Dear U.S. Senate Health, Education, Labor & Pensions Committee Members:
Thank you for this opportunity to bring attention to the significant problem of chronic pain in America. In terms of societal costs and personal human suffering, it is the highest health concern across our country.
Fibromyalgia is one of the most common chronic pain conditions, affecting 2 – 6% of the US population. This makes fibromyalgia the second most common rheumatological disorder, with only osteoarthritis being more common. Fibromyalgia is not only very common but is typically also very disabling; depending on the sample up to 15 – 20% of fibromyalgia patients may be on long-term disability.
The US pharmaceutical industry recognizes the importance and impact of this condition. Hundreds of millions of dollars have been spent translating our increased scientific understanding of this condition, into performing clinical trials. Three drugs have been specifically approved to treat this condition over the past five years. This has helped lead to significantly increased recognition of the condition amongst both patients and providers. But in spite of the acknowledged frequency and disability associated with fibromyalgia, this condition has received relatively little NIH funding. NIH funding of fibromyalgia is less than that for nearly any other common rheumatological disorder, averaging only $9M annually from 2007 – (est) 2012 (http://report.nih.gov/rcdc/categories/).
Investing in research in fibromyalgia will not just allow us to better understand fibromyalgia. For example, in addition to considering fibromyalgia as a “stand-alone” diagnosis (i.e., a given individual has fibromyalgia as their primary diagnosis), many individuals with other conditions develop fibromyalgia as a co-morbidity to their primary diagnosis. We now know that approximately 15 – 30% of individuals with osteoarthritis, rheumatoid arthritis, lupus, and even cancer develop co-morbid fibromyalgia, or “centralize their pain.” This means that instead of their pain primarily coming from damage or inflammation of peripheral tissues, the central nervous system amplifies and causes pain and other symptoms. Thus the study of why individuals develop fibromyalgia and how we can prevent or treat it can not only improve the lives of millions of individuals with the second most common rheumatological disorder, but also similarly help tens of millions of individuals that have developed fibromyalgia as a co-morbidity.
If these individuals with these conditions such as osteoarthritis, rheumatoid arthritis, and other disorders develop co-morbid fibromyalgia, this significantly worsens their pain and disability, unless/until the fibromyalgia is identified and treated. Worse yet, in addition to much co-morbid fibromyalgia going untreated, this lack of recognition of co-morbid fibromyalgia also leads to the use of expensive and toxic treatments that the patient may derive no benefit from. For example, if an individual with osteoarthritis suffers from co-morbid fibromyalgia, he or she may be one of the 10 – 20% of individuals who will not get better when they receive knee or hip replacement (costing roughly $50,000), because their pain is not coming from their knee or hip – but their brain. If an individual with rheumatoid arthritis has co-morbid fibromyalgia, he or she may fail to respond to toxic and expensive immunosuppressive drugs that are attacking peripheral inflammation, but not the central nervous system pain amplification of fibromyalgia. Thus the failure to recognize and treat fibromyalgia based on a better scientific understanding of this disorder is extremely costly, both in terms of pain and disability, but also misspent and unnecessary direct and indirect medical costs.
The concept of fibromyalgia (FM) being the prototypical “central” or “centralized” pain state. The term “central pain” was originally used to describe a condition that occurred in individuals who, following a stroke or spinal cord lesion, subsequently developed pain. In this case “central” referred to the fact that the lesion leading to pain occurred within the CNS—either spinal cord or brain. More recently, however, the term has expanded to describe any CNS dysfunction or pathology that may be contributing to the development or maintenance of chronic pain.1 Another term that has often been used to describe this same phenomenon is “central sensitization.”.
“Central pain,” (or central sensitization) was originally thought to be confined to individuals with idiopathic or functional pain syndromes, such as fibromyalgia (FM), headache, irritable bowel syndrome (IBS), temporomandibular joint disorder (TMJD), and interstitial cystitis (IC).2 These pain syndromes have been shown to be familial/genetic (e.g., the risk of developing FM is 8x higher in first degree relatives of patients with FM) and to co-aggregate in individuals and families.1,3 This type of pain often co-aggregates with other centrally-mediated symptoms such as fatigue, memory difficulties, and mood disturbances.4,5 Recent twin studies support a genetic basis of pain as well as this cluster of co-aggregating symptoms.6,7 Even if individuals are identified as having a new onset of a regional pain syndrome (e.g., Interstitial Cystis), closer questioning reveals very high rates of pain in other body regions, and somatic symptoms other than pain.8 Evidence suggests that what is often labeled as a single chronic regional pain syndrome is upon closer evaluation a chronic multisymptom illness, where the pain merely occurs in different body regions at different points in time, and is given different names by different sub-specialists focusing on “their region” of the body.1,5,9,10
The symptoms experienced by individuals with central pain syndromes have been well-characterized and consist of multifocal pain (i.e., with a high current and lifetime history of pain in many bodily regions), and the cluster of co-occurring somatic symptoms (i.e., fatigue, sleep disturbances, memory difficulties).1,8,10-13 Regarding the clustering of co-occurring somatic symptoms, as well as higher than expected rates of mood disorders, the leading pathogenic theory within these central pain states is that centrally acting neurotransmitters that are known to be abnormal and likely play a role in causing the pain in these conditions (e.g. low norepinephrine, GABA, serotonin; high glutamate, Substance P) also play prominent roles in controlling sleep, mood, alertness, etc.1,14
In addition to the study of symptom domains in central pain states, we have made significant advances in our understanding of chronic pain pathogenesis. Data from quantitative sensory testing (QST) and functional neuroimaging studies suggest wide individual variation in pain and sensory sensitivity that adheres to a bell-shape distribution across a wide variety of chronic pain states, with a subset of individuals displaying an “increased volume control” or gain in how the spinal cord and/or brain processes pain signals.1,3,15-17 Some of the discrete conditions consistently identified to have these characteristics include FM, IBS, TMJD, idiopathic low back pain, tension headache, IC, and vulvodynia.18-25
The prototypical central pain state, FM, may have peripheral contributions. Since fibrositis became fibromyalgia in the 1970’s, the predominant focus in FM has been on CNS mechanisms.26,27 However, emerging data suggest that peripheral nociceptive input may be playing a prominent role in symptom expression, at least in subsets of FM patients. For example, although there is no evidence of widespread inflammation or damage to the tissues in FM, there have been many studies suggesting that peripheral nociceptive input may be playing some role, as evidenced by elevations in peripheral pro-inflammatory cytokines in FM, as well as small fiber neuropathy.28-36 In addition, there is both experimental and clinical evidence that the central component of the pain might be partly maintained by peripheral nociceptive input.37-39 In fact a recent study in FM showed that when a co-morbid peripheral nociceptive problem (e.g.,myofascial pain or OA) was identifiable, treating this problem with peripherally-directed therapies led to an improvement in overall FM pain threshold and pain, suggesting that some centralization may be peripherally-maintained.40
Thus FM like any other chronic pain condition may indeed be a “mixed pain state.” Many individuals clearly develop FM precisely by mechanisms such as a motor vehicle accident, deployment to war, an infection, or some other painful and stressful event which first leads to regional pain, and then eventually becomes “centralized” and expressed as the full-blown FM phenotype.41-44 Research is needed to identify risk factors for, and the consequences of, developing “secondary” FM and centralization of pain. The reason for this is that centralization and chronicity in rheumatic disorders appears to occur at a much higher frequency (15 – 30%) than in individuals having an acute painful or stressful experience. The data suggesting that there is evidence of centralization of pain in each of these other rheumatic disorders is presented below. While the significance of only four overlapping conditions is discussed and suggested for research here, FM co-exists, or overlaps with virtually any chronic pain syndromes, as well as following cancer, and in association with deployment and especially traumatic brain injuries.
All classic rheumatic disorders, and many other medical conditions characterized by chronic pain, are mixed pain states, with co-morbid fibromyalgia playing a prominent role. The earliest evidence that FM may contribute to the pain and other symptoms associated with classic rheumatic disorders such as osteoarthritis (OA), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE) came from studies suggesting that approximately 15 – 30% of individuals with these disorders may have FM as a co-morbid diagnosis.45-48 In the pain field at present, when both “peripheral” and “central” contributions to pain are recognized, we then refer to a pain condition as “mixed pain state.” But roughly the same frequency of individuals with cancer, or deployed to war, may develop centralization of pain, or a mixed pain state (similar to FM). This is consistent with the broader literature suggesting that a variety of acute pain states and/or stressors can trigger the development of FM in susceptible individuals, including infections, trauma, and deployment to war.41,42,44,49-55 However, studies are needed to closely followed the longitudinal development of FM by following individuals from when they first develop acute symptoms, to when they develop co-morbid FM.
Summary.There has been an explosion in the knowledge and recognition of the importance of fibromyalgia amongst the general public, healthcare providers, and the pharmaceutical industry. NIH funding has simply failed to keep pace with these advances, in parallel with low funding for NIH pain research in general, as succinctly pointed out by the recent IOM report. Increased funding for FM will serve two constituents: the approximately 10 million individuals in the U.S. with FM, as well as the millions more that have this as a (usually unrecognized) co-morbidity.
I appreciate the opportunity to present my opinion.
Daniel J. Clauw, M.D.
Professor of Anesthesiology, Medicine (Rheumatology) and Allergy
Director, Chronic Pain and Fatigue Research Center
The University of Michigan
February 12, 2012
1. Williams DA, Clauw DJ. Understanding fibromyalgia: lessons from the broader pain research community. J Pain. 2009;10(8):777-791.
2. Clauw DJ, Schmidt M, Radulovic D, Singer A, Katz P, Bresette J. The relationship between fibromyalgia and interstitial cystitis. Journal of Psychiatric Research. 1997;31(1):125-131.
3. Diatchenko L, Nackley AG, Slade GD, Fillingim RB, Maixner W. Idiopathic pain disorders--pathways of vulnerability. Pain. 2006;123(3):226-230.
4. Fukuda K, Dobbins JG, Wilson LJ, Dunn RA, Wilcox K, Smallwood D. An epidemiologic study of fatigue with relevance for the chronic fatigue syndrome. Journal of Psychiatric Research. 1997;31(1):19-29.
5. Fukuda K, Nisenbaum R, Stewart G, et al. Chronic multisymptom illness affecting Air Force veterans of the Gulf War. Journal of the American Medical Association. 1998;280(11):981-988.
6. Kato K, Sullivan PF, Evengard B, Pedersen NL. Importance of genetic influences on chronic widespread pain. Arthritis Rheum. 2006;54(5):1682-1686.
7. Kato K, Sullivan PF, Evengard B, Pedersen NL. A population-based twin study of functional somatic syndromes. Psychol.Med. 2008:1-9.
8. Warren JW, Howard FM, Cross RK, et al. Antecedent Nonbladder Syndromes in Case-Control Study of Interstitial Cystitis/Painful Bladder Syndrome. Urology. 2008.
9. Khan AA, Khan A, Harezlak J, Tu W, Kroenke K. Somatic symptoms in primary care: etiology and outcome. Psychosomatics. 2003;44(6):471-478.
10. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Archives of Internal Medicine. 2000;160(2):221-227.
11. Yunus MB. Central sensitivity syndromes: a new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness. Semin.Arthritis Rheum. 2008;37(6):339-352.
12. Yunus MB. Role of central sensitization in symptoms beyond muscle pain, and the evaluation of a patient with widespread pain. Best.Pract.Res.Clin.Rheumatol. 2007;21(3):481-497.
13. Rodriguez MA, Afari N, Buchwald DS. Evidence for overlap between urological and nonurological unexplained clinical conditions. J Urol. Nov 2009;182(5):2123-2131.
14. Bannister K, Bee LA, Dickenson AH. Preclinical and early clinical investigations related to monoaminergic pain modulation. Neurotherapeutics. 2009;6(4):703-712.
15. Gwilym SE, Keltner JR, Warnaby CE, et al. Psychophysical and functional imaging evidence supporting the presence of central sensitization in a cohort of osteoarthritis patients. Arthritis Rheum. 2009;61(9):1226-1234.
16. Tracey I, Bushnell MC. How neuroimaging studies have challenged us to rethink: is chronic pain a disease? J Pain. 2009;10(11):1113-1120.
17. Coghill RC, McHaffie JG, Yen YF. Neural correlates of interindividual differences in the subjective experience of pain. Proc.Natl.Acad.Sci.U.S.A. 2003;100(14):8538-8542.
18. Kashima K, Rahman OI, Sakoda S, Shiba R. Increased pain sensitivity of the upper extremities of TMD patients with myalgia to experimentally-evoked noxious stimulation: Possibility of worsened endogenous opioid systems. Cranio. 1999;17(4):241-246.
19. Maixner W, Fillingim R, Booker D, Sigurdsson A. Sensitivity of patients with painful temporomandibular disorders to experimentally evoked pain. Pain. 1995;63(3):341-351.
20. Leffler AS, Hansson P, Kosek E. Somatosensory perception in a remote pain-free area and function of diffuse noxious inhibitory controls (DNIC) in patients suffering from long-term trapezius myalgia. Eur.J.Pain. 2002;6(2):149-159.
21. Whitehead WE, Holtkotter B, Enck P, et al. Tolerance for rectosigmoid distention in irritable bowel syndrome. Gastroenterology. 1990;98(5 Pt 1):1187-1192.
22. Gibson SJ, Littlejohn GO, Gorman MM, Helme RD, Granges G. Altered heat pain thresholds and cerebral event-related potentials following painful CO2 laser stimulation in subjects with fibromyalgia syndrome. Pain. 1994;58(2):185-193.
23. Kosek E, Ekholm J, Hansson P. Increased pressure pain sensibility in fibromyalgia patients is located deep to the skin but not restricted to muscle tissue [published erratum appears in Pain 1996 Mar;64(3):605]. Pain. 1995;63(3):335-339.
24. Giesecke J, Reed BD, Haefner HK, Giesecke T, Clauw DJ, Gracely RH. Quantitative sensory testing in vulvodynia patients and increased peripheral pressure pain sensitivity. Obstet Gynecol. Jul 2004;104(1):126-133.
25. Giesecke T, Gracely RH, Grant MA, et al. Evidence of augmented central pain processing in idiopathic chronic low back pain. Arthritis Rheum. 2004;50(2):613-623.
26. Simms RW. Fibromyalgia is not a muscle disorder. American Journal of Medical Science. 1998;315(6):346-350.
27. Raspe H, Croft P. Fibromyalgia. Baillieres Clinical Rheumatology. 1995;9(3):599-614.
28. Hernandez ME, Becerril E, Perez M, et al. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index. BMC Res Notes. 2010;3(1):156.
29. Menzies V, Lyon DE. Integrated review of the association of cytokines with fibromyalgia and fibromyalgia core symptoms. Biol Res Nurs. Apr 2010;11(4):387-394.
30. Feng J, Zhang Z, Li W, et al. Missense mutations in the MEFV gene are associated with fibromyalgia syndrome and correlate with elevated IL-1beta plasma levels. PLoS One. 2009;4(12):e8480.
31. Togo F, Natelson BH, Adler GK, et al. Plasma cytokine fluctuations over time in healthy controls and patients with fibromyalgia. Exp Biol Med (Maywood). Feb 2009;234(2):232-240.
32. Bazzichi L, Rossi A, Massimetti G, et al. Cytokine patterns in fibromyalgia and their correlation with clinical manifestations. Clin.Exp.Rheumatol. 2007;25(2):225-230.
33. Kaufmann I, Eisner C, Richter P, et al. Lymphocyte subsets and the role of TH1/TH2 balance in stressed chronic pain patients. Neuroimmunomodulation. 2007;14(5):272-280.
34. Macedo JA, Hesse J, Turner JD, et al. Adhesion molecules and cytokine expression in fibromyalgia patients: increased L-selectin on monocytes and neutrophils. J.Neuroimmunol. 2007;188(1-2):159-166.
35. Caro XJ, Winter EF, Dumas AJ. A subset of fibromyalgia patients have findings suggestive of chronic inflammatory demyelinating polyneuropathy and appear to respond to IVIg. Rheumatology.(Oxford). 2008;47(2):208-211.
36. Kim SH, Kim DH, Oh DH, Clauw DJ. Characteristic electron microscopic findings in the skin of patients with fibromyalgia--preliminary study. Clin.Rheumatol. 2008;27(3):407-411.
37. Staud R, Nagel S, Robinson ME, Price DD. Enhanced central pain processing of fibromyalgia patients is maintained by muscle afferent input: a randomized, double-blind, placebo-controlled study. Pain. Sep 2009;145(1-2):96-104.
38. Staud R, Robinson ME, Weyl EE, Price DD. Pain variability in fibromyalgia is related to activity and rest: role of peripheral tissue impulse input. J Pain. Dec 2010;11(12):1376-1383.
39. Ge HY, Nie H, Madeleine P, Danneskiold-Samsoe B, Graven-Nielsen T, Arendt-Nielsen L. Contribution of the local and referred pain from active myofascial trigger points in fibromyalgia syndrome. Pain. Dec 15 2009;147(1-3):233-240.
40. Affaitati G, Costantini R, Fabrizio A, Lapenna D, Tafuri E, Giamberardino MA. Effects of treatment of peripheral pain generators in fibromyalgia patients. Eur J Pain. Jan 2011;15(1):61-69.
41. Hassett AL, Clauw DJ. The role of stress in rheumatic diseases. Arthritis Res.Ther. 2010;12(3):123.
42. Clauw D. The health consequences of the first Gulf war. Bmj. 2003;327(7428):1357-1358.
43. Clauw DJ, Engel CC, Jr., Aronowitz R, et al. Unexplained symptoms after terrorism and war: an expert consensus statement. J.Occup.Environ.Med. 2003;45(10):1040-1048.
44. Buskila D, Atzeni F, Sarzi-Puttini P. Etiology of fibromyalgia: The possible role of infection and vaccination. Autoimmun.Rev. 2008;8(1):41-43.
45. Clauw DJ, Katz P. The Overlap Between Fibromyalgia and Inflammatory Rheumatic Disease: When and Why Does it Occur? J Clin Rheumatol. Dec 1995;1(6):335-342.
46. Wolfe F, Cathey MA. Prevalence of primary and secondary fibrositis. Journal of Rheumatology. 1983;10(6):965-968.
47. Middleton GD, McFarlin JE, Lipsky PE. The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum. Aug 1994;37(8):1181-1188.
48. Buskila D, Press J, Abu-Shakra M. Fibromyalgia in systemic lupus erythematosus: prevalence and clinical implications. Clinical reviews in allergy & immunology. Aug 2003;25(1):25-28.
49. Ablin JN, Cohen H, Clauw DJ, et al. A tale of two cities - the effect of low intensity conflict on prevalence and characteristics of musculoskeletal pain and somatic symptoms associated with chronic stress. Clin.Exp.Rheumatol. 2010.
50. Williams DA, Clauw DJ. Understanding fibromyalgia: lessons from the broader pain research community. J Pain. Aug 2009;10(8):777-791.
51. Arguelles LM, Afari N, Buchwald DS, Clauw DJ, Furner S, Goldberg J. A twin study of posttraumatic stress disorder symptoms and chronic widespread pain. Pain. Sep 2006;124(1-2):150-157.
52. McLean SA, Clauw DJ, Abelson JL, Liberzon I. The development of persistent pain and psychological morbidity after motor vehicle collision: integrating the potential role of stress response systems into a biopsychosocial model. Psychosom Med. Sep-Oct 2005;67(5):783-790.
53. Buskila D, Ablin JN, Ben-Zion I, et al. A painful train of events: increased prevalence of fibromyalgia in survivors of a major train crash. Clin Exp Rheumatol. Sep-Oct 2009;27(5 Suppl 56):S79-85.
54. Ablin K, Clauw DJ. From fibrositis to functional somatic syndromes to a bell-shaped curve of pain and sensory sensitivity: evolution of a clinical construct. Rheum.Dis.Clin North Am. 2009;35(2):233-251.
55. Jones GT, Nicholl BI, McBeth J, et al. Road traffic accidents, but not other physically traumatic events, predict the onset of chronic widespread pain: Results from the EpiFunD study. Arthritis Care Res (Hoboken). Mar 21 2011.