Fibromyalgia syndrome (FMS) is a chronic condition characterized by multiple symptom domains: pain, fatigue, sleep disturbance, mood disturbance, and quality-of-life and function impairment.1 Other common associated conditions and symptoms include irritable bowel syndrome, irritable bladder syndrome (interstitial cystitis), tension and migraine headache, cognitive dysfunction ("fibrofog"), stiffness, paresthesias, and restless legs syndrome. Optimal management of FMS involves multimodal treatment approaches that address the various symptom domains that patients may experience.
Over the past century, FMS has had several monikers, such as "fibrositis," but it was not until 1990 that the American College of Rheumatology (ACR) established classification criteria. The criteria defined FMS as a condition in which widespread pain has been present in at least 11 of 18 anatomically specific tender points for at least 3 months.2
The ACR classification criteria were intended to be used for research studies, but increasingly they have been used as diagnostic criteria in practice. This is problematic. Although the tender point examination helps physicians discriminate FMS as a condition characterized by augmented tenderness, an increased number of tender points is associated with female sex and "distress." This criterion lacks high specificity and excludes some patients with chronic widespread pain who do not fulfill the tender point criteria but whose pain probably arises from the same pathophysiology.3,4
Much remains that is not understood about the pathogenesis and proper classification of FMS, partly because clear-cut biomarkers and objective treatment parameters are lacking; this sometimes leads to physician skepticism and patient frustration. However, an increased awareness of the prevalence, clinical pattern, and pathophysiology of FMS—rooted in neural dysregulation, particularly "central sensitization"—is facilitating more prompt diagnosis and appropriate patient care.
Here, following a brief overview of the epidemiology and pathophysiology of FMS, we provide an update on the latest management approaches.
The prevalence of FMS, which occurs primarily in women, is estimated at 2% to 5% of the US population.5 FMS may exist on its own, or it may be associated with other painful conditions, such as degenerative or inflammatory arthritis and low back pain.6 Indeed, the disorder is reported to occur in up to 25% of patients who have rheumatoid arthritis or lupus.7
FMS also may occur with other conditions that are considered to be somatic syndromes—ie, symptomatic conditions that do not have demonstrable structural changes—and it may share genetic predisposition and pathophysiological mechanisms with them.7 Examples include irritable bowel syndrome, irritable bladder syndrome, and temporomandibular joint syndrome. Some patients ascribe the onset of FMS to specific "triggers," including viral illness (eg, Lyme disease or hepatitis C), physical trauma, and major emotional stress.7
PATHOPHYSIOLOGY: TARGETS OF THERAPY
In the 1970s, Moldofsky and colleagues8 conducted pioneering sleep physiology studies that suggested the presence of sleep architecture abnormalities in patients with FMS. Since then, numerous studies have centered the pathophysiology of FMS in the CNS. Earlier concepts about FMS having an inflammatory component or being a disorder of peripheral muscle largely have been set aside.6
It has been observed that patients with FMS perceive more pain from nonpainful stimuli (allodynia) than do healthy controls and experience greater pain from painful stimuli (hyperalgesia).9 Functional MRI studies conducted by Gracely and associates10 have provided dynamic neuroimaging confirmation of this observation. A unifying concept is that increased pain sensitivity is the result of dysregulation of neuropeptide and neuroreceptor physiology in the ascending and descending spinal cord pain signaling pathways as well as in brain processing centers (Figure).
Central sensitization connotes amplified ascending nerve activity and receptor fields, part of which is the phenomenon of temporal summation, or "wind-up," in which stimuli after an initial pain stimulus are experienced as more intensely painful.7 This phenomenon is at least partly the result of dysregulation of the N-methyl d-aspartic acid (NMDA) receptors in the dorsal horn in patients with FMS. Russell and coworkers11 noted increased amounts of pronociceptive substance P in the cerebrospinal fluid of patients who had FMS compared with controls. Therefore, treatments known to down-regulate such pronociceptive neuropeptides may be beneficial for patients with FMS.
1. Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment [published correction appears in J Rheumatol Suppl. 2005;32:2063]. J Rheumatol Suppl. 2005;75:6-21.
2. Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia: report of the multicenter criteria committee. Arthritis Rheum. 1990;33:160-172.
3. Harth M, Nielson WR. The fibromyalgia tender points: use them or lose them? A brief review of the controversy. J Rheumatol. 2007;34:914-922.
4. Clauw DJ, Crofford LJ. Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best Pract Res Clin Rheumatol. 2003;17:685-701.
5. Gran JT. The epidemiology of chronic generalized musculoskeletal pain. Best Pract Res Clin Rheumatol. 2003;17:547-561.
6. Goldenberg D, Burckhardt C, Crofford L. Management of fibromyalgia syndrome. JAMA. 2004;292:2388-2395.
7. Arnold LM. Biology and therapy of fibromyalgia: new therapies in fibromyalgia. Arthritis Res Ther. 2006;8:212.
8. Moldofsky H, Scarisbrick P, England R, Smythe H. Musculoskeletal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects. Psychosom Med. 1975;37:341-345.
9. Dadabhoy D, Clauw DJ. Therapy insight: fibromyalgia—a different type of pain needing a different type of treatment. Nat Clin Pract Rheumatol. 2006;2:364-372.
10. Gracely RH, Petzke F, Wolf JM, Clauw DJ. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum. 2002;46:1333-1343.
11. Russell IJ, Michalek JE, Xiao Y, et al. Therapy with a central alpha-2-adrenergic agonist (tizanidine) decreases cerebrospinal fluid substance P, and may reduce serum hyaluronic acid as it improves the clinical symptoms of the fibromyalgia syndrome. Arthritis Rheum. 2002;46(suppl 9):S614.
12. Kosek E, Hansson P. Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects. Pain. 1997;70:41-51.
13. Pillemer SR, Bradley LA, Crofford LJ, et al. The neuroscience and endocrinology of fibromyalgia. Arthritis Rheum. 1997;40:1928-1939.
14. Wood PB, Schweinhardt P, Jaeger E, et al. Fibromyalgia patients show an abnormal dopamine response to pain. Eur J Neurosci. 2007;25:3576-3582.
15. Geenen R, Jacobs JW, Bijlsma JW. Evaluation and management of endocrine dysfunction in fibromyalgia. Rheum Dis Clin North Am. 2002;28:389-404.
16. Moldofsky H, Scarisbrick P. Induction of neurasthetic musculoskeletal pain syndrome by se-
lective sleep stage deprivation. Psychosom Med. 1976;
17. Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline, cyclobenzaprine, and placebo in the treatment of fibromyalgia. A randomized, double-blind clinical trial. Arthritis Rheum. 1994;37:32-40.
18. Arnold LM, Keck PE Jr, Welge JA. Antidepressant treatment of fibromyalgia, A meta-analysis and review. Psychosomatics. 2000;41:104-113.
19. Rossy LA, Buckelew SP, Dorr N, et al. A meta-analysis of fibromyalgia treatment interventions. Ann Behav Med. 1999;21:180-191.
20. Wolfe F, Cathey MA, Hawley DJ. A double-blind placebo controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol. 1994;23:255-259.
21. Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebo-controlled, double-blind, flexible-dose study of fluoxetine in the treatment of women with fibromyalgia. Am J Med. 2002;112:191-197.
22. Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromyalgia. Ann Pharmacother. 2003;
23. Zijsltra TR, Barendregt PJ, van de Laar MA. Venlafaxine in fibromyalgia: results of a randomized, placebo-controlled, double-blind trial. Arthritis Rheum. 2002;46:S105.
24. Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain. 2005;119:5-15.
25. Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia. J Rheumatol. 2005;32:1975-1985.
26. Wiffen P, Collins S, McQuay H, et al. Anticonvulsant drugs for acute and chronic pain. Cochrane Database Syst Rev. 2005;(3):CD001133.
27. Arnold L, Russell I, Duan W, et al. A 14-week, randomized, double-blind, placebo-controlled,
monotherapy trial of pregabalin (BID) in patients with fibromyalgia syndrome (FMS). Presented at: American Pain Society Annual Meeting; May 2-5, 2007; Washington, DC. Abstract 695.
28. Crofford LJ, Simpson S, Young JP Jr, et al. A six-month, double-blind, placebo-controlled, durability of effect study of pregabalin for pain associated with fibromyalgia. Presented at: 2006 American College of Rheumatology Meeting; November 11-15, 2006; Washington, DC. Abstract L44.
29. Arnold L, Goldenberg DL, Stanford SB, et al. Gabapentin in the treatment of fibromyalgia. Arthritis Rheum. 2007;56:1336-1344.
30. Russell IJ, Bennett RM, Michalek JE. Sodium oxybate relieves pain and improves sleep in fibromyalgia syndrome [FM]: a randomized, double-blind, placebo-controlled, multi-center clinical trial. Presented at: ACR/ARHP Scientific Meeting; November 12-17, 2005; San Diego. Program Book Supplement. Late-breaking abstracts.
31. Wolfe F, Anderson J, Harkness D, et al. A prospective, longitudinal, multicenter study of service utilization and costs in fibromyalgia. Arthritis Rheum. 1997;40:1560-1570.
32. Sërensen J, Bengtsson A, Bäckman E, et al. Pain analysis in patients with fibromyalgia. Effects of intravenous morphine, lidocaine, and ketamine. Scand J Rheumatol. 1995;24:360-365.
33. Russell IJ, Kamin M, Bennett RM, et al. Efficacy of tramadol in treatment of pain in fibromyalgia. J Clin Rheumatol. 2000;6:250-257.
34. Bennett RM, Kamin M, Karim R, Rosenthal N. Tramadol and acetaminophen combination tablets in the treatment of fibromyalgia pain: a double-blind, randomized, placebo-controlled study. Am J Med. 2003;114:537-545.
35. Goldenberg DL, Felson DT, Dinerman H. A randomized, controlled trial of amitriptyline and naproxen in the treatment of patients with fibromyalgia. Arthritis Rheum. 1986;29:1371-1377.
36. Holman AJ, Myers RR. A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications. Arthritis Rheum. 2005;52:2495-2505.
37. Bennett RM, Clark SC, Walczyk J. A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. Am J Med. 1998;104:227-231.
38. Spath M, Stratz T, Neeck G, et al. Efficacy and tolerability of intravenous tropisetron in the treatment of fibromyalgia. Scand J Rheumatol. 2004;33:267-270.
39. Fregni F, Gimenes R, Valle AC, et al. A randomized, sham-controlled, proof of principle study of transcranial direct current stimulation for the treatment of pain in fibromyalgia. Arthritis Rheum. 2006;54:3988-3998.
40. Sampson SM, Rome JD, Rummans TA. Slow-frequency rTMS reduced fibromyalgia pain. Pain Med. 2006;7:115-118.