Fibromyalgia: Disease or Not?
Author: Steen E Mortensen MD, FACR, FACP, Department of Rheumatology, Wichita Clinic, Wichita, KS.
Peer Reviewer: Keith K. Colburn, MD, Associate Professor of Medicine, Loma Linda University, Chief of Rheumatology, Loma Linda University Medical Center and Loma Linda VA Hospital, Loma Linda, CA.
Editor's Note-As primary care physicians, we all know the frustration of being faced with a patient who complains of chronic pain for which we can find no medical cause. After trying all of the usual remedies, the patient still finds no relief, and the pain sometimes becomes so overpowering that the patient is unable to continue to work or carry out normal activities of daily living. In this article, the author reviews the history of fibromyalgia-giving an example of one case-and details the pathology, diagnosis, and treatment of this painful and puzzling disorder.
Introduction
Chronic complaints of pain are some of the most frequent and challenging problems facing the primary care physician.1 Local or diffuse pain problems account for a large number of all visits in primary care. The patient may or may not have identifiable pathology requiring specific therapy; at the same time, he may issue vague complaints not attributable to anatomical or physiological entities nor responding to usual analgesics. Due to the chronic nature of the symptoms, the patient gets increasingly worried, stressed, and depressed about `the problem the doctors cannot find' and, without intervention, eventually may become dysfunctional to the point of perceived disability. Fibromyalgia syndrome (FMS) is a term used since about 1984, replacing fibrositis, which describes such symptoms. To the patients, this term names the illness they perceive and legitimizes complaints that cannot be measured. To the physician, the term covers a set of symptoms about which a debate rages: Is this a disease, and, if so, does it fall within neurology, rheumatology, or, perhaps, psychiatry?
Example
A 40-year-old Caucasian female was seen, referred by her new internist, complaining of pains in joints (all over) for 15 years. She described pains that originated in the knees, gradually spreading and involving most other joints. At the time of evaluation, the knees, wrists, and shoulders were especially bothersome. The patient gave a history of the knees, wrists, and proximal interphalangeal joints having been swollen, red, and warm and stated that, many years ago, a physician in another state had tapped a knee, found bloody fluid, and told her she had arthritis. Apparently, he never stated what type she had and did not further describe his findings in the fluid. The patient also described pain in the elbows and shoulders. She felt increasingly weaker in the muscles due to the pains. She complained of some numbness in the index and long fingers and stated that she gets white fingers with cold exposure. She had pain in the xiphoid area, 1+ hour of morning stiffness, poor sleep, and was generally never rested in the mornings.
Laboratory data were unremarkable with erythrocyte sedimentation rate (ESR) 17 mm/hr, rheumatoid factor and antinuclear antibody negative, anti-streptolysin titer in normal range, and a Lyme disease antibody titer, performed due to traveling and possible exposure to ticks, was also negative.
The patient was married with no children, working full time caring for animals. Her husband was also employed full time. The couple enjoying travel and had no major stresses. She was a cigarette smoker of one pack per day, with a cumulative exposure of about 30 pack-years. She would take a rare drink socially maybe three or four times per year.
Past illnesses include two episodes of pneumonia three and 12 years ago; allergies including reactions to propoxyphene hydrochloride (Darvon), tetracycline, and erythromycin; and nausea with several codeine-containing painkillers.
Family history included heart disease, cancer, allergies, diabetes, and thyroid disease in first-degree relatives.
Present treatment included an unknown antibiotic for a scratch wound with right axillary lymph-adenopathy, vitamins C, E, and B-complex, and aspirin or ibuprofen as needed for pains.
The patient complained of reduced appetite, nausea, and constipation, as well as occasional diarrhea; recurrent hay fever; back and joint pains for 15 years; headaches; nervousness; and poor sleep. She had regular menses, with a recent normal period.
Physical examination revealed an alert, oriented patient in no acute distress. Her vitals were as follows: Wt, 126 lbs; Ht, 5 ft 6 inches; BP 100/62; P 84; and Tp 99.2°F on tympanic membrane.
The only findings were the use of glasses and painful `tender points' including, bilaterally, the sub-occiput, base of neck, trapezius mid edge, levator scapula origin from scapula, sub-deltoid bursa, second and third costochondral junctions, lower edge of the latisimus dorsi at the posterior axillary fold, medial and lateral epicondyles, low back at the sacro-iliac notches, trochanteres and both the medial fat-pad of the knee, and the insertion of the adductors on the tibia (anserine bursa). There was no evidence of any active or old inflammatory arthritis.
In this case, the complaint of "blue fingers" and swelling of the knees, wrists, and proximal interphalangeal joints with redness and warmth, as well as the bloody knee tap, would suggest a chronic inflammatory arthritis. This, however, is contradicted by the many further years without symptoms of inflammation, the examination without such findings, and the negative laboratory data. The many years of pain, the locale of the pain (tender points), the sleep disturbance, the complaint of weakness, and the morning stiffness would be consistent with FMS.
Definition
FMS as discussed is chronic (more than 3 months) pain associated with a number of other complaints, such as fatigue, problems with sleep, irritable bowel syndrome, headaches, sensation of swelling, particularly in the hands and feet, paresthesias, and anxiety and depression.2 These complaints are not associated with abnormal laboratory or X-ray findings per se but may occur together with acute illness or as co-complaints in a patient with chronic systemic disease such as rheumatoid arthritis or systemic lupus erythematosus. Through the last two decades, multiple studies have been completed, and, through the efforts of the American College of Rheumatology Committee, a set of working criteria has been developed defining FMS as:
Chronic widespread pain experienced and pain in at least 11 of 18 possible discrete "tender points" on digital palpation.3
A tender point is a localized area of tenderness to pressure in soft tissue (muscle, bursa, fat-pad, or tendon-insertion into muscle or bone) without radiation as in `trigger points.'4 The criteria clarify that `widespread' means symmetrical and above and below the waist. Digital pressure is to be exerted with approximately 4 kg force (rule of thumb: blanching of the palpating finger's nail), and pain at the `tender points,' not tenderness, is the key phrase in patient response.
History
The medical literature appears to be describing fibromyalgia as early as the 18th century, but the first description may actually have been by Hippocrates who, about 400 BC, described pains that were not well defined and were sensitive to changes of the weather. He continued, "the stiffness, tenderness, and fatigue they cause may be likened to that which results from violent exercise in the untrained athlete."5 Actual studies began in 1904 when Ralph Stockman's description of chronic rheumatism associated with the finding of inflammation in muscle biopsies6 seemed to confirm the concept of Sir William Gowers that "muscular rheumatism" was of inflammatory origin.7 Sir William theorized that lumbago was caused by an inflammation leading to "muscular rheumatism" and used the term "fibrositis." Stockman described patients with chronic, generalized stiffness and aching, tender nodules in muscles, and periarticular structures without evidence for actual arthritis. He also found associated symptoms such as sleep problems, bowel symptoms, and chronic fatigue. His interpretation was that the nodules were causative, and he biopsied some and described "inflammatory hyperplasia of intermuscular septa." The muscles themselves were described as normal. He suspected that toxins were the cause and in 1920 followed this up with the theory of an infectious process being the origin.8 A reevaluation of the original biopsy-photographs in 1940 by Collins,9 and biopsies performed by him and other authors, however, did not show pathology and the concept of an inflammatory "Fibrositis" came under question. Benign myalgic encephalomyelitis was a condition thought to be of viral origin, probably polio-virus, and responsible for many cases of fatigue and rheumatic pain through the 1930s to the 1950s.10 It was described in clusters of cases thought to represent epidemics in Los Angeles in 1934, Iceland in 1948, Australia in 1949, Alaska in 1951, South Africa in 1955, and again in the United States in 1956. The description of findings in patients typically included acute onset, muscular pains in neck and shoulders, and a female preponderance. Localized muscular pain and weakness but no clear neurological deficits were found. Follow-up varied but, on reevaluation of the Iceland patients six years later, 80% were still symptomatic. Examination of Alaska patients from 1952 in 1954 showed that 110 of the original 175 still complained of FMS-type symptoms. No etiological agent has been found, and, in 1984, Wallace pointed to the similarities with what we today call FMS.11 In his review of a possible connection between FMS and viral diseases, Goldenberg suggested that, although no infections have been found consistently in FMS, infection may still be the final clinical expression of FMS and other diseases through a common pathophysiological mechanism.12 Up through the 1940s, a number of studies either showed normal muscles or are difficult to interpret due to lack of criteria applied to the patient populations studied. In 1979, Smythe reviewed "fibrositis" in view of the newer research and findings in pain mechanisms.13 His perception at that time was that FMS in the absence of other identifiable disease was uncommon, somewhat at odds with today's thinking. In 1981, Yunus and coworkers described 50 consecutive patients with fibromyalgia/fibrositis and compared them with matched normal healthy controls, identifying the symptoms mostly associated with the syndrome.14 In reviewing the key features, the authors noted that tender points occur in healthy people but in much lower numbers. In addition to the rheumatic complaints, they identified many extra-articular ailments such as tiredness, anxiety, sleep problems, headaches (both migraines and non-migraine types), irritable bowel syndrome, and numbness. They further described the clinical features of FMS and noted that the youngest patient studied was 14, and 28% reported onset of symptoms between ages 9 and 15, while the most frequent age of onset was between 26 and 35. He separated the terms "psychogenic rheumatism" from FMS, emphasizing that, although anxiety may play a role, these entities are different. Through the years, the terms "fibrositis," "non-articular rheumatism," "muscular rheumatism," and now "fibromyalgia syndrome" have been applied to this set of symptoms. During the last 40 years, multiple studies have been done in an attempt to identify a specific etiology. Concepts of peripheral, central, and systemic pathology have been proposed and evaluated since the 1970s, when early criteria were proposed. Unfortunately, no study has identified THE problem while the patient population suffering from FMS continues to rise, with a present prevalence of 2.1% in a Family Practice Clinic,15 2% of the general population,16,17 and up to 6-15% in other studies.18,19
Pathology
Since a number of patients seem to develop symptoms after a flu-like syndrome, some studies have evaluated a viral origin for FMS. Epstein-Barr virus relationship was not found by Buchwald20 nor by Wallace,21 and a careful review by Goldenberg did not identify any documented etiology.12 Acute Lyme disease seems capable of triggering FMS,22 and increased titer of antibodies to human herpes virus-6 has been found in some patients.23 Overall, however, no causative link has been proven between any infection and FMS.
Because of the high number of patients complaining of the morning stiffness so common in rheumatoid arthritis (76-91%),24-26 as well as the observation of Livedo reticulare (in 64%),27 Raynaud's phenomenon (in 30-39%),28,29 and other symptoms commonly associated with autoimmune diseases, a number of studies have evaluated the possibility of an immune-regulatory etiology-either inherited or acquired.
Russell et al reported that 68% of all FMS patients reported at least one first-degree relative who they believed had fibrositis.30 Burda et al reported increased frequency of HLA-DR4;31 however, the larger follow-up study by Russell et al failed to confirm this relationship.30 To date, no large family accumulation nor genetic prevalence has been identified.
Auto-antibodies are not thought to be related to the occurrence of FMS. Several studies have found presence of ANA,32 rheumatoid factor,33 and elevated creatine kinase (CK)34 in subsets of patients. No clear evidence exists that links these findings to the pathogenesis of FMS. Enestrom and co-workers reported increased occurrence of IgG deposits in the skin of fibromyalgia patients.35 They concluded that the increased frequency of IgG deposits and higher number of mast cells also found supported a hypothesis of neurogenic inflammation in FMS. However, no such inflammation has been identified. Allergy per se has been considered important in fibromyalgia,36 but measurement of IgE and IgG4 by Caro et al failed to show any difference from age- and sex-matched controls.37 A later study by Wallace et al examined a number of immunologic parameters, including leukocyte subtypes, interleukin-1 and -2, interleukin-2 receptor, alpha- and gamma-interferon, tumor necrosis factor alpha, as well as mitogen stimulation indices, immunoglobulin sub-classes, and circulating immune complexes.38 No specific findings were identified in FMS, although a higher percentage of CD4+ leukocyte and CD4/CD8 ratio was seen.
Multiple muscle-biopsy studies have been done over the last 40 years, with various findings. Probably the most definitive was published by Yunus in 1989.39 This study used a carefully defined protocol and showed no abnormalities. Other studies have suggested changes secondary to spasm and/or ischemia,40 but none have been specific for FMS. Muscle-metabolism has been evaluated in controlled studies showing reduction of ATP and ADP at tender points in FMS patients,41 and changes suggesting reduced physical activity were reported by Lindh and colleagues.42 Neither could, however, be considered etiological for the syndrome. Studies using MR spectroscopy for P31 failed to reveal specific changes,43,44 as have a number of studies using EMG technique.
Central or systemic aberrancies have been identified in FMS patients and proposed as causative. In 1975, Moldofsky and coworkers described changed sleep-patterns in fibrositis patients.45 Further studies by other authors have shown the shortened time spent in Stage-1 and REM sleep, as well as the frequent arousals during sleep-both as perceived by the patient as un-restful sleep and as measured by polysomnography showing intrusion of alpha-waves into non-REM-sleep EEG.46,47
Since FMS is definitely influenced by stress, studies have investigated hormonal and CNS changes related to both acute and chronic stress.48 The hypothalamic-pituitary-adrenal (HPA) axis shows decrease in plasma- and urine-glucocorticoid levels,49-51 decreased responsiveness to corticotropin-releasing-hormone, with decreased cortisol release and increased corticotropin release, suggesting decreased response of the adrenal glands. At the same time, the corticotropin-releasing-hormone (CRH) levels in CSF are reported normal. This would suggest a decreased sensitivity to CRH or impaired production/release of corticotropin in the pituitary gland. Of interest is the finding by Bennett and coworkers that Somatomedin-C is reduced in FMS,52 suggesting reduced growth hormone (GH). GH is important for homeostasis of muscle and is normally produced during slow-wave sleep. This could possibly link the changed sleep pattern to the endocrine findings. Serotonin is lowered in some patients with FMS,53 and correlation has been found between pain and level of tryptophan,54 its precursor, although the concentration remained within the normal range. Also of note is that the HPA-axis has profound effect on the GH-axis. Most recently, Bennett and coworkers have investigated the level of insulin-like growth factor-I (IGF-I) and found it significantly lower in patients suffering FMS for several years.55 Also found was failure to secrete GH after stimulation with clonidine and l-dopa, further supporting the concept of hormonal dysfunction in fibromyalgia.
Patients often also describe symptoms for which we as physicians see no clear relationship to the anatomy, physiology, and clinical findings. Most of the literature, as well as most of my patients with FMS, describe neuropathic type pains with no apparent relationship to dermatomes or sensory nerve distribution. Most commonly mentioned are the hands and feet. This is different from the patients who suffer identifiable neurological symptoms, such as carpal tunnel syndrome. The symptoms are mostly difficult or impossible to reproduce during examination. Similarly, a high number of patients complain of swelling perceived in the hands and feet. The timing of occurrence varies, as does the length and intensity. But, generally, this is a feeling rather than an observation, and, typically, the examiner cannot verify this symptom. The fatigue so typically felt often follows a cyclic rhythm. In some patients, it will occur in the morning, while in some it occurs when they try to relax after a workday. Often, however, the patient will describe a fatigue present in the morning after a night of less than restorative sleep. This then eases as the morning progresses and usually gives a few hours of more energy around midday, after which the patient gets increasingly fatigued through the afternoon. Then, suddenly, without warning, a day breaks with little or no symptoms, the patients revels in the sense of well being, tries to `catch up,' and the same evening or next morning is many times worse. The opposite also occurs. A patient just doesn't feel able to move for one day or maybe several days. A recent article by Buskila et al reviews the occurrence of FMS in 102 patients after neck injury in comparison to 59 patients with leg fractures.56 All patients were working, and no difference was identified in frequency of insurance claims filed. FMS was not recorded in any patient before injury; however, 22 patients with neck injury developed symptoms vs. only one in the fracture group. No one developed chronic disability, and the authors concluded that social circumstances may influence the outcome of FMS caused by acute trauma.
Diagnosis
The diagnosis of fibromyalgia is made first and foremost by recognizing the complaints presented through history and physical examination. Key phrases include "pains all over," "always tired," "nobody can figure out what is wrong." Some patients may, however, complain of much more localized pain such as in the low back, one shoulder, or hand/wrist,57 and only through physical examination does it become clear that the pain is perceived in multiple areas. The patient may present with laboratory data already obtained, including the ubiquitous "arthritis profile," which may include some abnormalities such as a slightly positive rheumatoid factor or ANA. Under these circumstances, it is helpful to consider whether the fibromyalgia is presenting as a singular entity or is co-existing with a potentially destructive entity. Specific questioning and examination as to the typical clinical findings of systemic diseases associated with such abnormal values permits the clinician to establish or rule out such diagnoses. Active rheumatoid arthritis and SLE are typical diseases that make the similar symptoms or coexist with fibromyalgia syndrome. Hypo- or hyperthyroidism, parathyroidism, and other entities may cause identical symptoms to FMS but can be distinguished through additional clinical findings and abnormal laboratory data.58 Since the "tender points" are the sine qua non for the diagnosis, several authors have evaluated the reliability of such clinical measurements.59,60 Manual palpation was found capable of discriminating patients and normals and as good as use of a dolorimeter. The inter-observer/evaluator correlation was good. However, Tunks et al commented that no good correlation was found between patients' clinical complaints of pain and tender point/control point evaluation.60
Treatment
Education: When first encountered, the majority of patients are quite fearful and often quite ignorant as to their symptoms' origin. Winning the patient's trust and providing understandable instruction and resources goes far toward establishing the environment in which improvement is possible. The concept of chronic pain without specific damaging pathology is not easy to convey. It is, however, necessary in order for the patient to pursue the regular and consistent lifestyle and exercise program required for successful therapy. Vlayen, Goossens, and colleagues studied 131 patients with FMS in a controlled, randomized trial of cognitive-educational treatment of fibromyalgia.61,62 The use of group education and discussion significantly improved the outcome, while the addition of a group cognitive treatment did not lead to further improvement and cost more.
Physical Therapy: A short course of PT with instruction in appropriate stretching and exercises can be helpful. A formalized cardiovascular training program was shown to provide statistical benefit to FMS patients.63 Application of heat or cold, "stretch and spray," or, better, "chill and stretch," using ethyl-chloride as well as massage may give short-term relief.64 However, no controlled studies have proven the efficacy of this approach. I reserve local injections for focal exacerbations or non-responding areas. A helpful mixture is 50/50 triamcinolone hexacetonide (Aristospan) and Marcaine 0.25%; however, a large number of compounds and even dry needling have been tried successfully.65 The use of a local anesthetic reduces post-injection tenderness, and, typically, immediate relief is a good prognosticator for success of the injection.
Tricyclics: Improvement of sleep pattern and some pain-reduction can often be induced by use of tricyclics.66 Due to patients' perception that such use means that "it's all in my head," I usually start with the muscle relaxant cyclobenzaprine. Five to 20 mg taken about two hours before bed minimizes morning tiredness. The dose can gradually be increased over 1-2 months, and the effect can be enhanced by addition of 10-30 mg amitriptyline. Other tricyclics, such as doxepin, have been used to reduce side effects such as oral dryness; however, no formal studies have proven their effect.
Exercise: Most patients have experienced the "worn-out" feeling after seemingly normal physical activities. The general consensus is that patients need to exercise to improve,67 but few studies have been done to prove this contention. McCain and coworkers did show some improvement in objective and subjective parameters of FMS,63 and Martin and coworkers also found improvement, as well as lack of adverse effects in the short term.68 Most patients can be started on a regular exercise program when their problems with sleep and pains have been addressed and they feel a change in their symptoms. Instruction in a gradually increasing, non- or low-impact aerobic exercise program should be given carefully. Patients will need to maintain this for a long time, so a slow introduction with initially low intensity and much encouragement is most helpful. The intent is to win over oneself-not setting a record or satisfying an instructor. Intensity and progression should be tailored and personalized. Warm-up and cool-down periods and stretching should be included.
NSAIDs: Short half-life versions may be helpful in some patients for pain reduction;69,70 however, they are often found most effective when concomitant disease, such as arthritis, exists. Many patients will self-medicate by habit or frustration and sometimes inadvertently may duplicate either specific drugs or a class such as NSAID or acetaminophen-containing mixtures. This significantly increases risk of side effects.
Analgesics: Acetaminophen taken at fixed intervals is sometimes helpful The newer drug Tramadol seems to be worthwhile, but no long-term studies are available in FMS. Narcotics are typically not used in FMS due to the significant risk for addiction and studies with morphine that showed no effect.71 Recently, Sorensen and coworkers have shown response in some FMS patients to ketamine IV when compared to lidocaine and morphine in randomized, double-blinded studies.72,73 This raises the question as to whether different patients' pains are really mediated differently.
Antidepressants: Studies have shown synergism between the use of tricyclics and the selective serotonin reuptake inhibitors (SSRIs).74 Using amitriptyline and fluoxetine in a randomized, double-blind, cross-over fashion, the investigators showed that not only did amitriptyline- and fluoxetine-treated patients do better than placebo but the combination of both drugs gave even further effect. Even if no true depression exist, further improvement can be expected with the addition of low doses of SSRIs.
Steroids: In spite of the apparent lower concentration of cortisol in plasma, no effect was found in its therapeutic use.75
Alternative Medicine: As commonly occurs when a diagnosis is controversial and no fast cure is available, a number of medical and non-medical treatments have evolved. These include various dietary restrictions, additives and contents; vitamins; massage; reflexology; chiropractic therapies; special exercises; and more esoteric approaches to still the pain. Quite a number of patients have tried these, and some feel they have benefitted. Unfortunately, few scientific data are available to support the efficacy of such approaches. A recent Internet search for `fibromyalgia' using `HotBot,' a search tool, yielded 7791 addresses. Some contain valuable resources and advice, some histories of suffering and misconceptions, and quite a number have directions or advertisements for `cures'-all in all, more than enough to confuse both the public and some health care providers.
Disability: This is an area of major controversy. Some patients with severe fibromyalgia truly feel incapable of gainful employment, while others with equally severe pains maintain their jobs. Reporting an eight-year follow-up of 1604 FMS patients at six centers, Wolfe et al found 70% employed or homemakers and 64% able to work all or most days.76 Of those self-reporting disability, 70% were receiving some form of disability payment. Significant differences were noted between centers thought to reflect geographic, physician, and/or socioeconomic patterns. In investigating this issue, Turk and coworkers identified subgroups of FMS patients with different perceptions of pain and capabilities and suggested that we may have to identify these for selective evaluation and treatment.77,78 Wigers identified permanent disability as a negative predictor for outcome.79 A careful review of the problem was written by Wolfe and Potter, concluding that data are presently not available in the literature to show causality between fibromyalgia and trauma.80 Thus, there seems to be no general answer, and the physician is left to his skill and compassion to decide in the individual case.
Summary
Fibromyalgia syndrome describes a common set of symptoms, typically presented by a younger female, with enough discomfort to interfere with activities of normal living and typically no relevant laboratory or X-ray abnormalities. Treatment includes a good communication and trust between physician and patient and a quite regimented lifestyle, including a regular aerobic exercise program. Pharmacologic intervention is directed toward sleep enhancement, muscle relaxation, and agents particularly known to be helpful in treatment of chronic pain. A successful outcome is definitely possible but often requires quite long term treatment and follow-up, as well as plenty of encouragement. A recent report by Wolfe et al reviewed the seven-year follow-up of 538 patients at six centers.81 This group of patients was found to have high utilization of all medical services-those related to the FMS and to other complaints. Thus, anything one can do to help the individual's suffering from this painful condition should benefit patient, family and friends, and society.
Some physicians still think FMS is a non-entity based upon imprecise information; however, reviewing the literature, it seems we just haven't found the fire generating the smoke. One disease it is not, as we presently understand pathology, but a syndrome-recognizable, sometimes treatable, and perhaps representing several pathologies or being their common outcome. As in medicine's historic past, a syndrome is the description of symptoms not yet understood as a specific disease, and the question posed in this article's title must be answered: Insufficient data so far.
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