Challenge: Findings from brain neuroimaging may support a better understanding of FM, but the wealth of technical information needs to be made relevant for a primary care audience and better communicated to these providers.
There has been a surge of interest in using brain neuroimaging to study pain in a more quantitative, objective manner and to better understand the potential pathophysiology of FM. As reported in a recent systematic review, evidence from numerous imaging studies have demonstrated multiple, specific CNS changes related to central sensitization.21 However, the information can be difficult to understand. For example, it is unclear whether the CNS changes are a cause or consequence of centralized pain, and the overlap with CNS changes caused by more peripheral types of chronic pain (eg, RA) is not well defined. As a result, this information is often not adequately synthesized and disseminated to practitioners to enhance their understanding of FM and its treatment.
Suggestion: Distill the findings of seminal imaging studies into clear, simple terms and pictures to provide a better understanding of the processes underlying pain centralization/amplification/hypersensitivity, thereby enabling a better understanding of FM.
These messages should focus on the following:
- Patients with FM display altered levels of key neurotransmitters (ie, increased excitatory and reduced inhibitory neurotransmitter levels),22,23 altered receptor binding,24 altered resting brain activity (ie, connectivity25,26), and differences in activation of pain-sensitive areas of the brain (Fig. 3).27,28 For example, in patients with FM, greater connectivity is observed between pain-promoting regions such as the insula and the default mode network, a network that is activated when an individual is not engaged with the external environment. Greater connectivity between the insula and the default mode network is associated with greater spontaneous clinical pain.26 These data and others imply aberrant brain neurotransmission is a hallmark of FM.26,29,30
- Recent neuroimaging studies suggest that the CNS changes in patients with FM can be altered with pharmacologic and nonpharmacologic treatment.30,31 For example, an antiepileptic drug approved by the US Food and Drug Administration for the management of FM reduces glutamine/glutamate levels within the posterior insula and reduces connectivity between the posterior insula and default mode network. These changes track with changes in clinical pain.31 As such, imaging studies in diseases like FM provide a biological underpinning to better understand centralized pain. In addition, identification of functional brain “signatures” for drug action (analgesia) or disease state (neuropathic pain) could provide objective biomarkers to guide drug development.32
Challenge: FM epidemiology data are available from different regions worldwide but are fragmented owing to different methods of data collection, patient selection, or health outcomes studied. In addition, available data are not collated in one place to facilitate learning and to guide future research to address the biggest knowledge gaps.
Reports of the prevalence of FM vary widely by geographic region for a number of reasons, including the diagnostic criteria used, differing study methodologies and designs, and different definitions of FM, among other reasons.33 In addition, even in advanced health care delivery systems, common data standards for pain and its impact on the patient (eg, function, sleep, mood) are ill defined, greatly limiting the utility of a potentially rich source of real-world data.
Suggestion: Perform a quality review of the existing data, collate reliable information, and recommend standards for gathering quality data.
As noted, several steps would be involved:
- The first step is to identify and consolidate existing quality data that provide reliable insight into FM epidemiology and to determine where epidemiologic gaps currently exist. To date, widely accepted data on the epidemiology of FM include the points listed in Sidebar 2 (Supplemental Digital Content 2, http://links.lww.com/CJP/A345).18,33–44 However, the generalizability of these findings across different global regions remains to be determined, as does the collection of more consistent data regarding the prevalence of FM in different regions.
- A key step is to create standards for gathering epidemiologic data to provide consistency in data collection moving forward. Toward this end, generating standard FM criteria and severity scales for use in epidemiologic and clinical studies would prove useful. Such standardization recently has been attempted by Wolfe et al45 through development of the Widespread Pain Index, Symptom Severity scale, and Fibromyalgia Survey Questionnaire,46 but global consensus among FM researchers is needed to establish such metrics as the de facto standards for epidemiologic data collection.
- As quality epidemiologic data are identified or generated, efforts should be made to disseminate this information to clinicians and policymakers to underscore the breadth and magnitude of FM as a medical concern.
Ideally, with such efforts, sufficient epidemiologic data would be generated to enable the identification of different FM subgroups based on:
- Trigger factors (psychosocial, trauma/abuse, infection, inflammation, sleep disorder, etc.).
- Pain characteristics, including severity, perceptual pain qualities, temporal characteristics, and pain-related interference.
- Overlap with other chronic pain syndromes (eg, irritable bowel syndrome, migraine, chronic fatigue syndrome, dysmenorrhea, temporomandibular joint disorder, restless legs syndrome, female urethral syndrome or overactive bladder, as well as rheumatic disorders such as OA and RA).
- Genetic polymorphism associations.
- Response to interventions.
- Comorbid mood disorders.
- Preexisting psychosocial traits, catastrophizing, education, income.
Equally important, establishing standards for data collection would also enable a more systematic exploration of centralized/amplified/hypersensitive pain in other common pain conditions.
Issue: The FM Lexicon Needs to be Framed in the Context of the Pain Continuum
Challenge: The lexicon for FM is still in flux and presents a disconnect hampering a uniform understanding and approach to FM diagnosis and interdisciplinary management.
Both the definition and understanding of FM continue to evolve, resulting in outdated and inconsistent use of sometimes arbitrary terminology.47 For example, FM was initially termed fibrositis based on early studies that described inflammatory abnormalities in the muscle or soft tissues.48 The term fibromyalgia syndrome emerged, eliminating the connotation of an underlying inflammatory connection but still implying a condition of the muscle and surrounding tissue and offering a way to compile the different symptoms of FM into one disorder. Fibromyalgia syndrome has transitioned to become just FM based on scientific evidence that FM is a distinct entity. FM is recognized by the World Health Organization with several ICD codes (ICD-9 codes: 728.79, 729.0, and 729.1; ICD-10 code: M79.7). In addition to the evolving delineation of FM, there is inconsistent use of several other terms related to the type of pain associated with FM, such as central pain, central sensitivity, centralized pain, sensory hypersensitivity, secondary FM, and so forth. The lack of common FM terminology used by clinicians undermines the willingness of some to accept or treat the disease, which poses challenges to optimizing care and outcomes for patients with FM or conditions with a predominant centralized component. In addition, opposition by certain clinicians to the term FM persists in some regions.49–51
Suggestion: A common “FM language” needs to be established.
Initial efforts toward this end include the following:
- Determine whether the term FM should remain or whether an alternative term is needed (eg, central sensitization syndrome) to accurately describe the condition and the mechanisms involved in pathogenesis.
- Professional associations could align on a clear, simple definition of FM (or alternative term) within the context of centralized pain; this would facilitate alignment among clinicians within different medical disciplines.
- A definitive cause of FM is currently unknown and may be multifactorial. Although there is abundant useful information on FM and chronic pain syndromes, this information is fragmented. A definitive trusted source for expert opinion and guidance is needed to serve as a universal sentinel FM knowledge base.
- Use clear, common language to describe the pathophysiology of FM (as discussed previously) and show where FM sits in the chronic pain continuum, to establish alignment among clinicians within different medical disciplines.
- Information could highlight the following:
- Typically, FM is characterized by chronic pain caused by alterations in sensory processing in the CNS. Although this pain is centralized, a subset of patients with FM may also present with peripheral pain generators.37
- Aberrant neurochemical processing of sensory signals in the CNS may lower the threshold of pain, amplify normal sensory signals, and alter gene expression,52 thereby leading to hypersensitivity and central sensitization that result in chronic pain. Changes in the CNS that lead to FM also likely contribute to multiple associated symptoms, including sleep disturbance, fatigue, cognitive symptoms, and mood problems.18
Issue: Unified Diagnostic Guidelines for FM are Lacking
Challenge: Although there are a number of FM guidelines, no international consensus guidelines on FM diagnosis and management currently exist.
As an example, 3 different sets of ACR classification/diagnostic criteria are in use: the 1990 criteria, which review a patient’s history of widespread pain and require a tender point examination; the preliminary 2010 criteria, which provide a quantifiable measurement of chronic widespread pain and replace the tender point examination with an assessment of fatigue, waking unrefreshed, cognitive symptoms, and somatic symptoms; and the modified 2010 criteria, which rely on patient self-report of pain and a simplified listing of somatic symptoms. A recent study found that FM prevalence varies >4-fold with the application of these different criteria sets. In fact, prevalence is not only higher with the modified 2010 criteria, but a greater proportion of men are identified.33
In addition, accurate and timely diagnosis of FM currently falls far below what many would consider to be reasonable standards. In a recent survey of FM patients conducted in 6 European countries, Mexico, and South Korea, respondents reported that on average it took 2.3 years and presentation to 3.7 different physicians before they received a diagnosis of FM.53 In a separate study of 277 Brazilian women newly diagnosed with FM in a nationwide databank, analysis revealed that 74% of patients had suffered with chronic widespread pain for >3 years, 70% visited >3 doctors before a diagnosis of FM was established, and 44% experienced a lapse of >3 years between their first consultation with a medical professional and ultimately being seen by a rheumatologist.54
Clinical practice guidelines have the potential to offer much-needed assistance to practitioners tasked with diagnosing FM and delivering appropriate care; however, problems with such guidelines exist. Current guidelines to manage patients with chronic pain typically are siloed by country/region, if they exist at all.9,55–57 Even within each country/region, there can be a lack of consensus regarding the criteria used and recommendations made by such guidelines or consensus statements.44,58
Suggestion: Endeavors should be made to gain consensus on FM diagnostic and treatment guidelines from multiple stakeholders (interdisciplinary health care providers, different countries/regions) to promote widespread adoption and uptake.
Ideally, such guidelines should adhere to a number of basic principles:
- The guidelines should help orient clinicians to recognize the spectrum of chronic pain syndromes, comorbid illnesses associated with FM, and the psychological and cognitive effects of FM (eg, depression, anxiety).
- The guidelines should be simple and should focus on a biopsychosocial approach to FM diagnosis and management (eg, utilize a numeric rating scale to assess pain, global improvement, functional improvement, response to treatment, activities of daily living, and patient quality of life).
- The guidelines should recognize that symptom intensity and functional outcomes in FM may fluctuate over time.
- The guidelines should align with evidence-based classification systems for chronic pain (eg, the ACTTION-American Pain Society Pain Taxonomy).59
- The guidelines should present the strength of each recommendation and indicate the quality of the scientific evidence supporting the recommendation.
- The guidelines should help support clinical practice but not dictate clinical practice.
- The guidelines should be written in such a way to be applicable across regions and/or to accommodate cultural differences and interprofessional differences, given the importance of multimodal approaches to care.
- The guidelines should underscore the need for multimodal management of FM symptoms, including approaches that address the biological and psychosocial factors eliciting FM.
- An overarching goal should be to develop streamlined approaches to reduce the office time required for clinicians to diagnose and manage FM across regions, without compromising the quality of care or patient satisfaction.
- Development of such guidelines may best be accomplished through the actions of a credible global organization, as discussed next (eg, International Association for the Study of Pain [IASP]).
Issue: There is No Focused, Organized Leadership Charged With Research and Patient Care in FM and Other Chronic Pain Disorders
Challenge: No single group of physicians or other health care providers has taken ownership of FM or most other chronic pain disorders.
Patients with FM typically initially present to their primary care providers (PCPs) but thereafter consult with a variety of health care providers. In the United States and other regions, clinical services and research generally are organized along disease-specific lines. Although such an approach can be useful in disciplines such as cardiology, this organization does not lend itself to optimal care of individuals with chronic pain.
Various medical and surgical subspecialties have carved out an isolated piece of the chronic pain puzzle. Departments of anesthesiology, neurology, neurosurgery, orthopedics, and cancer take charge of treating pain etiologically associated with their diseases of interest, often without taking a more holistic view of the widespread manifestations of pain. This leads to a situation in which distinct clinical and research silos are spread across chronic pain management, which in turn hinders cross-fertilization of ideas and best practices and rejects a unifying approach to chronic pain syndromes.
This disconnect between disciplines is also reflected in national research institutes. For example, in the United States, the National Institutes of Health (NIH) has no dedicated pain institute, although there is an NIH Pain Consortium that was established to enhance pain research and promote collaboration among researchers (http://www.painconsortium.nih.gov). Some efforts have been made to collate information across institutes to better understand diseases like FM and other overlapping conditions (eg, the Workshop on Chronic Overlapping Pain Conditions; http://www.nidcr.nih.gov/NewsAndFeatures/Calendar/CalendarListing08132012.htm), but more work in this regard is necessary.
Suggestion: Promote opportunities for interprofessional collaboration on the management of FM within medical institutions.
In an ideal world, it would be preferable for PCPs to adopt the role of initial FM management, as they have done increasingly for headache and depression, with referral to a specialist when appropriate. However, this may not be a feasible approach in all countries. Opportunities for interprofessional collaboration on FM management that span a variety of medical settings may take various forms:
- Develop a framework to ensure delivery of a simple, holistic, multidisciplinary care plan or pathway that enables interprofessional approaches to complex pain conditions, regardless of country or region.
- Promote awareness and access to resources developed at the national level that provide practical approaches to diseases like FM. Examples of such resources include print-based articles (eg, FibroCollaborative framework for FM management),9,57 simple online tools (eg, http://fibroguide.med.umich.edu/),60 and lectures, workshops, and presentations organized by specialty societies (eg, the ACR).
- Incorporate innovative diagnostic tools into daily practice (eg, treatment algorithms linked to patient electronic medical records) that facilitate optimal management of FM, including the need for referral to specialists in complex cases.
- Assess the impact of educational and change initiatives on outcomes and resource utilization to further refine learning and change.
- Offer grand rounds and medical conference presentations to a broad group of physicians, residents, and medical students that focus on FM and underscore the need for interdisciplinary consultation and management. This training should seek to provide guidance on when and how to refer patients with FM to other specialists, including neurologists, rheumatologists, psychologists, and others.
- Ensure that other health care providers, such as nurses, physician assistants, nurse practitioners, physical therapists, and pharmacists, receive education and training on FM to help support the education and management of FM patients within primary care settings.
- Arrange for pain specialists in pain management, neurology, rheumatology, psychiatry, and other departments to periodically participate in case review to offer insight into how to manage pain in complex cases.
- Advocate for interdisciplinary teams of pain specialists to be collocated or embedded in primary care settings so that they can be more available for consultation during regularly scheduled PCP visits devoted to patients with FM.
- Emphasize that the presence of FM can be a predictor of poorer analgesic outcomes following various pain interventions—potentially an important consideration for specialists.61,62
Challenge: Professional bodies and patient organizations are disjointed, with no recognized source of support and trusted information.
FM advocacy—as well as advocacy for other chronic pain conditions—is not organized, strong, or effective in most countries. In general, FM and related chronic pain conditions are not integrated into the chronic pain continuum, which leads to fragmented approaches to pain management. Funding agencies, pharmaceutical companies, and patient organizations tend to align themselves with specific interest groups rather than supporting broader efforts to address FM and other chronic pain disorders. Although the scientific community sometimes aligns on the goals of treating pain, different routes of distributing data and information result in fragmentation and potential confusion.
Suggestion: Establish or identify a credible global organization to serve as the flagship for FM education, advocacy, and changes to practice.
Ideally, this global organization would strive to achieve certain fundamental goals to unite the various stakeholders impacted by FM:
- The organization should champion an interprofessional, comprehensive approach to chronic pain education and management by bringing together medical professionals from various specialties that deal with chronic pain, for example, pain management specialists, neurologists, rheumatologists, psychiatrists, orthopedic surgeons, gastroenterologists, gynecologists, otolaryngologists, cardiologists, pain specialists, nurse practitioners, and clinical psychologists, among others.
- The organization should engage the interprofessional community to innovate solutions to increase FM understanding, learning, and change, such as through scientific meetings, a Web site, and continuing medical education programming, to ultimately improve patient outcomes.
- The organization should endeavor to integrate the voice of the patient into its undertakings and offerings (eg, through “patient society days” before chapter meetings).
Of note, the IASP, which currently has >7000 members in 133 countries and 90 national chapters, may be the ideal organization to adopt this role by creating a special interest group focused on FM (http://www.iasp-pain.org/). As noted in its mission statement, IASP “brings together scientists, clinicians, health care providers, and policymakers to stimulate and support the study of pain and to translate that knowledge into improved pain relief worldwide.” Alternatively, more regional organizations already focused on FM (eg, the EFNA, http://www.enfa-europe.eu) could be bolstered and expanded to establish a worldwide presence, or a new global organization specifically focused on FM could be created.
Issue: Clear Global Regulatory Pathways for FM Treatments are Lacking
Challenge: Clear regulatory pathways are needed for FM treatment approval.
In general, approval of a therapeutic product comprises multiple stages: applying to conduct clinical trials, conducting clinical trials, applying for marketing authorization of a drug, and conducting postmarketing studies. However, there is marked variation globally in the drug-approval process within the area of chronic pain. First, not all regions have a regulatory pathway. Second, different regulatory agencies offer different approaches to pain indications.63,64 At present, draft analgesic guidances do not address FM or chronic pain syndromes. Both of these factors pose major barriers to the development of effective therapies for FM, as innovation and investment in FM conditions is contingent on regulatory pathways.
Suggestion: FM stakeholders within individual regions/countries should work to identify the regulatory pathway through which to facilitate approval of FM therapies and strengthen relations with those regulatory bodies. To emphasize the importance of these approval pathways, both pain experts and patients should be engaged in the development of regulatory requirements, and regulatory authorities from different countries should discuss and achieve consensus on these requirements.
Toward this end, several strategies may prove fruitful:
- Each country’s government could develop and publish a health services plan for patients with chronic pain, including FM, and then work with regulatory authorities and other stakeholders to devise clear strategies and pathways for meeting the objectives delineated in the health services plan.
- To improve acceptance of FM as a valid medical condition, each country could create a national consensus document on the diagnosis and treatment of FM (including both pharmacologic and nonpharmacologic treatment modalities), publish the document, and make it available through the Internet.
- Each country could establish a “guidelines project” with its respective national medical association (eg, the American Medical Association), involving participation of medical professionals from several specialties that deal with chronic pain.
- A primary care society or rheumatology society of each country could create a “Fibromyalgia Study Commission” that brings together specialists from other medical fields with knowledge about FM. This organization could endeavor to:
- Create a Web site for doctors and another for patients containing the most relevant educational and scientific information pertinent to each group.
- Translate and validate established questionnaires and other tools to gauge the impact of FM on patient function and quality of life.
- Create a national databank on FM with the participation of interested physicians from academic, public, and private institutions.
- Engage with the ministry of health within the country to raise awareness about the need for approval of FM therapies.
Currently, many clinicians worldwide struggle to understand, recognize, diagnose, and manage FM and other chronic pain syndromes, particularly within the broader context of the pain continuum, but this need not be so. By delineating the current challenges within the FM field, this white paper lays the initial groundwork for how to translate the perceived complexity of FM into meaningful action. With this foundation, we can begin to move forward to overcome some of the obstacles facing FM and other chronic pain syndromes. The intent is for this white paper and the points raised herein to serve as a call to action to stimulate key opinion leaders worldwide to unite, collaborate, and reach consensus on seminal issues pertaining to FM, thereby fostering a collective global effort to advance the field of FM specifically and of chronic pain in general.
The authors thank Stephen Watt, BSc, MBChB, MPhil, Andrew G. Clair, PhD, and Joanna Atkinson, MD, of Pfizer for their critical review and input during development of the manuscript.
1. Institute of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press; 2011.
2. Lawrence RC, Felson DT, Helmick CG, et al.. National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum. 2008;58:26–35.
3. Knight T, Schaefer C, Chandran A, et al.. Health-resource use and costs associated with fibromyalgia
in France, Germany, and the United States. Clinicoecon Outcomes Res. 2013;5:171–180.
4. Clauw DJ, Arnold LM, McCarberg BH. FibroCollaborative. The science of fibromyalgia
. Mayo Clin Proc. 2011;86:907–911.
6. Wolfe F, Walitt B. Culture, science and the changing nature of fibromyalgia
. Nat Rev Rheumatol. 2013;9:751–755.
7. Wolfe F, Clauw DJ, Fitzcharles MA, et al.. Fibromyalgia
criteria and severity scales for clinical and epidemiological studies: a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia
. J Rheumatol. 2011;38:1113–1122.
8. Clauw DJ, Crofford LJ. Chronic widespread pain
: what we know, and what we need to know. Best Pract Res Clin Rheumatol. 2003;17:685–701.
9. Arnold LM, Clauw DJ, McCarberg BH. FibroCollaborative. Improving the recognition and diagnosis of fibromyalgia
. Mayo Clin Proc. 2011;86:457–464.
10. 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;37:339–352.
11. Mu R, Li C, Zhu JX, et al.. National survey of knowledge, attitude and practice of fibromyalgia
among rheumatologists in China. Int J Rheum Dis. 2013;16:258–263.
12. Perrot S, Choy E, Petersel D, et al.. Survey of physician experiences and perceptions about the diagnosis and treatment of fibromyalgia
. BMC Health Serv Res. 2012;12:356.
13. Homma M, Ishikawa H, Kiuchi T. Association of physicians’ illness perception of fibromyalgia
with frustration and resistance to accepting patients: a cross-sectional study. Clin Rheumatol. 2016;35:1019–1027.
14. Lobo CP, Pfalzgraf AR, Giannetti V, et al.. Impact of invalidation and trust in physicians on health outcomes in fibromyalgia
patients. Prim Care Companion CNS Disord. 2014;16. doi: 10.4088/PCC.14m01664. eCollection 2014.
15. Kool MB, Van Middendorp H, Boeije HR, et al.. Understanding the lack of understanding: invalidation from the perspective of the patient with fibromyalgia
. Arthritis Rheum. 2009;61:1650–1656.
16. Arnold LM, Crofford LJ, Mease PJ, et al.. Patient perspectives on the impact of fibromyalgia
. Patient Educ Couns. 2008;73:114–120.
17. Kool MB, Geenen R. Loneliness in patients with rheumatic diseases: the significance of invalidation and lack of social support. J Psychol. 2012;146:229–241.
18. Phillips K, Clauw DJ. Central pain
mechanisms in the rheumatic diseases: future directions. Arthritis Rheum. 2013;65:291–302.
19. Wolfe F. New American College of Rheumatology criteria for fibromyalgia
: a twenty-year journey. Arthritis Care Res (Hoboken). 2010;62:583–584.
20. Yunus MB. The prevalence of fibromyalgia
in other chronic pain conditions. Pain Res Treat. 2012;2012:584573.
21. Cagnie B, Coppieters I, Denecker S, et al.. Central sensitization in fibromyalgia
? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum. 2014;44:68–75.
22. Harris RE, Sundgren PC, Craig AD, et al.. Elevated insular glutamate in fibromyalgia
is associated with experimental pain. Arthritis Rheum. 2009;60:3146–3152.
23. Foerster BR, Petrou M, Edden RA, et al.. Reduced insular γ-aminobutyric acid in fibromyalgia
. Arthritis Rheum. 2012;64:579–583.
24. Harris RE, Clauw DJ, Scott DJ, et al.. Decreased central µ-opioid receptor availability in fibromyalgia
. J Neurosci. 2007;27:10000–10006.
25. Jensen KB, Loitoile R, Kosek E, et al.. Patients with fibromyalgia
display less functional connectivity in the brain’s pain inhibitory network. Mol Pain. 2012;8:32.
26. Napadow V, LaCount L, Park K, et al.. Intrinsic brain connectivity in fibromyalgia
is associated with chronic pain intensity. Arthritis Rheum. 2010;62:2545–2555.
27. Gracely RH, Petzke F, Wolf JM, et al.. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia
. Arthritis Rheum. 2002;46:1333–1343.
28. Jensen KB, Kosek E, Petzke F, et al.. Evidence of dysfunctional pain inhibition in fibromyalgia
reflected in rACC during provoked pain. Pain. 2009;144:95–100.
29. Emad Y, Ragab Y, Zeinhom F, et al.. Hippocampus dysfunction may explain symptoms of fibromyalgia
syndrome. A study with single-voxel magnetic resonance spectroscopy. J Rheumatol. 2008;35:1371–1377.
30. Becker S, Schweinhardt P. Dysfunctional neurotransmitter systems in fibromyalgia
, their role in central stress circuitry and pharmacological actions on these systems. Pain Res Treat. 2012;2012:741746.
31. Harris RE, Napadow V, Huggins JP, et al.. Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients. Anesthesiology. 2013;119:1453–1464.
32. Borsook D. Biomarkers for chronic pain and analgesia. Part 1: the need, reality, challenges, and solutions. Discov Med. 2011;11:197–207.
33. Jones GT, Atzeni F, Beasley M, et al.. The prevalence of fibromyalgia
in the general population—a comparison of the American College of Rheumatology 1990, 2010 and modified 2010 classification criteria. Arthritis Rheumatol. 2015;67:568–575.
34. Vincent A, Lahr BD, Wolfe F, et al.. Prevalence of fibromyalgia
: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project. Arthritis Care Res (Hoboken). 2013;65:786–792.
35. Adams E, Daniel S, Chandran AB, et al.. A population-based survey and physician assessment of the characteristics and prevalence of fibromyalgia
(Abstract 137). Arthritis Rheum. 2013;65(suppl 10):S55.
36. Kato K, Sullivan PF, Evengård B, et al.. Chronic widespread pain
and its comorbidities: a population-based study. Arch Intern Med. 2006;166:1649–1654.
37. Clauw DJ. Fibromyalgia
: a clinical review. JAMA. 2014;311:1547–1555.
38. Helfenstein M, Heymann R, Feldman D. Prevalence of irritable bowel syndrome in patients with fibromyalgia
[Portuguese]. Rev Bras Reumatol. 2006;46:16–23.
39. Hassett AL, Hilliard PE, Goesling J, et al.. Reports of chronic pain in childhood and adolescence among patients at a tertiary care pain clinic. J Pain. 2013;14:1390–1397.
40. Breivik H, Collett B, Ventafridda V, et al.. Survey of chronic pain in Europe: prevalence, impact on daily life, and treatment. Eur J Pain. 2006;10:287–333.
41. Queiroz LP. Worldwide epidemiology of fibromyalgia
. Curr Pain Headache Rep. 2013;17:356.
42. 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;35:233–251.
43. Arnold LM, Hudson JI, Hess EV, et al.. Family study of fibromyalgia
. Arthritis Rheum. 2004;50:944–952.
44. Clauw DJHochberg MC, Silman AJ, Smolen JS, et al.. Fibromyalgia
and related syndromes. Rheumatology, 6th ed. Philadelphia, PA: Elsevier; 2015:80–1-80-12.
45. Wolfe F, Hassett AL, Katz RS, et al.. Do we need core sets of fibromyalgia
domains? The assessment of fibromyalgia
(and other rheumatic disorders) in clinical practice. J Rheumatol. 2011;38:1104–1112.
46. Häuser W, Jung E, Erbslöh-Möller B, et al.. Validation of the Fibromyalgia
Survey Questionnaire within a cross-sectional survey. PLoS One. 2012;7:e37504.
47. Phillips K, Clauw DJ. Central pain
mechanisms in chronic pain states—maybe it is all in their head. Best Pract Res Clin Rheumatol. 2011;25:141–154.
48. Llewellyn LJ. A discussion on fibrositis. Proc R Soc Med. 1913;6:27–35. (Balneol Climatol Sect).
49. Ehrlich GE. Pain is real; fibromyalgia
isn’t. J Rheumatol. 2003;30:1666–1667.
50. Wolfe F. Fibromyalgia
wars. J Rheumatol. 2009;36:671–678.
51. Bass C, Henderson M. Fibromyalgia
: an unhelpful diagnosis for patients and doctors. BMJ. 2014;348:g2168.
52. Bjersing JL, Lundborg C, Bokarewa MI, et al.. Profile of cerebrospinal microRNAs in fibromyalgia
. PLoS One. 2013;8:e78762.
53. Choy E, Perrot S, Leon T, et al.. A patient survey of the impact of fibromyalgia
and the journey to diagnosis. BMC Health Serv Res. 2010;10:102.
54. Rezende MC, Paiva ES, Helfenstein M Jr, et al.. EpiFibro—a nationwide databank for fibromyalgia
syndrome: the initial analysis of 500 women. Rev Bras Reumatol. 2013;53:382–387.
55. de Miquel CA, Campayo J, Flórez MT, et al.. Interdisciplinary consensus document for the treatment of fibromyalgia
. Actas Esp Psiquiatr. 2010;38:108–120.
56. Fitzcharles MA, Ste-Marie PA, Goldenberg DL, et al.. 2012 Canadian Guidelines for the diagnosis and management of fibromyalgia
syndrome: executive summary. Pain Res Manag. 2013;18:119–126.
57. Arnold LM, Clauw DJ, Dunegan LJ, et al.. FibroCollaborative. A framework for fibromyalgia
management for primary care providers. Mayo Clin Proc. 2012;87:488–496.
58. Mease PJ, Clauw DJ, Christensen R, et al.. Toward development of a fibromyalgia
responder index and disease activity score: OMERACT module update. J Rheumatol. 2011;38:1487–1495.
59. Fillingim RB, Bruehl S, Dworkin RH, et al.. The ACTTION-American Pain Society Pain Taxonomy (AAPT): an evidence-based and multidimensional approach to classifying chronic pain conditions. J Pain. 2014;15:241–249.
60. Williams DA, Kuper D, Segar M, et al.. Internet-enhanced management of fibromyalgia
: a randomized controlled trial. Pain. 2010;151:694–702.
61. Brummett CM, Goesling J, Tsodikov A, et al.. Prevalence of the fibromyalgia
phenotype in patients with spine pain presenting to a tertiary care pain clinic and the potential treatment implications. Arthritis Rheum. 2013;65:3285–3292.
62. Brummett CM, Urquhart AG, Hassett AL, et al.. Characteristics of fibromyalgia
independently predict poorer long-term analgesic outcomes following total knee and hip arthroplasty. Arthritis Rheumatol. 2015;67:1386–1394.
63. US Food and Drug Administration (FDA). Guidance for Industry Analgesic Indications: Developing Drug and Biological Products [Draft Guidance]. Silver Spring, MD: FDA; 2014.
64. European Medicines Agency (EMA). Guideline on the Clinical Development of Medicinal Products Intended for the Treatment of Pain [Draft Guideline]. London, UK: EMA; 2013.
fibromyalgia; chronic widespread pain; central pain; sensory hypersensitivity; central amplification; central sensitivity syndromes; neuroimaging; regulatory pathway; unified diagnostic guidelines; interprofessional collaboration
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