The authors caution to watch for depression in this disorder. Patients were enrolled from tertiary care, or academic, medical institutions.

F. Mengshoel AM Haugen M. Health status in fibromyalgia -- a follow-up study. J Rheumatol. 2001 Sep;28(9):2085-9.
This study is a long-term reevaluation of 33 women with fibromyalgia involved in exercise and patient education programs six to eight years earlier. All 33 participants still had widespread pain, but 7/33 had fewer than 11 tender points (and wouldn't now "qualify" as having fibromyalgia by ACR criteria). No patient had additional disease. No worsening in symptoms was found. There was a significant reduction in fatigue. Seventy-six percent engaged in regular physical activity, and 30% in regular organized exercise classes. Employment status was unchanged. Patients used active coping strategies. The authors feel the data "suggest a benign prognosis". Of note, patients were originally recruited from primary care centers, in contrast to the study noted above.

G. Gedalia A, Garcia CO, Melin JF, Bradford MJ, Spinoza LR. Fibromyalgia syndrome: Experience in a pediatric rheumatology clinic. Clin Exp Rheumatol. 2000 May-Jun;18(3):415-9.
Fibromyalgia occurs in all age groups. Here, 59 children with fibromyalgia followed in a single pediatric rheumatology clinic are described. Mean age at diagnosis is 15.5 years. Symptoms are largely comparable to those in adult patients, although symptoms of stiffness, subjective joint swelling and fatigue are slightly less common. At four years of follow-up, 60% children were improved, 36% were unchanged and 4% were worse. Prognosis of fibromyalgia in children may be better than in adults, but longer term follow-up is needed. Exercise was associated with better outcome: 22/30 children in the improved group continued with exercise compared with 7/20 children in the unchanged or worse group.

H. Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, et al. The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum. 1990 Feb;33(2):160-72.
The ACR committee developed classification criteria for fibromyalgia by studying 558 consecutive patients, 293 with fibromyalgia and 265 control patients. Control patients had disorders that could be confused with fibromyalgia, including inflammatory arthritis, axial skeletal syndromes, osteoarthritis, tendonitis, and regional syndromes. Widespread pain as defined by the committee was found in 97.6% fibromyalgia patients. The criteria of widespread pain plus tender points had an overall sensitivity 88.4% and specificity of 81.1%. This landmark report provided much-needed classification criteria for studies, as well as an ACR validation of fibromyalgia as a distinct clinical diagnosis.

I. Park DC, Glass JM, Minear M, Crofford LJ. Cognitive function in fibromyalgia patients. Arthritis Rheum. 2001 Sep;44(9):2125-33.
This study documents cognitive impairment in fibromyalgia patients (in areas of memory and vocabulary) when compared with two groups of controls. Cognitive deficits in fibromyalgia are not global. Impaired cognition correlates with pain but not with depressive or anxiety symptoms. Deficits are similar to those seen in cognitive aging; however, speed of processing is not impaired in fibromyalgia patients. Complaints of FM patients about their memory are legitimate and are not due to psychological distress.

J. Hadhazy VA, Ezzo J, Creamier P, Berman B. Mind-body therapies for the treatment of fibromyalgia. A systematic review. J Rheumatol. 2000 Dec;27(12):2911-8. Review.
This is a systematic review of randomized and "quasi-randomized" trials of mind-body therapy (MBT) for fibromyalgia. Thirteen trials included a total of 802 subjects who were compared to waiting list or treatment-as-usual controls. The analysis provided strong evidence that MBT is more effective for improving self-efficacy than are other therapies. There is limited evidence for improved quality of life with MBT. Results were inconclusive for other outcomes. Overall, the authors feel that long-term within-group results show the greatest benefit for MBT in combination with exercise. This defines a focus for further controlled clinical research.

K. Barrows KA, Bradley BP. Mind-body medicine: An introduction and review of the literature. Mind-body medicine. An introduction and review of the literature. Med Clin North Am. 2002 Jan;86(1):11-31. Review.
This comprehensive review is an excellent introduction to the area termed "mind-body medicine" and encompasses meditation (transcendental meditation, relaxation response, mindfulness meditation), hypnosis, guided imagery, biofeedback, and relaxation therapy. Relevant clinical data are reviewed.

L. Al-Allaf AW, Ottewell L, Pullar T. The prevalence and significance of positive antinuclear antibodies in patients with fibromyalgia syndrome: 2-4 years' follow-up. Clinical Rheumatology 2002 Nov;21(6):472-477.
A large rheumatology clinic population of patients with fibromyalgia (n=137) was screened for ANA antibodies: 12 ANA-positive patients were identified and matched for age and sex with 12 ANA-negative fibromyalgia patients; a further control group of osteoarthritis patients was also studied. Prevalence of symptoms of connective tissue disease was similar in both the ANA-positive and ANA-negative fibromyalgia groups and the ANA-positive osteoarthritis group. Two of 137 patients with fibromyalgia (one ANA-positive and one ANA-negative) fulfilled criteria for a connective tissue disease (CTD): lupus and Sjogren's syndrome respectively. One ANA-positive patient (of 225) in the osteoarthritis control group was diagnosed with rheumatoid arthritis. New diagnoses of CTD did not develop over the 2-4 year follow-up period.

M. Sorenson J, Bengtsson A, Ahler J, et al. Fibromyalgia: are there different mechanisms in the processing of pain? A double blind crossover comparison of analgesic drugs. J Rheumatol 1997;24:1615-1621.
Report of administration of intravenous morphine, lidocaine, and ketamine (as well as a placebo) over a 30-minute period in 16 fibromyalgia patients. Three patients did not respond to any medication, and 13 responded to one or several drugs (but not to placebo). The authors conclude there may be differences in pain processing between subgroups of patients with fibromyalgia, suggesting that specific pharmacologic agents may be effective for different individual patients.

N. Richards SC, Scott DL. Prescribed exercise in people with fibromyalgia: parallel group randomized controlled trial. British Med J 2002:325:185.
This recent study confirmed the benefit of graded aerobic exercise by comparing a prescribed graded aerobic exercise program with one of relaxation and flexibility exercises. More patients in the graded aerobic exercise group reported themselves much or very much better at three months (35% vs. 18%) with a reduction in tender point count and improvement in score on the Fibromyalgia Impact Questionnaire, or FIQ (a functional assessment instrument validated specifically for patients with fibromyalgia). Most importantly, benefits were still demonstrated at a one-year follow-up evaluation, a relatively long period of follow-up for any study of fibromyalgia therapies.

O. Jones KD, Burckhardt CS, Clark SR, et al. A randomized controlled trial of muscle strengthening versus flexibility training in fibromyalgia. J Rheumatol 2002;29:1041- 1048.
Muscle-strengthening was shown to be superior to flexibility exercise alone in this controlled trial, which tailored the individual exercise program to the patient's baseline fibromyalgia status. While no statistically significant differences emerged between the two groups, there was a trend toward superiority of the muscle-strengthening protocol, and most patients in both groups completed the program without the post-exertional pain that often leads to high drop-out rates, a common problem for patients with fibromyalgia.

P. Fitzcharles MA, Costa DD, Poyhia R. A study of standard care in fibromyalgia syndrome: a favorable outcome. J Rheumatol 2003 Jan;30(1):154-159.
A longitudinal prospective cohort study at the Montreal General Hospital in Canada to evaluate outcome of standard medical care and to identify factors that might predict or influence outcome. Seventy women with fibromyalgia were followed for a mean of 40 months while under the care of their usual physicians. Primary outcome was determined by patient-reported overall status, secondary outcomes included measures of pain and fatigue on standardized instruments, HAQ (Health Assessment Questionnaire) and FIQ (Fibromyalgia Impact Questionnaire). Forty-seven percent of patients reported an overall moderate to marked improvement in disease status, with significant differences seen in tender point count, sleep disturbance, fatigue, pain, and score on FIQ. Age and lower sleep disturbance were the only variables linked to favorable outcome.


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