Advertisement

AAPT Diagnostic Criteria for Fibromyalgia

Open AccessPublished:November 16, 2018DOI:https://doi.org/10.1016/j.jpain.2018.10.008

      Abstract

      Fibromyalgia (FM) is a common chronic pain disorder that presents diagnostic challenges for clinicians. Several classification, diagnostic and screening criteria have been developed over the years, but there continues to be a need to develop criteria that reflect the current understanding of FM and are practical for use by clinicians and researchers. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. The AAPT established an international FM working group consisting of clinicians and researchers with expertise in FM to generate core diagnostic criteria for FM and apply the multidimensional diagnostic framework adopted by AAPT to FM. The process for developing the AAPT criteria and dimensions included literature reviews and synthesis, consensus discussions, and analyses of data from large population-based studies conducted in the United Kingdom. The FM working group established a revised diagnosis of FM and identified risk factors, course, prognosis, and pathophysiology of FM. Future studies will assess the criteria for feasibility, reliability, and validity. Revisions of the dimensions will also be required as research advances our understanding of FM.

      Perspective

      The ACTTION-APS FM taxonomy provides an evidence-based diagnostic system for FM. The taxonomy includes diagnostic criteria, common features, comorbidities, consequences, and putative mechanisms. This approach might improve the recognition of FM in clinical practice.

      Key Words

      Over many decades, there have been efforts to develop diagnostic criteria for the condition we now recognize as fibromyalgia (FM). The multiple symptoms and comorbidities associated with FM make it difficult to diagnose, and FM is still underdiagnosed and undertreated.
      • Arnold LM
      • Clauw DJ
      • McCarberg BH
      FibroCollaborative
      Improving the recognition and diagnosis of fibromyalgia.
      • Choy E
      • Perrot S
      • Leon T
      • Kaplan J
      • Petersel D
      • Ginovker A
      • Kramer E
      A patient survey of the impact of fibromyalgia and the journey to diagnosis.
      ,
      • Hadker N
      • Garg S
      • Chandran AB
      • Crean SM
      • McNett M
      • Silverman SL
      Primary care physicians’ perceptions of the challenges and barriers in the timely diagnosis, treatment and management of fibromyalgia.
      The diagnosis of FM might take >2 years, with patients seeing an average of 3.7 different physicians during that time.
      • Choy E
      • Perrot S
      • Leon T
      • Kaplan J
      • Petersel D
      • Ginovker A
      • Kramer E
      A patient survey of the impact of fibromyalgia and the journey to diagnosis.
      Many health care providers, particularly in primary care, report unclear diagnostic criteria, a lack of confidence in using existing criteria for diagnosis, insufficient training or skill in diagnosing FM, and a lack of knowledge of treatment options.
      • Hadker N
      • Garg S
      • Chandran AB
      • Crean SM
      • McNett M
      • Silverman SL
      Primary care physicians’ perceptions of the challenges and barriers in the timely diagnosis, treatment and management of fibromyalgia.
      Therefore, despite progress in the understanding and management of FM, there remain barriers in the recognition and diagnosis of FM in clinical practice.
      To address problems related to the diagnosis of different chronic pain disorders, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration (FDA) and the American Pain Society (APS) initiated the ACTTION-APS Pain Taxonomy (AAPT) to develop a diagnostic system that would be clinically useful and consistent across chronic pain disorders. Fillingim et al
      • Fillingim RB
      • Bruehl S
      • Dworkin RH
      • Dworkin SF
      • Loeser JD
      • Turk DC
      • Widerstrom-Noga E
      • Arnold L
      • Bennett R
      • Edwards RR
      • Freeman R
      • Gewandter J
      • Hertz S
      • Hochberg M
      • Krane E
      • Mantyh PW
      • Markman J
      • Neogi T
      • Ohrbach R
      • Paice JA
      • Porreca F
      • Rappaport BA
      • Smith SM
      • Smith TJ
      • Sullivan MD
      • Verne GN
      • Wasan AD
      • Wesselmann U
      The ACTTION-American Pain Society Pain Taxonomy (AAPT): An evidence-based and multidimensional approach to classifying chronic pain conditions.
      provides more information about the rationale and background for the AAPT. In 2013, the AAPT Steering Committee invited L.M.A., R.M.B., and L.J.C. to be co-chairs of the Fibromyalgia Working Group. The co-chairs subsequently selected international FM experts as members of the working group. The goal of the Fibromyalgia Working Group was to apply the multidimensional diagnostic framework adopted by AAPT to FM and evaluate new approaches to the diagnosis of FM that might improve the recognition of FM in clinical practice. Briefly, in the AAPT taxonomy, there are 5 dimensions: dimension 1: core diagnostic criteria; dimension 2: common features; dimension 3: common medical co-morbidities; dimension 4: neurobiological, psychosocial, and functional consequences; and dimension 5: putative neurobiological and psychosocial mechanisms, risk factors, and protective factors.
      • Fillingim RB
      • Bruehl S
      • Dworkin RH
      • Dworkin SF
      • Loeser JD
      • Turk DC
      • Widerstrom-Noga E
      • Arnold L
      • Bennett R
      • Edwards RR
      • Freeman R
      • Gewandter J
      • Hertz S
      • Hochberg M
      • Krane E
      • Mantyh PW
      • Markman J
      • Neogi T
      • Ohrbach R
      • Paice JA
      • Porreca F
      • Rappaport BA
      • Smith SM
      • Smith TJ
      • Sullivan MD
      • Verne GN
      • Wasan AD
      • Wesselmann U
      The ACTTION-American Pain Society Pain Taxonomy (AAPT): An evidence-based and multidimensional approach to classifying chronic pain conditions.
      As part of the AAPT process, the Fibromyalgia Working Group members held in-person meetings, teleconferences, and email communications to review the literature on FM symptoms and diagnostic criteria and establish consensus on the approach to FM diagnosis. This article details the development of the dimensions for FM.

      Dimension 1

      Core Diagnostic Criteria

      There have been many efforts to improve the identification of patients with FM, and several classifications, diagnostic and screening criteria have been developed over the years.
      • Arnold LM
      • Stanford SB
      • Welge JA
      • Crofford LJ
      Development and testing of the fibromyalgia diagnostic screen for primary care.
      • Bennett RM
      • Friend R
      • Marcus D
      • Bernstein C
      • Han BK
      • Yachoui R
      • Deodhar A
      • Kaell A
      • Bonafede P
      • Chino A
      • Jones KD
      Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
      ,
      • Martin SA
      • Coon CD
      • McLeod LD
      • Chandran A
      • Arnold LM
      Evaluation of the fibromyalgia diagnostic screen in clinical practice.

      Smythe HA: Non-articular rheumatism and the fibrositis syndrome, in Hollander JL, McCarty DJ Jr (eds). Arthritis and Allied Conditions. Philadelphia, PA, Lea and Febiger, 1972, pp 874–884

      ,
      • Wolfe F
      • Clauw DJ
      • Fitzcharles MA
      • Goldenberg DL
      • Hauser W
      • Katz RL
      • Mease PJ
      • Russell AS
      • Russell IJ
      • Walitt B
      2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria.
      • Wolfe F
      • Clauw DJ
      • Fitzcharles MA
      • Goldenberg DL
      • Hauser W
      • Katz RS
      • Mease P
      • Russell AS
      • Russell IJ
      • Winfield JB
      Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia.
      • Wolfe F
      • Clauw DJ
      • Fitzcharles MA
      • Goldenberg DL
      • Katz RS
      • Mease P
      • Russell AS
      • Russell IJ
      • Winfield JB
      • Yunus MB
      The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity.
      ,
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • Bennett RM
      • Bombardier C
      • Goldenberg DL
      • Tugwell P
      • Campbell SM
      • Abeles M
      • Clark P
      The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
      • Yunus M
      • Masi AT
      • Calabro JJ
      • Miller KA
      • Feigenbaum SL
      Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls.
      Early efforts focused on FM as a chronic widespread pain disorder with other associated symptoms.

      Smythe HA: Non-articular rheumatism and the fibrositis syndrome, in Hollander JL, McCarty DJ Jr (eds). Arthritis and Allied Conditions. Philadelphia, PA, Lea and Febiger, 1972, pp 874–884

      • Yunus M
      • Masi AT
      • Calabro JJ
      • Miller KA
      • Feigenbaum SL
      Primary fibromyalgia (fibrositis): Clinical study of 50 patients with matched normal controls.
      The American College of Rheumatology (ACR) 1990 classification criteria
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • Bennett RM
      • Bombardier C
      • Goldenberg DL
      • Tugwell P
      • Campbell SM
      • Abeles M
      • Clark P
      The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
      eliminated associated symptoms and focused solely on chronic widespread pain (CWP) (defined as pain in the left side of the body, pain in the right side of the body, pain above the waist, pain below the waist, and axial skeletal pain [cervical spine or anterior chest or thoracic spine or low back]) and tenderness (defined as pain on palpation of ≥11 of 18 specific tender point sites on the body). Although the ACR 1990 criteria helped to advance research studies of FM, the criteria were not intended for use in clinical practice, did not include commonly associated symptoms, and required a tender point exam, which was impractical for use in the clinical setting.
      • Gracely RH
      • Grant MA
      • Giesecke T
      Evoked pain measures in fibromyalgia.
      With the publication of the 2010 and 2011 criteria,
      • Wolfe F
      • Clauw DJ
      • Fitzcharles MA
      • Goldenberg DL
      • Hauser W
      • Katz RS
      • Mease P
      • Russell AS
      • Russell IJ
      • Winfield JB
      Fibromyalgia criteria and severity scales for clinical and epidemiological studies: A modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia.
      • Wolfe F
      • Clauw DJ
      • Fitzcharles MA
      • Goldenberg DL
      • Katz RS
      • Mease P
      • Russell AS
      • Russell IJ
      • Winfield JB
      • Yunus MB
      The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity.
      the definition of FM moved from a predominantly chronic pain disorder to a multi-symptom disorder and eliminated the tender point exam as a requirement for diagnosis. Although the authors of the 2010/2011 criteria re-emphasized the importance of associated symptoms, there may have been too much movement away from chronic pain as the core symptom of FM.
      • Jones GT
      • Atzeni F
      • Beasley M
      • Fluss E
      • Sarzi-Puttini P
      • Macfarlane GJ
      The prevalence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria.
      Studies of alternative criteria evaluated a variety of associated symptoms along with various definitions of widespread pain in the diagnosis of FM.
      • Arnold LM
      • Stanford SB
      • Welge JA
      • Crofford LJ
      Development and testing of the fibromyalgia diagnostic screen for primary care.
      • Arnold LM
      • Williams DA
      • Hudson JI
      • Martin SA
      • Clauw DJ
      • Crofford LJ
      • Wang F
      • Emir B
      • Lai C
      • Zablocki R
      • Mease PJ
      Development of responder definitions for fibromyalgia clinical trials.
      • Bennett RM
      • Friend R
      • Marcus D
      • Bernstein C
      • Han BK
      • Yachoui R
      • Deodhar A
      • Kaell A
      • Bonafede P
      • Chino A
      • Jones KD
      Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
      The authors of the revised 2016 criteria
      • Wolfe F
      • Clauw DJ
      • Fitzcharles MA
      • Goldenberg DL
      • Hauser W
      • Katz RL
      • Mease PJ
      • Russell AS
      • Russell IJ
      • Walitt B
      2016 Revisions to the 2010/2011 fibromyalgia diagnostic criteria.
      addressed the problem with the 2010/2011 criteria regarding misclassification of patients who did not have generalized pain,
      • Egloff N
      • von Kanel R
      • Muller V
      • Egle UT
      • Kokinogenis G
      • Lederbogen S
      • Durrer B
      • Stauber S
      Implications of proposed fibromyalgia criteria across other functional pain syndromes.
      which occurred because the 2010/2011 criteria do not consider the spatial distribution of painful sites. The 2016 criteria now require that patients have pain in 4 of 5 regions, called “generalized pain” to distinguish it from the 1990 definition of “widespread pain.” Even though there are different definitions of widespread pain and associated symptoms, most of the previous FM criteria appear to identify a similar group of patients most clinicians would agree have FM.
      Based on the review of existing criteria, the consensus of the Fibromyalgia Working Group was to devise core diagnostic criteria (dimension 1) that would reflect the current understanding of FM and be practical for use by clinicians and to provide a basis for clinical trial inclusion and exclusion criteria. The multidimensional diagnostic framework of the AAPT allowed the group to identify the core symptoms of FM and include other associated symptoms and signs in dimension 2. The group members agreed that dimension 1 would include only a core set of diagnostic symptoms, and that signs such as tender points would be relegated to dimension 2.

      Definition of FM Pain in Dimension 1

      The Fibromyalgia Working Group members agreed that dimension 1 should identify FM as predominantly a chronic pain disorder. In other words, all patients would be required to have chronic pain to be diagnosed with FM. However, the members raised a question about how to define FM pain, that is, whether FM-related pain should be defined by the 1990 ACR criteria (CWP) or by multisite pain (MSP) as in the ACR 2010/2016 criteria. The main distinguishing feature between CWP and MSP is that MSP is a simple count of the number of body sites with pain, whereas CWP requires a specific anatomical distribution of the pain reported. To address this question, members of the working group analyzed data from large population-based studies of 34,818 subjects conducted in the United Kingdom.
      The first previously published study
      • Dean LE
      • Arnold L
      • Crofford L
      • Bennett R
      • Goldenberg D
      • Fitzcharles MA
      • Paiva ES
      • Staud R
      • Clauw D
      • Sarzi-Puttini P
      • Jones GT
      • Ayorinde A
      • Fluss E
      • Beasley M
      • Macfarlane GJ
      Impact of moving from a widespread to multisite pain definition on other fibromyalgia symptoms.
      investigated whether associations between pain and the additional symptoms associated with FM are different in persons with CWP as defined by the ACR 1990 criteria compared to MSP, with or without joint areas. Briefly, 6 studies were used: the National Child Development (1958 British birth cohort),
      • Atherton K
      • Fuller E
      • Shepherd P
      • Strachan DP
      • Power C
      Loss and representativeness in a biomedical survey at age 45 years: 1958 British birth cohort.
      the Epidemiology of Functional Disorders (EpiFund),
      • McBeth J
      • Nicholl BI
      • Cordingley L
      • Davies KA
      • Macfarlane GJ
      Chronic widespread pain predicts physical inactivity: Results from the prospective EPIFUND study.
      the Kid Low Back Pain (Kid LBP),
      • Watson KD
      • Papageorgiou AC
      • Jones GT
      • Taylor S
      • Symmons DP
      • Silman AJ
      • Macfarlane GJ
      Low back pain in schoolchildren: Occurrence and characteristics.
      the Managing Unexplained Symptoms (Chronic Widespread Pain) in Primary Care: Involving Traditional and Accessible New Approaches (MUSICIAN),
      • Macfarlane GJ
      • Beasley M
      • Jones EA
      • Prescott GJ
      • Docking R
      • Keeley P
      • McBeth J
      • Jones GT
      • Team MS
      The prevalence and management of low back pain across adulthood: Results from a population-based cross-sectional study (the MUSICIAN study).
      the Study of Health and its Management (SHAMA),
      • Fluss E
      • Bond CM
      • Jones GT
      • Macfarlane GJ
      The re-evaluation of the measurement of pain in population-based epidemiological studies: The SHAMA study.
      and the Women's Health Study (WHEST).
      • Ayorinde AA
      • Bhattacharya S
      • Druce KL
      • Jones GT
      • Macfarlane GJ
      Chronic pelvic pain in women of reproductive and post-reproductive age: A population-based study.
      In all of the population studies, participants were asked “Have you experienced pain in the past month lasting at least a day?”; those responding positively shaded the sites of pain on 4-view body manikins and indicated whether pain had been present for ≥3 months. Manikins were coded for pain at 35 individual sites. The number of pain sites were determined, including whether the subjects met the ACR 1990 criteria for CWP. MSP was defined as the number of pain sites needed to reach a prevalence similar to that of CWP (as defined by the ACR 1990 criteria) from the same population. As there are no gold-standard definitions of FM, and the prevalence differs depending on the criteria used,
      • Jones GT
      • Atzeni F
      • Beasley M
      • Fluss E
      • Sarzi-Puttini P
      • Macfarlane GJ
      The prevalence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria.
      a prevalence of 2 to 5% was chosen to reflect both this variability and the expected prevalence using the ACR 1990 criteria. Information was also collected across at least 2 studies on each of the following symptoms: fatigue (Chalder fatigue
      • Chalder T
      • Berelowitz G
      • Pawlikowska T
      • Watts L
      • Wessely S
      • Wright D
      • Wallace EP
      Development of a fatigue scale.
      or SF-36 vitality scale
      • Brazier JE
      • Harper R
      • Jones NM
      • O'Cathain A
      • Thomas KJ
      • Usherwood T
      • Westlake L
      Validating the SF-36 health survey questionnaire: New outcome measure for primary care.
      ), sleep (Sleep Problem Scale
      • Jenkins CD
      • Stanton BA
      • Niemcryk SJ
      • Rose RM
      A scale for the estimation of sleep problems in clinical research.
      or 2010 modified preliminary ACR criteria question), mood (General Health Questionnaire,
      • Goldberg DP
      The detection of psychiatric illness by questionnaire; a technique for the identification and assessment of non-psychotic psychiatric illness.
      Hospital Anxiety and Depression Scale,
      • Zigmond AS
      • Snaith RP
      The hospital anxiety and depression scale.
      PROMIS Global Mental Health score,
      • Hays RD
      • Bjorner JB
      • Revicki DA
      • Spritzer KL
      • Cella D
      Development of physical and mental health summary scores from the patient-reported outcomes measurement information system (PROMIS) global items.
      and SF-36 mental health
      • Brazier JE
      • Harper R
      • Jones NM
      • O'Cathain A
      • Thomas KJ
      • Usherwood T
      • Westlake L
      Validating the SF-36 health survey questionnaire: New outcome measure for primary care.
      ), and the presence of somatic symptoms.
      • Othmer E
      • DeSouza C
      A screening test for somatization disorder (hysteria).
      Relationships with pain were determined by multiple binary logistic regression models, specifically comparing among those with MSP, and subjects with and without CWP. Among those reporting the nonpain symptoms associated with FM (fatigue, sleep disturbance, somatic symptoms, and mood impairment), there was an increased likelihood of reporting pain, the magnitude of which was similar regardless of the pain definition used. Additionally, there were no indications of differences in the magnitude of the associations by sex. The findings support the continued collection of both pain and associated symptoms when classifying FM and highlight that pain may not require the definition of CWP as used in the 1990 ACR criteria. Classification of pain simply by self-reported number of sites distributed throughout the body, including joint sites, is sufficient when defining the pain of FM. The number of pain sites needed to define MSP in FM was found to be ≥8, which is consistent with previous studies.
      • Wolfe F
      Pain extent and diagnosis: Development and validation of the regional pain scale in 12,799 patients with rheumatic disease.

      Nonpain FM Symptoms in Dimension 1

      The Fibromyalgia Working Group proposed a reduction in nonpain symptoms for inclusion in dimension 1 as core diagnostic criteria to reduce the complexity of diagnosis and make the FM criteria easier to use in practice. The Fibromyalgia Working Group identified fatigue and sleep problems as 2 key associated symptoms for several reasons. First, these symptoms, along with chronic pain, occur in most patients with FM.
      • Arnold LM
      • Clauw DJ
      • McCarberg BH
      FibroCollaborative
      Improving the recognition and diagnosis of fibromyalgia.
      Second, pain, sleep disturbance, and fatigue were identified by OMERACT as core symptoms of FM.
      • Mease PJ
      • Clauw DJ
      • Arnold LM
      • Goldenberg DL
      • Witter J
      • Williams DA
      • Simon LS
      • Strand CV
      • Bramson C
      • Martin S
      • Wright TM
      • Littman B
      • Wernicke JF
      • Gendreau RM
      • Crofford LJ
      Fibromyalgia syndrome.
      • Wu YL
      • Chang LY
      • Lee HC
      • Fang SC
      • Tsai PS
      Sleep disturbances in fibromyalgia: A meta-analysis of case-control studies.
      Finally, responder definitions using fatigue and sleep problems, in combination with pain and physical function, were shown to be responsive to change in FM clinical trials.
      • Arnold LM
      • Williams DA
      • Hudson JI
      • Martin SA
      • Clauw DJ
      • Crofford LJ
      • Wang F
      • Emir B
      • Lai C
      • Zablocki R
      • Mease PJ
      Development of responder definitions for fibromyalgia clinical trials.
      Other nonpain symptoms and signs are included in dimension 2 and may be considered when evaluating a patient but are not required for diagnosis. However, more study was required to determine whether the presence and severity of fatigue and sleep problems along with MSP would suffice for the core diagnostic criteria.
      A second study was conducted using data from the UK population-based studies to address this issue and answer the following questions: 1) What is the prevalence of CWP or MSP in conjunction with the key symptoms of fatigue and/or sleep problems? Is this similar to the prevalence we would expect for FM? and 2) If fatigue and/or sleep problems are present in addition to pain, how many pain sites would it take to result in the same prevalence as CWP or FM without the presence of these symptoms? “Any pain” was defined as a positive response to the following pain stem question that was collected across all of the study populations: “Thinking back over the past month, have you had any aches or pains that have lasted for 1 day or longer?” The prevalence of “any pain” in conjunction with fatigue and/or sleep problems
      • Dean LE
      • Arnold L
      • Crofford L
      • Bennett R
      • Goldenberg D
      • Fitzcharles MA
      • Paiva ES
      • Staud R
      • Clauw D
      • Sarzi-Puttini P
      • Jones GT
      • Ayorinde A
      • Fluss E
      • Beasley M
      • Macfarlane GJ
      Impact of moving from a widespread to multisite pain definition on other fibromyalgia symptoms.
      was estimated and subsequently recalculated after the addition of each pain site as indicated by body manikin (eg, 1 site or more, 2 sites or more) until a similar prevalence of CWP or FM was reached.
      There were a total of 28,789 subjects across the studies (mean age 42–55 years; males 43–52% [WHEST was conducted only in females]) included in this second study. The prevalence of CWP (defined per the ACR 1990 criteria) across studies was 12 to 17%, and in each study the equivalent prevalence was obtained by defining MSP as ≥8 sites, as noted in Dean et al.
      • Dean LE
      • Arnold L
      • Crofford L
      • Bennett R
      • Goldenberg D
      • Fitzcharles MA
      • Paiva ES
      • Staud R
      • Clauw D
      • Sarzi-Puttini P
      • Jones GT
      • Ayorinde A
      • Fluss E
      • Beasley M
      • Macfarlane GJ
      Impact of moving from a widespread to multisite pain definition on other fibromyalgia symptoms.
      In separate analyses using manikins without joint areas included, MSP was consistently defined as reporting ≥8 sites. Therefore, joint areas were included in all subsequent analyses in this study.
      The prevalence of CWP in conjunction with fatigue was 6% within WHEST and 7% within SHAMA. Using the multisite definition of pain (ie, ≥8 of 35 pain sites), the prevalence of MSP in conjunction with fatigue was 7% in both populations. The prevalence of CWP and sleep problems was 6% within WHEST, 6.5% within SHAMA, and 7% within EpiFund. The prevalence of MSP in conjunction with sleep problems was 7% across all populations. Thus, the prevalence of CWP or MSP (≥8 pain sites) in addition to either fatigue or sleep problems was between 6 and 7% and was greater than the prevalence expected for FM (2–5%). To reach a similar population prevalence expected for FM, ≥10 pain sites are needed in addition to either fatigue or sleep problems.
      The prevalence of CWP in conjunction with fatigue and sleep problems was 3% within WHEST and 5% within SHAMA, which is in line with the prevalence expected for FM. Using an MSP definition of ≥8 of 35 sites, the prevalence of MSP in conjunction with fatigue and sleep problems was 4% within WHEST and 5% within SHAMA. Therefore, the prevalence of CWP or MSP in addition to both fatigue and sleep problems was between 3 and 5%, similar to the prevalence for FM established by prior studies.
      Additional analyses were conducted to examine the number of pain sites required to reach expected FM prevalence using different combinations of pain, fatigue, and sleep problems. Using the WHEST, SHAMA, EpiFund, and 1958 databases, at least 13 to 15 pain sites were needed if the subject had no sleep or fatigue problems. Using SHAMA, WHEST, and EpiFund, at least 10 to 11 pain sites were needed if the subject had sleep problems, but no fatigue. In the SHAMA and WHEST databases, at least 10 to 11 pain sites were needed if the subject had fatigue but no sleep problems. Finally, if both sleep problems and fatigue were present in the SHAMA and WHEST databases, at least 6 to 8 sites were needed to reach the expected FM prevalence.

      Number of Pain Sites

      Based on the results of the analyses conducted on the population-based databases and the consensus of the Fibromyalgia Working Group, the proposed criteria for FM dimension 1 require ≥11 pain sites be endorsed on the 35-point body manikin. However, the working group considered that the 35-point manikin would likely be impractical for use by most clinicians and researchers. To reduce the number of possible sites, appropriate sites were grouped together, while keeping key body areas separated such as arms and legs. This resulted in a new body manikin that had only 9 defined sites: head, left arm, right arm, chest, abdomen, upper back and spine, lower back and spine (including buttocks), left leg, and right leg. Another analysis was then conducted using the 4 studies (SHAMA, WHEST [women only], 1958 Birth Cohort, and EpiFund) to determine a new definition of MSP based on the 9-point body manikin that produced the same prevalence as the ACR 1990 CWP definition from the same population. The results indicated that the minimum number of sites required to reach a similar prevalence to that of CWP was between 5 and 6 sites depending on the study used. A conservative approach was taken to define MSP as the reporting of ≥6 pain sites using the 9-point body manikin. Further analysis was undertaken to assess the association between the new definition of MSP and the additional nonpain factors associated with FM, compared with the original MSP definition. This analysis demonstrated that the associations between the new definition of MSP using a 9-point manikin were generally comparable to those using the original MSP definition using a 35-point manikin (data summarized in Supplementary Tables 1 and 2).

      Duration of Symptoms and Presence of Other Disorders in Dimension 1

      When considering the necessary duration of symptoms that are required for diagnosis of FM, the working group consensus was to maintain the 3-month time frame, which best reflects the chronicity of FM. The group also agreed that the presence of another pain disorder or related symptoms does not rule out a diagnosis of FM, consistent with the 1990 ACR criteria.
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • Bennett RM
      • Bombardier C
      • Goldenberg DL
      • Tugwell P
      • Campbell SM
      • Abeles M
      • Clark P
      The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
      However, as noted in Bennett et al
      • Bennett RM
      • Friend R
      • Marcus D
      • Bernstein C
      • Han BK
      • Yachoui R
      • Deodhar A
      • Kaell A
      • Bonafede P
      • Chino A
      • Jones KD
      Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
      criteria, a careful clinical evaluation is recommended to identify any condition that could fully account for the patient's symptoms and/or contribute to the severity of the symptoms.

      FM Criteria in Dimension 1

      Based on the results of the analyses conducted on the population-based databases and the consensus of the Fibromyalgia Working Group, the criteria for FM, dimension 1, are presented in Table 1 and Fig 1. The pre-shaded areas within the body manikin in Fig 1 were included to prevent users from counting the same area twice (for example front and back of the same leg). At least 6 of 9 pain sites are required along with fatigue or sleep problems. Fatigue is defined as physical or mental fatigue judged as at least moderate severity by the health care professional. Physical fatigue may manifest as a complaint of physical exhaustion after physical activity, including an inability to function within normal limits for activities that constitute normal daily activities and the requirement for rest periods after activity. Sleep problems are defined as difficulty falling or staying asleep, frequent awakening that is disturbing during a sleep period, or feeling unrefreshed after sleep. These symptoms must be assessed as at least moderate severity by the health care professional. In assessing the severity of fatigue and sleep problems, the clinician may use multiple sources of information, including patient history and exam, as well as self-reported questionnaires or other corroborating data.
      Table 1AAPT Diagnostic Criteria for Fibromyalgia
      Dimension 1: Core Diagnostic Criteria
       1. MSP defined as 6 or more pain sites from a total of 9 possible sites (see Fig 1)
       2. Moderate to severe sleep problems OR fatigue
       3. MSP plus fatigue or sleep problems must have been present for at least 3 months
      NOTE. The presence of another pain disorder or related symptoms does not rule out a diagnosis of FM. However, a clinical assessment is recommended to evaluate for any condition that could fully account for the patient's symptoms or contribute to the severity of the symptoms.
      Figure 1.
      Figure 1Number of painful body sites.
      Patients are asked to check the areas in which they experience pain on the 2-view manikins (ignoring the pre-shaded areas). Alternatively, patients may use the checklist of body sites. The number of separate sites are summed from a maximum of 9 body sites.

      Differential Diagnosis

      These new criteria for FM recommend that clinicians evaluate for the presence of other disorders so that appropriate treatments can be initiated. This can be challenging in clinical practice because comorbid disorders, including other chronic pain disorders, are common in patients with FM.
      • Arnold LM
      • Clauw DJ
      • McCarberg BH
      FibroCollaborative
      Improving the recognition and diagnosis of fibromyalgia.
      Several disorders can mimic FM, such as hypothyroidism and inflammatory rheumatic diseases. In addition, some medications may contribute to pain, such as statins, aromatase inhibitors, bisphosphonates, and opioids (ie, opioid-induced hyperalgesia). However, these conditions and many others (eg, rheumatoid arthritis, osteoarthritis, systemic lupus erythematosus [SLE], spinal stenosis, neuropathies, Ehlers Danlos syndrome,
      • Di Stefano G
      • Celletti C
      • Baron R
      • Castori M
      • Di Franco M
      • La Cesa S
      • Leone C
      • Pepe A
      • Cruccu G
      • Truini A
      • Camerota F
      Central sensitization as the mechanism underlying pain in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.
      sleep disorders such as sleep apnea, and mood and anxiety disorders
      • Macfarlane GJ
      • Barnish MS
      • Pathan E
      • Martin KR
      • Haywood KL
      • Siebert S
      • Packham J
      • Atzeni F
      • Jones GT
      Co-occurrence and characteristics of patients with axial spondyloarthritis who meet criteria for fibromyalgia: Results from a UK national register.
      ) also co-occur in patients with FM. The clinician must determine the possible contribution of various disorders to the patient's presentation. The presence of other disorders does not necessarily exclude a diagnosis of FM, and all disorders will need clinical attention. Table 2 summarizes some of the key medical disorders considered in the differential diagnosis of FM that require additional assessment, tests, and specific treatment. A description of several differentiating signs and symptoms are provided in the table, but a detailed review of the diagnostic tests for each medical disorder is beyond the scope of this article.
      Table 2Differentiating Key Disorders From Fibromyalgia
      Medical DisorderDifferentiating Signs and Symptoms
      Rheumatologic
       Rheumatoid arthritisPredominant joint pain, symmetric joint swelling, joint line tenderness, morning stiffness >1 hour
       Systemic lupus erythematosusMultisystem involvement, joint/muscle pain, rash, photosensitivity, fever
       Polyarticular osteoarthritisJoint stiffness, crepitus, multiple painful joints
       Polymyalgia rheumaticaProximal shoulder and hip girdle pain, weakness, stiffness, more common in the elderly
       Polymyositis or other myopathiesSymmetric, proximal muscle weakness and pain
       SpondyloarthropathyLocalization of spinal pain to specific sites in the neck, mid-thoracic, anterior chest wall, or lumbar regions, objective limitation of spinal mobility due to pain and stiffness
       OsteomalaciaDiffuse bone pain, fractures, proximal myopathy with muscle weakness
      Neurologic
       NeuropathyShooting or burning pain, tingling, numbness, weakness
       Multiple sclerosisVisual changes (unilateral partial or complete loss, double vision), ascending numbness in a leg or bandlike truncal numbness, slurred speech (dysarthria)
      Infectious
       Lyme diseaseRash, arthritis or arthralgia, occurs in areas of endemic disease
       HepatitisRight upper quadrant pain, nausea, decreased appetite
      Endocrine
       HyperparathyroidismIncreased thirst and urination, kidney stones, nausea/vomiting, decreased appetite, thinning bones, constipation
       Cushing syndromeHypertension, diabetes, hirsutism, moon facies, weight gain
       Addison diseasePostural hypotension, nausea, vomiting, skin pigmentation, weight loss
       HypothyroidismCold intolerance, mental slowing, constipation, weight gain, hair loss
      In general, extensive laboratory testing is not necessary to diagnose FM.
      • Arnold LM
      • Clauw DJ
      • McCarberg BH
      FibroCollaborative
      Improving the recognition and diagnosis of fibromyalgia.
      Screening laboratory tests are sometimes obtained to evaluate other possible causes of symptoms or signs. These tests include erythrocyte sedimentation rate and/or C-reactive protein, complete blood count, comprehensive metabolic panel, and thyroid function test. Routine testing for rheumatoid factor or antinuclear antibodies to diagnose FM is not recommended unless the patient has signs or symptoms suggesting an autoimmune disorder, or if initial inflammatory indices are abnormal (recognizing that some patients with rheumatoid arthritis or SLE may have normal erythrocyte sedimentation rate and/or C-reactive protein values). Depending on symptoms, medical history and physical exam, other tests such as ferritin, iron-binding capacity and percentage of saturation, and vitamin B12 and vitamin D levels may be indicated.

      Dimension 2

      Common Features

      Features that are not included in dimension 1 but may be used to support a diagnosis of FM are described below.
      Tenderness, defined as a generalized sensitivity of soft tissues and muscles to pressure that would not normally be expected to cause pain, is a universal complaint and in the 1990 ACR criteria was codified by the “tender point” examination.
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • Bennett RM
      • Bombardier C
      • Goldenberg DL
      • Tugwell P
      • Campbell SM
      • Abeles M
      • Clark P
      The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
      Although the tender point evaluation has been eliminated from the more recent criteria, with the exception of the 2012 FM screen,
      • Arnold LM
      • Stanford SB
      • Welge JA
      • Crofford LJ
      Development and testing of the fibromyalgia diagnostic screen for primary care.
      • Martin SA
      • Coon CD
      • McLeod LD
      • Chandran A
      • Arnold LM
      Evaluation of the fibromyalgia diagnostic screen in clinical practice.
      the symptom of “tenderness to touch” is included in the 2014 Bennett et al criteria
      • Bennett RM
      • Friend R
      • Marcus D
      • Bernstein C
      • Han BK
      • Yachoui R
      • Deodhar A
      • Kaell A
      • Bonafede P
      • Chino A
      • Jones KD
      Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
      and the 2012 FM screen
      • Arnold LM
      • Stanford SB
      • Welge JA
      • Crofford LJ
      Development and testing of the fibromyalgia diagnostic screen for primary care.
      • Martin SA
      • Coon CD
      • McLeod LD
      • Chandran A
      • Arnold LM
      Evaluation of the fibromyalgia diagnostic screen in clinical practice.
      ; this question was ranked third in importance as a diagnostic question in the 2014 Bennett et al criteria.
      • Bennett RM
      • Friend R
      • Marcus D
      • Bernstein C
      • Han BK
      • Yachoui R
      • Deodhar A
      • Kaell A
      • Bonafede P
      • Chino A
      • Jones KD
      Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
      A tender point exam, either as part of the 1990 ACR criteria
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • Bennett RM
      • Bombardier C
      • Goldenberg DL
      • Tugwell P
      • Campbell SM
      • Abeles M
      • Clark P
      The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
      or an abbreviated version,
      • Arnold LM
      • Stanford SB
      • Welge JA
      • Crofford LJ
      Development and testing of the fibromyalgia diagnostic screen for primary care.
      • Martin SA
      • Coon CD
      • McLeod LD
      • Chandran A
      • Arnold LM
      Evaluation of the fibromyalgia diagnostic screen in clinical practice.
      may provide valuable information to the clinician about the overall status of the patient's condition
      • Gracely RH
      • Grant MA
      • Giesecke T
      Evoked pain measures in fibromyalgia.
      and support the diagnosis of FM.
      Dyscognition (eg, trouble concentrating, forgetfulness, and disorganized or slow thinking) is increasingly recognized as a major feature of FM, with dysfunction being seen in working memory and executive function.
      • Glass JM
      Review of cognitive dysfunction in fibromyalgia: A convergence on working memory and attentional control impairments.
      Self-reported questionnaires are useful to screen for dyscognition in patients with FM, but full neuropsychological testing may be required to delineate the extent of cognitive dysfunction.
      • Soriano-Maldonado A
      • Artero EG
      • Segura-Jimenez V
      • Aparicio VA
      • Estevez-Lopez F
      • Alvarez-Gallardo IC
      • Munguia-Izquierdo D
      • Casimiro-Andujar AJ
      • Delgado-Fernandez M
      • Ortega FB
      al-Andalus Project Research Group
      Association of physical fitness and fatness with cognitive function in women with fibromyalgia.
      In brain functional magnetic resonance imaging (fMRI) studies,
      • Glass JM
      • Williams DA
      • Fernandez-Sanchez ML
      • Kairys A
      • Barjola P
      • Heitzeg MM
      • Clauw DJ
      • Schmidt-Wilcke T
      Executive function in chronic pain patients and healthy controls: Different cortical activation during response inhibition in fibromyalgia.
      • Tesio V
      • Torta DM
      • Colonna F
      • Leombruni P
      • Ghiggia A
      • Fusaro E
      • Geminiani GC
      • Torta R
      • Castelli L
      Are fibromyalgia patients cognitively impaired? Objective and subjective neuropsychological evidence.
      FM patients showed lower activation in the inhibition and attention networks and increased activation in other areas. Because inhibition and pain perception may use overlapping networks, resources taken up by pain processing may be unavailable for other processes.
      • Glass JM
      • Williams DA
      • Fernandez-Sanchez ML
      • Kairys A
      • Barjola P
      • Heitzeg MM
      • Clauw DJ
      • Schmidt-Wilcke T
      Executive function in chronic pain patients and healthy controls: Different cortical activation during response inhibition in fibromyalgia.
      Musculoskeletal stiffness is experienced, in varying degrees, by all FM patients.
      • Bennett RM
      • Jones J
      • Turk DC
      • Russell IJ
      • Matallana L
      An internet survey of 2,596 people with fibromyalgia.
      Interestingly, stiffness in FM patients is difficult to distinguish from the stiffness in conditions such as rheumatoid arthritis, polymyalgia rheumatica, and ankylosing spondylitis. FM-related stiffness, like that described in these other conditions, is typically more severe in the early morning and improves as the day goes on.
      • Hazes JM
      • Hayton R
      • Silman AJ
      A reevaluation of the symptom of morning stiffness.
      However, unlike these other conditions, it is not responsive to corticosteroids.
      • Clark S
      • Tindall E
      • Bennett RM
      A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis.
      This feature is only used in the 2014 Bennett et al criteria and was ranked fifth in importance as a diagnostic question.
      • Bennett RM
      • Friend R
      • Marcus D
      • Bernstein C
      • Han BK
      • Yachoui R
      • Deodhar A
      • Kaell A
      • Bonafede P
      • Chino A
      • Jones KD
      Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
      Environmental sensitivity or hypervigilance, manifesting as intolerance to bright lights, loud noises, perfumes and cold, is a common complaint of FM patients. It is probably a reflection of central sensitization.
      • Dohrenbusch R
      • Sodhi H
      • Lamprecht J
      • Genth E
      Fibromyalgia as a disorder of perceptual organization? An analysis of acoustic stimulus processing in patients with widespread pain.
      • Orriols R
      • Costa R
      • Cuberas G
      • Jacas C
      • Castell J
      • Sunyer J
      Brain dysfunction in multiple chemical sensitivity.
      A recent study has provided clues as to how sensitivity to bright lights modulates brain connectivity, such that previously innocuous inputs are experienced as being painful.
      • Martenson ME
      • Halawa OI
      • Tonsfeldt KJ
      • Maxwell CA
      • Hammack N
      • Mist SD
      • Pennesi ME
      • Bennett RM
      • Mauer KM
      • Jones KD
      • Heinricher MM
      A possible neural mechanism for photosensitivity in chronic pain.
      This feature is only used in the 2014 Bennett et al criteria
      • Bennett RM
      • Friend R
      • Marcus D
      • Bernstein C
      • Han BK
      • Yachoui R
      • Deodhar A
      • Kaell A
      • Bonafede P
      • Chino A
      • Jones KD
      Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
      and was ranked second in importance as a diagnostic question.

      Epidemiology

      The prevalence of FM varies from .5 to 12%, depending on the population sampled and the method of ascertainment.
      • Kim C
      • Kim H
      • Kim J
      Prevalence of chronic widespread pain and fibromyalgia syndrome: A Korean hospital-based study.
      • McBeth J
      • Jones K
      Epidemiology of chronic musculoskeletal pain.
      ,
      • Nakamura I
      • Nishioka K
      • Usui C
      • Osada K
      • Ichibayashi H
      • Ishida M
      • Turk DC
      • Matsumoto Y
      • Nishioka K
      An epidemiologic internet survey of fibromyalgia and chronic pain in Japan.
      • Perrot S
      • Vicaut E
      • Servant D
      • Ravaud P
      Prevalence of fibromyalgia in France: A multi-step study research combining national screening and clinical confirmation: The DEFI study (Determination of Epidemiology of Fibromyalgia).
      ,
      • Senna ER
      • De Barros AL
      • Silva EO
      • Costa IF
      • Pereira LV
      • Ciconelli RM
      • Ferraz MB
      Prevalence of rheumatic diseases in Brazil: A study using the COPCORD approach.
      • Vincent A
      • Lahr BD
      • Wolfe F
      • Clauw DJ
      • Whipple MO
      • Oh TH
      • Barton DL
      • St Sauver J
      Prevalence of fibromyalgia: A population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project.
      ,
      • White KP
      • Speechley M
      • Harth M
      • Ostbye T
      The London Fibromyalgia Epidemiology Study: The prevalence of fibromyalgia syndrome in London, Ontario.
      • Wolfe F
      • Ross K
      • Anderson J
      • Russell IJ
      • Hebert L
      The prevalence and characteristics of fibromyalgia in the general population.
      Females outnumber males in a ratio of about 3:1 in studies that do not use tender points as a criterion. Major ethnic variations in prevalence have not been well documented.
      • Queiroz LP
      Worldwide epidemiology of fibromyalgia.
      A survey in 5 European countries (Germany, Italy, Portugal, France, and Spain), using the 1990 ACR criteria,
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • Bennett RM
      • Bombardier C
      • Goldenberg DL
      • Tugwell P
      • Campbell SM
      • Abeles M
      • Clark P
      The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
      estimated prevalence of FM in the general population and also in 8 participating rheumatology clinics; the overall presence of FM in the 5 countries ranged from 2.9 to 14% in outpatients treated in rheumatology practices.
      • Branco JC
      • Bannwarth B
      • Failde I
      • Abello Carbonell J
      • Blotman F
      • Spaeth M
      • Saraiva F
      • Nacci F
      • Thomas E
      • Caubere JP
      • Le Lay K
      • Taieb C
      • Matucci-Cerinic M
      Prevalence of fibromyalgia: A survey in five European countries.
      The prevalence of FM increases with age, rising in middle age (50–59 years) and then dropping off in the oldest age groups (80+ years).
      • Wolfe F
      • Ross K
      • Anderson J
      • Russell IJ
      Aspects of fibromyalgia in the general population: Sex, pain threshold, and fibromyalgia symptoms.
      The average age of onset is between 30 and 50 years. FM in children is now well recognized. Estimates of the general population prevalence of FM in children and adolescents vary from 1.0% up to 6.2%.
      • Buskila D
      Pediatric fibromyalgia.
      • Buskila D
      • Press J
      • Gedalia A
      • Klein M
      • Neumann L
      • Boehm R
      • Sukenik S
      Assessment of nonarticular tenderness and prevalence of fibromyalgia in children.
      ,
      • Clark P
      • Burgos-Vargas R
      • Medina-Palma C
      • Lavielle P
      • Marina FF
      Prevalence of fibromyalgia in children: A clinical study of Mexican children.
      • Mikkelsson M
      • Sourander A
      • Piha J
      • Salminen JJ
      Psychiatric symptoms in preadolescents with musculoskeletal pain and fibromyalgia.
      ,
      • Zapata AL
      • Moraes AJ
      • Leone C
      • Doria-Filho U
      • Silva CA
      Pain and musculoskeletal pain syndromes in adolescents.
      FM in adolescents is associated with significant impairment in physical function and lower perceived health status compared with peers.
      • Kashikar-Zuck S
      • Cunningham N
      • Sil S
      • Bromberg MH
      • Lynch-Jordan AM
      • Strotman D
      • Peugh J
      • Noll J
      • Ting TV
      • Powers SW
      • Lovell DJ
      • Arnold LM
      Long-term outcomes of adolescents with juvenile-onset fibromyalgia in early adulthood.
      • Kashikar-Zuck S
      • Ting TV
      Juvenile fibromyalgia: Current status of research and future developments.
      There is often peer-related discrimination with resulting unpopularity, isolation, and school absenteeism.
      • Kashikar-Zuck S
      • Johnston M
      • Ting TV
      • Graham BT
      • Lynch-Jordan AM
      • Verkamp E
      • Passo M
      • Schikler KN
      • Hashkes PJ
      • Spalding S
      • Banez G
      • Richards MM
      • Powers SW
      • Arnold LM
      • Lovell D
      Relationship between school absenteeism and depressive symptoms among adolescents with juvenile fibromyalgia.
      • Kashikar-Zuck S
      • Lynch AM
      • Graham TB
      • Swain NF
      • Mullen SM
      • Noll RB
      Social functioning and peer relationships of adolescents with juvenile fibromyalgia syndrome.
      As peer relationships are a key element in the psychological development of children, the occurrence of FM can lead to adjustment problems and other psychopathology in adulthood.
      • Lommel K
      • Kapoor S
      • Bamford J
      • Melguizo MS
      • Martin C
      • Crofford L
      Juvenile primary fibromyalgia syndrome in an inpatient adolescent psychiatric population.
      The symptoms of FM persist into adulthood for the majority of patients experiencing childhood or adolescent FM.
      • Kashikar-Zuck S
      • Cunningham N
      • Sil S
      • Bromberg MH
      • Lynch-Jordan AM
      • Strotman D
      • Peugh J
      • Noll J
      • Ting TV
      • Powers SW
      • Lovell DJ
      • Arnold LM
      Long-term outcomes of adolescents with juvenile-onset fibromyalgia in early adulthood.
      The incidence of FM was determined in a population-based sample of Norwegian women between the ages of 20 and 49 years who were followed for 5.5 years.
      • Forseth KO
      • Gran JT
      • Husby G
      A population study of the incidence of fibromyalgia among women aged 26-55 yr.
      The incidence of FM among women who began the observation period without any complaints of musculoskeletal pain was 3.2%, corresponding to an average annual incidence of 583 cases/100,000 women between 20 and 49 years of age. For those with any self-reported pain at the beginning of the study, the incidence was 25%, and risk factors for the development of FM included pain for ≥6 years, self-assessed depression, lack of professional education, and the presence of 4 or more associated symptoms, such as disturbed bowel function, unrefreshing sleep, paresthesia, and subjective swelling. In another cohort of 1,198 early arthritis patients followed by rheumatologists, the incidence of FM was 6.77/100 person-years in the first year after diagnosis of arthritis, and declined to 3.58/100 person-years in the second year. Pain severity and poor mental health predicted FM risk.
      • Lee YC
      • Lu B
      • Boire G
      • Haraoui BP
      • Hitchon CA
      • Pope JE
      • Thorne JC
      • Keystone EC
      • Solomon DH
      • Bykerk VP
      Incidence and predictors of secondary fibromyalgia in an early arthritis cohort.

      Dimension 3

      Common Medical and Psychiatric Comorbidities

      FM is associated with many comorbidities that may be categorized as other somatic pain disorders, psychiatric conditions, sleep disorders, rheumatic diseases, and other conditions. It is commonly conjectured that many of these associations are a result of central sensitization,
      • Yunus MB
      Central sensitivity syndromes: A new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness.
      but this mechanism cannot explain all associations. Chronic fatigue syndrome is a condition that has considerable overlap with FM, with the predominance of pain an identifier of FM.
      • Meeus M
      • Nijs J
      Central sensitization: A biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome.
      Among the somatic pain conditions that associate with FM, the best recognized are irritable bowel syndrome, chronic pelvic pain and interstitial cystitis, chronic head and orofacial conditions such as temporomandibular disorder, otologic symptoms, chronic headaches, and migraine disorder.
      • Aaron LA
      • Burke MM
      • Buchwald D
      Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.
      • Alagiri M
      • Chottiner S
      • Ratner V
      • Slade D
      • Hanno PM
      Interstitial cystitis: Unexplained associations with other chronic disease and pain syndromes.
      ,
      • Ifergane G
      • Buskila D
      • Simiseshvely N
      • Zeev K
      • Cohen H
      Prevalence of fibromyalgia syndrome in migraine patients.
      • Lubrano E
      • Iovino P
      • Tremolaterra F
      • Parsons WJ
      • Ciacci C
      • Mazzacca G
      Fibromyalgia in patients with irritable bowel syndrome. An association with the severity of the intestinal disorder.
      ,
      • Marcus DA
      • Bernstein C
      • Rudy TE
      Fibromyalgia and headache: An epidemiological study supporting migraine as part of the fibromyalgia syndrome.
      • Riedl A
      • Schmidtmann M
      • Stengel A
      • Goebel M
      • Wisser AS
      • Klapp BF
      • Monnikes H
      Somatic comorbidities of irritable bowel syndrome: A systematic analysis.
      Psychiatric conditions that associate with FM include major mood disorder (eg, major depressive disorder and bipolar disorder), anxiety disorders (eg, generalized anxiety disorder, panic disorder, post-traumatic stress disorder, social phobia, and obsessive compulsive disorder), and substance abuse disorder.
      • Arnold LM
      • Hudson JI
      • Keck PE
      • Auchenbach MB
      • Javaras KN
      • Hess EV
      Comorbidity of fibromyalgia and psychiatric disorders.
      • Bradley LA
      Psychiatric comorbidity in fibromyalgia.
      Sleep disorders that can occur concomitantly with FM include obstructive and central sleep apnea and restless leg syndrome.
      • Roizenblatt S
      • Neto NS
      • Tufik S
      Sleep disorders and fibromyalgia.
      • Stehlik R
      • Ulfberg J
      • Hedner J
      • Grote L
      High prevalence of restless legs syndrome among women with multi-site pain: A population-based study in Dalarna, Sweden.
      Various rheumatic conditions, both inflammatory and degenerative, may act as a peripheral pain generator and associate with FM including inflammatory rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, scleroderma, Sjogren's syndrome and others, and osteoarthritis.
      • Atzeni F
      • Cazzola M
      • Benucci M
      • Di Franco M
      • Salaffi F
      • Sarzi-Puttini P
      Chronic widespread pain in the spectrum of rheumatological diseases.
      • Brummett CM
      • Goesling J
      • Tsodikov A
      • Meraj TS
      • Wasserman RA
      • Clauw DJ
      • Hassett AL
      Prevalence of the fibromyalgia phenotype in patients with spine pain presenting to a tertiary care pain clinic and the potential treatment implications.
      ,
      • Choi BY
      • Oh HJ
      • Lee YJ
      • Song YW
      Prevalence and clinical impact of fibromyalgia in patients with primary Sjogren's syndrome.
      • Fan A
      • Pereira B
      • Tournadre A
      • Tatar Z
      • Malochet-Guinamand S
      • Mathieu S
      • Couderc M
      • Soubrier M
      • Dubost JJ
      Frequency of concomitant fibromyalgia in rheumatic diseases: Monocentric study of 691 patients.
      ,
      • Haliloglu S
      • Carlioglu A
      • Akdeniz D
      • Karaaslan Y
      • Kosar A
      Fibromyalgia in patients with other rheumatic diseases: Prevalence and relationship with disease activity.
      • Iannuccelli C
      • Spinelli FR
      • Guzzo MP
      • Priori R
      • Conti F
      • Ceccarelli F
      • Pietropaolo M
      • Olivieri M
      • Minniti A
      • Alessandri C
      • Gattamelata A
      • Valesini G
      • Di Franco M
      Fatigue and widespread pain in systemic lupus erythematosus and Sjogren's syndrome: Symptoms of the inflammatory disease or associated fibromyalgia?.
      ,
      • Murphy SL
      • Phillips K
      • Williams DA
      • Clauw DJ
      The role of the central nervous system in osteoarthritis pain and implications for rehabilitation.
      Joint hypermobility as in joint hypermobility syndrome and Ehler's Danlos syndrome may predispose to recurrent pain and subsequent FM.
      • Castori M
      • Morlino S
      • Celletti C
      • Ghibellini G
      • Bruschini M
      • Grammatico P
      • Blundo C
      • Camerota F
      Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.
      The association with rhinitis and urticaria is especially interesting, as gene expression profiling in FM has reported an up-regulation of genes involved in allergic responses.
      • Jones KD
      • Gelbart T
      • Whisenant TC
      • Waalen J
      • Mondala TS
      • Ikle DN
      • Salomon DR
      • Bennett RM
      • Kurian SM
      Genome-wide expression profiling in the peripheral blood of patients with fibromyalgia.
      Obesity is common in patients with FM and is associated with greater pain severity, poorer sleep, and reduced physical strength and flexibility.
      • Gota CE
      • Kaouk S
      • Wilke WS
      Fibromyalgia and obesity: The association between body mass index and disability, depression, history of abuse, medications, and comorbidities.
      • Okifuji A
      • Donaldson GW
      • Barck L
      • Fine PG
      Relationship between fibromyalgia and obesity in pain, function, mood, and sleep.

      Dimension 4

      Neurobiological, Psychosocial, and Functional Consequences

      General Outcome, Including Cost of FM

      Long-term outcome data for FM are limited. Although available studies indicate that symptoms of FM often persist, many patients are able to identify strategies over time that can moderate symptoms. In one of the earliest prospective studies, 538 FM patients from U.S. rheumatology centers that had a special interest in FM were followed every 6 months for 7 years.
      • Wolfe F
      • Anderson J
      • Harkness D
      • Bennett RM
      • Caro XJ
      • Goldenberg DL
      • Russell IJ
      • Yunus MB
      Health status and disease severity in fibromyalgia: Results of a six-center longitudinal study.
      • Wolfe F
      • Anderson J
      • Harkness D
      • Bennett RM
      • Caro XJ
      • Goldenberg DL
      • Russell IJ
      • Yunus MB
      A prospective, longitudinal, multicenter study of service utilization and costs in fibromyalgia.
      Most outcome measures, including functional disability, did not change or worsened slightly over time. Sixty percent of patients who were diagnosed with FM rated their health as fair or poor. FM patients averaged 1 outpatient visit each month. Costs increased over the 7 years, with a mean yearly per-patient cost of $2,274 in 1996 U.S. dollars.
      In single-center prospective reports, there was also little change in symptoms or function over time. In 1 report from Boston, all patients had persistent FM symptoms and 55% reported moderate or severe pain after 10 to 15 years.
      • Felson DT
      • Goldenberg DL
      The natural history of fibromyalgia.
      • Kennedy M
      • Felson DT
      A prospective long-term study of fibromyalgia syndrome.
      However, 70% of patients reported that their overall FM symptoms were a little or a lot better than when first diagnosed, and 50% reported that they were doing well. Sleep disturbances were the most persistent symptom. In a report from the U.K., 97% of FM patients still had symptoms, and 60% felt worse than their initial visit.
      • Ledingham J
      • Doherty S
      • Doherty M
      Primary fibromyalgia syndrome—An outcome study.
      Another multicenter study conducted in the U.S. of 1,555 FM patients found that pain, fatigue, and global well-being had not changed much over 11 years, but there was significant individual variability in outcome measures.
      • Walitt B
      • Fitzcharles MA
      • Hassett AL
      • Katz RS
      • Hauser W
      • Wolfe F
      The longitudinal outcome of fibromyalgia: A study of 1555 patients.
      In contrast, in a prospective study of FM patients followed in Australian primary care, 47% no longer fulfilled FM criteria and 24% were in remission,
      • Granges G
      • Zilko P
      • Littlejohn GO
      Fibromyalgia syndrome: Assessment of the severity of the condition 2 years after diagnosis.
      and one-third of FM patients in Canada experienced good outcomes at 3 years.
      • Poyhia R
      • Da Costa D
      • Fitzcharles MA
      Pain and pain relief in fibromyalgia patients followed for three years.
      An ongoing prospective study from Spain comparing women with FM to matched controls found a greater impact on physical than on psychological outcomes, although both were markedly impaired.
      • Segura-Jimenez V
      • Alvarez-Gallardo IC
      • Carbonell-Baeza A
      • Aparicio VA
      • Ortega FB
      • Casimiro AJ
      • Delgado-Fernandez M
      Fibromyalgia has a larger impact on physical health than on psychological health, yet both are markedly affected: The al-Andalus project.
      That group also noted the combined effect of lack of physical fitness, obesity, and mood disturbances on poor quality of life in FM.
      • Soriano-Maldonado A
      • Estevez-Lopez F
      • Segura-Jimenez V
      • Aparicio VA
      • Alvarez-Gallardo IC
      • Herrador-Colmenero M
      • Ruiz JR
      • Henriksen M
      • Amris K
      • Delgado-Fernandez M
      • al-Andalus P
      Association of physical fitness with depression in women with fibromyalgia.
      FM has been associated with significant direct medical costs.
      • Lacasse A
      • Bourgault P
      • Choiniere M
      Fibromyalgia-related costs and loss of productivity: A substantial societal burden.
      In a large U.S. health care database of >30,000 FM patients, health care costs were 3 times greater than controls.
      • Berger A
      • Dukes E
      • Martin S
      • Edelsberg J
      • Oster G
      Characteristics and healthcare costs of patients with fibromyalgia syndrome.
      In another survey of 16,000 patients with FM, there were greater comorbidities, physician visits, and costs compared with controls.
      • Lachaine J
      • Beauchemin C
      • Landry PA
      Clinical and economic characteristics of patients with fibromyalgia syndrome.
      In Quebec, the mean direct annual cost of FM was estimated to be $3,804, and an average of 6 days were lost due to pain during the prior 3 months.
      • Lacasse A
      • Bourgault P
      • Choiniere M
      Fibromyalgia-related costs and loss of productivity: A substantial societal burden.
      Indirect costs are also high,
      • Lacasse A
      • Bourgault P
      • Choiniere M
      Fibromyalgia-related costs and loss of productivity: A substantial societal burden.
      mainly driven by lost work productivity, with the highest direct annual cost in the U.S. compared to France and Germany.
      • Knight T
      • Schaefer C
      • Chandran A
      • Zlateva G
      • Winkelmann A
      • Perrot S
      Health-resource use and costs associated with fibromyalgia in France, Germany, and the United States.
      In a recent report from Australia, one-quarter of working FM subjects stopped work within 5 years of the diagnosis and one-third were receiving financial support because of FM.
      • Guymer EK
      • Littlejohn GO
      • Brand CK
      • Kwiatek RA
      Fibromyalgia onset has a high impact on work ability in Australians.
      Compared with controls, patients with CWP had worse quality of life, greater disability, mood and sleep disturbances, cardiovascular comorbidity, and higher mortality rates.
      • Morales-Espinoza EM
      • Kostov B
      • Salami DC
      • Perez ZH
      • Rosalen AP
      • Molina JO
      • Gonzalez-de Paz L
      • Momblona JM
      • Areu JB
      • Brito-Zeron P
      • Ramos-Casals M
      • Siso-Almirall A
      CPSGPC Study Group
      Complexity, comorbidity, and health care costs associated with chronic widespread pain in primary care.
      In the 2012 U.S. National Health Interview Survey, FM patients had high levels of self-reported pain, physical and psychological comorbidities, and high medical costs, as well as high rates of Social Security and work disability.
      • Walitt B
      • Nahin RL
      • Katz RS
      • Bergman MJ
      • Wolfe F
      The prevalence and characteristics of fibromyalgia in the 2012 National Health Interview Survey.
      Fifty-six percent of FM patients <65 years old were unable to work compared with 6% without FM. Disability payments in the prior year were 30% in FM patients compared with 3% in controls.
      In a more recent study from Canada, one-third of FM patients were receiving disability payments.
      • Fitzcharles MA
      • Ste-Marie PA
      • Rampakakis E
      • Sampalis JS
      • Shir Y
      Disability in fibromyalgia associates with symptom severity and occupation characteristics.
      Disability compensation was associated with illness severity, number of medications used, and previous employment in physically demanding jobs. Illness burden was evaluated in 125 individuals not complaining of CWP, 176 with CWP, and 171 with FM.
      • Schaefer C
      • Mann R
      • Masters ET
      • Cappelleri JC
      • Daniel SR
      • Zlateva G
      • McElroy HJ
      • Chandran AB
      • Adams EH
      • Assaf AR
      • McNett M
      • Mease P
      • Silverman S
      • Staud R
      The comparative burden of chronic widespread pain and fibromyalgia in the United States.
      The FM patients had more comorbidities, pain-related medications, poorer health status and function, worse sleep, lower productivity, and greater health care costs. Those investigators also reported that over 2 years, about one-quarter of FM patients no longer met criteria for FM and that symptoms wax and wane.
      • Adams EH
      • McElroy HJ
      • Udall M
      • Masters ET
      • Mann RM
      • Schaefer CP
      • Cappelleri JC
      • Clair AG
      • Hopps M
      • Daniel SR
      • Mease P
      • Silverman SL
      • Staud R
      Progression of fibromyalgia: Results from a 2-year observational fibromyalgia and chronic pain study in the US.

      Morbidity and Mortality

      In older European men, CWP was associated with slower cognition
      • Lee DM
      • Pendleton N
      • Tajar A
      • O'Neill TW
      • O'Connor DB
      • Bartfai G
      • Boonen S
      • Casanueva FF
      • Finn JD
      • Forti G
      • Giwercman A
      • Han TS
      • Huhtaniemi IT
      • Kula K
      • Lean ME
      • Punab M
      • Silman AJ
      • Vanderschueren D
      • Moseley CM
      • Wu FC
      • McBeth J
      EMAS Study Group
      Chronic widespread pain is associated with slower cognitive processing speed in middle-aged and older European men.
      and increased frailty.
      • Wade KF
      • Lee DM
      • McBeth J
      • Ravindrarajah R
      • Gielen E
      • Pye SR
      • Vanderschueren D
      • Pendleton N
      • Finn JD
      • Bartfai G
      • Casanueva FF
      • Forti G
      • Giwercman A
      • Huhtaniemi IT
      • Kula K
      • Punab M
      • Wu FC
      • O'Neill TW
      Chronic widespread pain is associated with worsening frailty in European men.
      There was a 1.25-fold higher risk of stroke in FM compared with controls and a 2.3-fold higher risk in younger subjects.
      • Tseng CH
      • Chen JH
      • Wang YC
      • Lin MC
      • Kao CH
      Increased risk of stroke in patients with fibromyalgia: A population-based cohort study.
      Initial reports suggested that FM and CWP were associated with increased mortality, including from cancer and cardiovascular disease.
      • McBeth J
      • Symmons DP
      • Silman AJ
      • Allison T
      • Webb R
      • Brammah T
      • Macfarlane GJ
      Musculoskeletal pain is associated with a long-term increased risk of cancer and cardiovascular-related mortality.
      • Torrance N
      • Elliott AM
      • Lee AJ
      • Smith BH
      Severe chronic pain is associated with increased 10 year mortality. A cohort record linkage study.
      Although there has been variability across studies conducted,
      • Dreyer L
      • Kendall S
      • Danneskiold-Samsoe B
      • Bartels EM
      • Bliddal H
      Mortality in a cohort of Danish patients with fibromyalgia: Increased frequency of suicide.
      • Wolfe F
      • Hassett AL
      • Walitt B
      • Michaud K
      Mortality in fibromyalgia: A study of 8,186 patients over thirty-five years.
      the largest study that has examined this (UK Biobank)
      • Macfarlane GJ
      • Barnish MS
      • Jones GT
      Persons with chronic widespread pain experience excess mortality: Longitudinal results from UK Biobank and meta-analysis.
      combined into a meta-analysis has confirmed that patients with CWP do have an important excess risk of death. As expected, suicidal ideation and risk of suicide were associated primarily with depression and global mental health and were much greater in patients with FM than in patients with low back pain and controls.
      • Calandre EP
      • Navajas-Rojas MA
      • Ballesteros J
      • Garcia-Carrillo J
      • Garcia-Leiva JM
      • Rico-Villademoros F
      Suicidal ideation in patients with fibromyalgia: A cross-sectional study.
      • Jimenez-Rodriguez I
      • Garcia-Leiva JM
      • Jimenez-Rodriguez BM
      • Condes-Moreno E
      • Rico-Villademoros F
      • Calandre EP
      Suicidal ideation and the risk of suicide in patients with fibromyalgia: A comparison with non-pain controls and patients suffering from low-back pain.

      Dimension 5

      Putative Neurobiological and Psychosocial Mechanisms, Risk Factors, and Protective Factors

      Risk Factors and Comorbidities

      Individuals who develop FM nearly always have a lifelong history of chronic pain in various regions of the body, as well as other central nervous system symptoms such as fatigue, sleep, memory, and mood difficulties.
      • Arnold LM
      • Clauw DJ
      • McCarberg BH
      FibroCollaborative
      Improving the recognition and diagnosis of fibromyalgia.
      Often beginning in childhood or adolescence, individuals who eventually go on to develop FM are more likely to experience headaches, dysmenorrhea, temporomandibular joint disorder, chronic fatigue, irritable bowel syndrome and other functional GI disorders, interstitial cystitis/painful bladder syndrome, endometriosis, and other regional pain syndromes (especially back and neck pain).
      • Aaron LA
      • Buchwald D
      A review of the evidence for overlap among unexplained clinical conditions.
      • Clauw DJ
      • Schmidt M
      • Radulovic D
      • Singer A
      • Katz P
      • Bresette J
      The relationship between fibromyalgia and interstitial cystitis.
      • Hudson JI
      • Pope HG
      The concept of affective spectrum disorder: Relationship to fibromyalgia and other syndromes of chronic fatigue and chronic muscle pain.
      As a result, many in the field have started to believe that these “centralized” pain states are best thought of as a single, lifelong disease that merely tends to manifest in multiple different bodily regions over time.
      • Tracey I
      • Bushnell MC
      How neuroimaging studies have challenged us to rethink: Is chronic pain a disease?.
      • Williams DA
      • Clauw DJ
      Understanding fibromyalgia: Lessons from the broader pain research community.
      ,
      • Woolf CJ
      Central sensitization: Implications for the diagnosis and treatment of pain.
      In addition to FM patients frequently having a personal lifetime history of chronic pain, a strong family history of chronic pain is often identifiable. The first-degree relatives of FM patients are 8 times as likely to have this condition as the family members of controls, and also have very high rates of other chronic pain states.
      • Arnold LM
      • Hudson JI
      • Hess EV
      • Ware AE
      • Fritz DA
      • Auchenbach MB
      • Starck LO
      • Keck Jr, PE
      Family study of fibromyalgia.
      This familial and personal co-aggregation of conditions that includes FM was originally collectively termed affective spectrum disorder
      • Hudson JI
      • Goldenberg DL
      • Pope Jr, HG
      • Keck Jr, PE
      • Schlesinger L
      Comorbidity of fibromyalgia with medical and psychiatric disorders.
      and, more recently, central sensitivity syndromes,
      • Yunus MB
      Central sensitivity syndromes: A new paradigm and group nosology for fibromyalgia and overlapping conditions, and the related issue of disease versus illness.
      chronic multisymptom illnesses, and chronic overlapping pain conditions. In population-based studies, the key symptoms that often co-aggregate besides pain are fatigue, memory difficulties, and mood disturbances.
      • Fukuda K
      • Dobbins JG
      • Wilson LJ
      • Dunn RA
      • Wilcox K
      • Smallwood D
      An epidemiologic study of fatigue with relevance for the chronic fatigue syndrome.
      • Fukuda K
      • Nisenbaum R
      • Stewart G
      • Thompson WW
      • Robin L
      • Washko RM
      • Noah DL
      • Barrett DH
      • Randall B
      • Herwaldt BL
      • Mawle AC
      • Reeves WC
      Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
      Twin studies suggest that ∼50% of the risk of developing FM or related pain conditions such as irritable bowel syndrome and headache is genetic and 50% environmental.
      • Kato K
      • Sullivan PF
      • Evengard B
      • Pedersen NL
      A population-based twin study of functional somatic syndromes.
      The environmental factors that are most likely to trigger the development of FM are various types of “stressors.” These stressors include the following: early lifetime adverse events, medical illness (including infections), trauma, and psychosocial stressors.
      • McLean SA
      • Clauw DJ
      Predicting chronic symptoms after an acute "stressor"—Lessons learned from 3 medical conditions.
      For example, FM or similar illnesses are found at much higher than expected rates in individuals who have experienced certain types of infections
      • Buskila D
      • Atzeni F
      • Sarzi-Puttini P
      Etiology of fibromyalgia: The possible role of infection and vaccination.
      • Buskila D
      • Shnaider A
      • Neumann L
      • Zilberman D
      • Hilzenrat N
      • Sikuler E
      Fibromyalgia in hepatitis C virus infection. Another infectious disease relationship.
      (eg, Epstein Barr virus, Lyme disease, Q fever, viral hepatitis), trauma
      • Buskila D
      • Neumann L
      • Vaisberg G
      • Alkalay D
      • Wolfe F
      Increased rates of fibromyalgia following cervical spine injury. A controlled study of 161 cases of traumatic injury [see comments].
      • McLean SA
      • Diatchenko L
      • Lee YM
      • Swor RA
      • Domeier RM
      • Jones JS
      • Jones CW
      • Reed C
      • Harris RE
      • Maixner W
      • Clauw DJ
      • Liberzon I
      Catechol O-methyltransferase haplotype predicts immediate musculoskeletal neck pain and psychological symptoms after motor vehicle collision.
      (eg, motor vehicle collisions), and deployment to war.
      • Lewis JD
      • Wassermann EM
      • Chao W
      • Ramage AE
      • Robin DA
      • Clauw DJ
      Central sensitization as a component of post-deployment syndrome.
      FM also is very commonly seen as a comorbidity in other chronic pain conditions such as osteoarthritis, rheumatoid arthritis, and lupus.
      • Atzeni F
      • Cazzola M
      • Benucci M
      • Di Franco M
      • Salaffi F
      • Sarzi-Puttini P
      Chronic widespread pain in the spectrum of rheumatological diseases.
      • Fan A
      • Pereira B
      • Tournadre A
      • Tatar Z
      • Malochet-Guinamand S
      • Mathieu S
      • Couderc M
      • Soubrier M
      • Dubost JJ
      Frequency of concomitant fibromyalgia in rheumatic diseases: Monocentric study of 691 patients.
      ,
      • Murphy SL
      • Phillips K
      • Williams DA
      • Clauw DJ
      The role of the central nervous system in osteoarthritis pain and implications for rehabilitation.
      This phenomenon had previously been termed “secondary FM”; however, because this is so common and might occur in a subset of nearly any chronic pain cohort, the preferred terminology is that there has been a centralization of pain that manifests as co-morbid FM. FM, especially the “primary” form, is also very comorbid with early life and current stress, and many, if not most, individuals will have a lifetime history of a psychiatric disorder such as depression or anxiety.
      • Epstein SA
      • Kay GG
      • Clauw DJ
      • Heaton R
      • Klein D
      • Krupp L
      • Kuck J
      • Leslie V
      • Masur D
      • Wagner M
      • Waid R
      • Zisook S
      Psychiatric disorders in patients with fibromyalgia. A multicenter investigation.
      There is typically more psychiatric and psychological comorbidity seen in tertiary care settings or in individuals who are refractory to treatment.

      Pathophysiology

      Although few would purport that there is an animal model that mimics all of the key clinical features of FM, nonetheless animal models can be very helpful in understanding the pathogenesis of this condition.
      • Sluka KA
      • Clauw DJ
      Neurobiology of fibromyalgia and chronic widespread pain.
      Animals develop the critical features of central sensitization or centralization of pain when exposed to swim stress,
      • Suarez-Roca H
      • Silva JA
      • Arcaya JL
      • Quintero L
      • Maixner W
      • Pinerua-Shuhaibar L
      Role of mu-opioid and NMDA receptors in the development and maintenance of repeated swim stress-induced thermal hyperalgesia.
      neonatal separation from their mothers,
      • Pierce AN
      • Christianson JA
      Stress and chronic pelvic pain.
      and many other nonpainful stimuli.
      • Sluka KA
      • Clauw DJ
      Neurobiology of fibromyalgia and chronic widespread pain.
      Features of central sensitization and animal pain behaviors consistent with diffuse pain are also seen when central nervous system neurotransmitters are purposefully altered in the direction found in FM. For example, chronic reserpine administration, which depletes bioamines, leads to features consistent with FM,

      Sluka KA: Is it possible to develop an animal model of fibromyalgia? Pain 146:3-4, 2009

      • Taguchi T
      • Katanosaka K
      • Yasui M
      • Hayashi K
      • Yamashita M
      • Wakatsuki K
      • Kiyama H
      • Yamanaka A
      • Mizumura K
      Peripheral and spinal mechanisms of nociception in a rat reserpine-induced pain model.
      as does directly increasing glutamate levels in the insulae.
      The strong familial predisposition to FM has led many to study specific genes that may be associated with a higher risk of developing FM. First, candidate gene studies showed that genetic findings such as the serotonin 5-HT2A receptor polymorphism T/T phenotype, serotonin transporter, dopamine 4 receptor, and COMT (catecholamine o-methyl transferase) polymorphisms all were noted in higher frequency in FM patients than controls. Subsequent studies confirmed some of these associations, whereas others did not.
      • Buskila D
      • Sarzi-Puttini P
      • Ablin JN
      The genetics of fibromyalgia syndrome.
      • Diatchenko L
      • Fillingim RB
      • Smith SB
      • Maixner W
      The phenotypic and genetic signatures of common musculoskeletal pain conditions.
      Subsequent larger genome-wide linkage and candidate gene studies identified other putative targets.
      • Arnold LM
      • Fan J
      • Russell IJ
      • Yunus MB
      • Khan MA
      • Kushner I
      • Olson JM
      • Iyengar SK
      The fibromyalgia family study: a genome-wide linkage scan study.
      • Smith SB
      • Maixner DW
      • Fillingim RB
      • Slade G
      • Gracely RH
      • Ambrose K
      • Zaykin DV
      • Hyde C
      • John S
      • Tan K
      • Maixner W
      • Diatchenko L
      Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia.
      Linkage studies confirmed the strong genetic contribution to FM and suggested linkage of FM to the chromosome 17p11.2-q11.2 region.
      • Arnold LM
      • Fan J
      • Russell IJ
      • Yunus MB
      • Khan MA
      • Kushner I
      • Olson JM
      • Iyengar SK
      The fibromyalgia family study: a genome-wide linkage scan study.
      The large candidate gene study identified significant differences in allele frequencies between cases and controls for 3 genes: GABRB3 (rs4906902, P = 3.65 × 10–6), TAAR1 (rs8192619, P = 1.11 × 10–5), and GBP1 (rs7911, P = 1.06 × 10–4). These 3 genes, and 7 other genes with suggestive evidence for association, were examined in a second, independent cohort of FM patients, and evidence of association in the replication cohort was observed for TAAR1, RGS4, CNR1, and GRIA4.
      • Smith SB
      • Maixner DW
      • Fillingim RB
      • Slade G
      • Gracely RH
      • Ambrose K
      • Zaykin DV
      • Hyde C
      • John S
      • Tan K
      • Maixner W
      • Diatchenko L
      Large candidate gene association study reveals genetic risk factors and therapeutic targets for fibromyalgia.
      Because classic genetic studies have not yet identified strong, reproducible polymorphisms or haplotypes associated with FM, and because there is clear evidence of environmental factors such as stress playing a prominent role in the pathogenesis, other groups have postulated that epigenetic findings might be important in FM.
      • Ciampi de Andrade D
      • Maschietto M
      • Galhardoni R
      • Gouveia G
      • Chile T
      • Victorino Krepischi AC
      • Dale CS
      • Brunoni AR
      • Parravano DC
      • Cueva Moscoso AS
      • Raicher I
      • Kaziyama HHS
      • Teixeira MJ
      • Brentani HP
      Epigenetics insights into chronic pain: DNA hypomethylation in fibromyalgia-a controlled pilot-study.
      There is also emerging evidence of functional genetic polymorphisms affecting pain severity in FM.
      • Kosek E
      • Martinsen S
      • Gerdle B
      • Mannerkorpi K
      • Lofgren M
      • Bileviciute-Ljungar I
      • Fransson P
      • Schalling M
      • Ingvar M
      • Ernberg M
      • Jensen KB
      The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia.
      The physiological hallmark of FM, centralization of pain or central sensitization, is thought to be augmented central pain processing. This was originally identified in FM (and still can be clinically) by noting that an individual is diffusely tender to palpation. In 1990, when the original classification criteria for FM were first published, this feature of diffuse tenderness was incorporated into the diagnostic criteria by requiring that an individual had a certain number of tender points (≥11), in addition to CWP to qualify for this diagnosis.
      • Wolfe F
      • Smythe HA
      • Yunus MB
      • Bennett RM
      • Bombardier C
      • Goldenberg DL
      • Tugwell P
      • Campbell SM
      • Abeles M
      • Clark P
      The American College of Rheumatology 1990 Criteria for the Classification of Fibromyalgia. Report of the Multicenter Criteria Committee.
      Subsequent studies using more sophisticated measures of experimental pain testing showed that individuals with FM are more tender everywhere in the body, not just in the 18 regions considered to be “tender points.”
      • Petzke F
      • Clauw DJ
      • Ambrose K
      • Khine A
      • Gracely RH
      Increased pain sensitivity in fibromyalgia: Effects of stimulus type and mode of presentation.
      • Petzke F
      • Gracely RH
      • Park KM
      • Ambrose K
      • Clauw DJ
      What do tender points measure? Influence of distress on 4 measures of tenderness.
      Subsequent experimental pain testing studies have identified multiple potential mechanisms that may be responsible for pain amplification in FM, including a decrease in the activity of descending analgesic pathways,
      • Julien N
      • Goffaux P
      • Arsenault P
      • Marchand S
      Widespread pain in fibromyalgia is related to a deficit of endogenous pain inhibition.
      • Kosek E
      • Hansson P
      Modulatory influence on somatosensory perception from vibration and heterotopic noxious conditioning stimulation (HNCS) in fibromyalgia patients and healthy subjects.
      an increase in pain facilitatory pathways,
      • Staud R
      • Vierck CJ
      • Cannon RL
      • Mauderli AP
      • Price DD
      Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome.
      and a diffuse increase in the processing of all sensory stimuli (not just pain).
      • Geisser ME
      • Glass JM
      • Rajcevska LD
      • Clauw DJ
      • Williams DA
      • Kileny PR
      • Gracely RH
      A psychophysical study of auditory and pressure sensitivity in patients with fibromyalgia and healthy controls.
      • Geisser ME
      • Strader Donnell C
      • Petzke F
      • Gracely RH
      • Clauw DJ
      • Williams DA
      Comorbid somatic symptoms and functional status in patients with fibromyalgia and chronic fatigue syndrome: Sensory amplification as a common mechanism.
      The notion that FM and related syndromes might represent biological amplification of all sensory stimuli has significant support from functional imaging studies that suggest that the insula is the most consistently hyperactive region, as this region is critical in sensory appraisal, with the posterior insula serving a purer sensory role, and the anterior insula being associated with the emotional processing of sensations.
      • Craig AD
      Interoception: The sense of the physiological condition of the body.
      • Craig AD
      Human feelings: Why are some more aware than others?.
      ,
      • Dehghan M
      • Schmidt-Wilcke T
      • Pfleiderer B
      • Eickhoff SB
      • Petzke F
      • Harris RE
      • Montoya P
      • Burgmer M
      Coordinate-based (ALE) meta-analysis of brain activation in patients with fibromyalgia.
      • Tracey I
      Neuroimaging of pain mechanisms.
      ,
      • Tracey I
      • Mantyh PW
      The cerebral signature for pain perception and its modulation.
      These initial observations that individuals with FM were diffusely tender led to subsequent functional, chemical, and structural brain neuroimaging studies that have been among the best “objective” evidence that the pain in FM is real.
      • Harris RE
      • Clauw DJ
      How do we know that the pain in fibromyalgia is "real"?.
      These methods, such as fMRI, clearly demonstrate that when individuals with FM are given a mild pressure or heat stimuli, that most individuals would feel as “touch” rather than “pain,” they experience pain and similar brain activation patterns in brain areas involved in pain processing.
      • Cook DB
      • Lange G
      • Ciccone DS
      • Liu WC
      • Steffener J
      • Natelson BH
      Functional imaging of pain in patients with primary fibromyalgia.
      • Gracely RH
      • Petzke F
      • Wolf JM
      • Clauw DJ
      Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia.
      fMRI has also proved useful in determining how comorbid psychological factors influence pain processing in FM. For example, in FM patients with variable degrees of comorbid depression, the anterior insula and amygdala activations were correlated with depressive symptoms, consistent with these “medial” and pre-frontal brain regions being involved with affective or motivational aspects of pain processing (and being more closely related to unpleasantness rather than the sensory intensity of pain).
      • Berna C
      • Leknes S
      • Holmes EA
      • Edwards RR
      • Goodwin GM
      • Tracey I
      Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness.
      A more recent advance in the use of fMRI is to look at the extent brain regions are functionally “connected” to each other, that is, simultaneously activated (or deactivated).
      • Ploner M
      • Lee MC
      • Wiech K
      • Bingel U
      • Tracey I
      Prestimulus functional connectivity determines pain perception in humans.
      The advantage of resting-state connectivity analysis is that it is a window into brain changes associated with the chronic, ongoing spontaneous pain common in FM. Individuals with FM have increased connectivity between brain regions involved in increasing pain transmission and neural networks not normally involved in pain, such as the default mode network, and the degree of this hyper-connectedness is related to the severity of ongoing pain.
      • Napadow V
      • Kim J
      • Clauw DJ
      • Harris RE
      Decreased intrinsic brain connectivity is associated with reduced clinical pain in fibromyalgia.
      • Napadow V
      • Lacount L
      • Park K
      • As-Sanie S
      • Clauw DJ
      • Harris RE
      Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity.
      During a painful stimulus, connectivity is decreased between key antinociceptive regions (eg, the brainstem—the origin of descending analgesic pathways) and a region previously identified to be a potential source of dysfunctional pain inhibition in FM.
      • Jensen KB
      • Kosek E
      • Petzke F
      • Carville S
      • Fransson P
      • Marcus H
      • Williams SC
      • Choy E
      • Giesecke T
      • Mainguy Y
      • Gracely R
      • Ingvar M
      Evidence of dysfunctional pain inhibition in fibromyalgia reflected in rACC during provoked pain.
      • Jensen KB
      • Loitoile R
      • Kosek E
      • Petzke F
      • Carville S
      • Fransson P
      • Marcus H
      • Williams SC
      • Choy E
      • Mainguy Y
      • Vitton O
      • Gracely RH
      • Gollub R
      • Ingvar M
      • Kong J
      Patients with fibromyalgia display less functional connectivity in the brain's pain inhibitory network.
      Imaging studies have confirmed quantitative sensory testing studies that these individuals are more sensitive to a number of sensory stimuli other than pain, and that machine-learning paradigms can accurately distinguish FM from non-FM patients with >90% accuracy using these results.
      • Lopez-Sola M
      • Pujol J
      • Wager TD
      • Garcia-Fontanals A
      • Blanco-Hinojo L
      • Garcia-Blanco S
      • Poca-Dias V
      • Harrison BJ
      • Contreras-Rodriguez O
      • Monfort J
      • Garcia-Fructuoso F
      • Deus J
      Altered functional magnetic resonance imaging responses to nonpainful sensory stimulation in fibromyalgia patients.
      • Lopez-Sola M
      • Woo CW
      • Pujol J
      • Deus J
      • Harrison BJ
      • Monfort J
      • Wager TD
      Towards a neurophysiological signature for fibromyalgia.
      Other imaging techniques have been used to identify the neurotransmitter abnormalities that may be driving the pain amplification seen in FM and other chronic pain disorders. Positron emission tomography studies show that attenuated dopaminergic activity may be playing a role in pain transmission in FM, and there is evidence of decreased µ opioid receptor availability (possibly owing to increased release of endogenous µ opioids) in FM.
      • Harris RE
      • Clauw DJ
      • Scott DJ
      • McLean SA
      • Gracely RH
      • Zubieta JK
      Decreased central mu-opioid receptor availability in fibromyalgia.
      • Wood PB
      • Schweinhardt P
      • Jaeger E
      • Dagher A
      • Hakyemez H
      • Rabiner EA
      • Bushnell MC
      • Chizh BA
      Fibromyalgia patients show an abnormal dopamine response to pain.
      This latter finding as well as previous studies showing increases in endogenous opioids in the cerebrospinal fluid of FM patients has been suggested as evidence of why opioid analgesics clinically appear to not be effective in FM. There are increases in brain concentrations of the body's major excitatory neurotransmitter, glutamate, in pain-processing regions such as the insula in FM.
      • Harris RE
      Elevated excitatory neurotransmitter levels in the fibromyalgia brain.
      This finding has also been noted in the cerebrospinal fluid in FM.
      • Sarchielli P
      • Di Filippo M
      • Nardi K
      • Calabresi P
      Sensitization, glutamate, and the link between migraine and fibromyalgia.
      Drugs such as pregabalin and gabapentin likely work in FM in part by reducing glutamatergic activity.
      • Maneuf YP
      • Hughes J
      • McKnight AT
      Gabapentin inhibits the substance P-facilitated K(+)-evoked release of [(3)H]glutamate from rat caudial trigeminal nucleus slices.
      Individuals with FM that had the highest pretreatment levels of glutamate in the posterior insula were those most likely to respond to pregabalin.
      • Harris RE
      • Napadow V
      • Huggins JP
      • Pauer L
      • Kim J
      • Hampson J
      • Sundgren PC
      • Foerster B
      • Petrou M
      • Schmidt-Wilcke T
      • Clauw DJ
      Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.
      When pregabalin led to improvement in symptoms in these individuals, there was normalization of fMRI and connectivity findings, all suggesting that this neurotransmitter is playing a critical role in the pathogenesis of FM in some individuals. Conversely, magnetic resonance spectroscopy has recently been used to demonstrate low levels of GABA in several brain regions.
      • Foerster BR
      • Petrou M
      • Edden RA
      • Sundgren PC
      • Schmidt-Wilcke T
      • Lowe SE
      • Harte SE
      • Clauw DJ
      • Harris RE
      Reduced insular gamma-aminobutyric acid in fibromyalgia.
      This likely accounts for the efficacy of drugs such as gamma-hydroxybutyrate in FM.
      • Russell IJ
      • Holman AJ
      • Swick TJ
      • Alvarez-Horine S
      • Wang YG
      • Guinta D
      Sodium oxybate reduces pain, fatigue, and sleep disturbance and improves functionality in fibromyalgia: Results from a 14-week, randomized, double-blind, placebo-controlled study.
      This finding may also suggest biological plausibility for the finding that FM patients who have low alcohol consumption (compared to none or high) have fewer symptoms and better functionality.
      • Kim CH
      • Vincent A
      • Clauw DJ
      • Luedtke CA
      • Thompson JM
      • Schneekloth TD
      • Oh TH
      Association between alcohol consumption and symptom severity and quality of life in patients with fibromyalgia.
      Because of the link between FM and exposure to stress, and because both the neuroendocrine and autonomic nervous systems could cause many of the symptoms of FM, these factors have been fairly extensively studied.
      • Clauw DJ
      • Crofford LJ
      Chronic widespread pain and fibromyalgia: What we know, and what we need to know.
      • Crofford LJ
      The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome.
      ,
      • Demitrack MA
      • Crofford LJ
      Evidence for and pathophysiologic implications of hypothalamic- pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.
      In fact, for several decades after it was understood that conditions such as FM or chronic fatigue syndrome were not due to inflammation or infection, these areas were receiving considerable attention. The problem is that this research has generally yielded inconsistent findings and treatment studies targeting these systems have failed; therefore, these factors are now generally thought to play a role in some individuals, but not to be central pathogenic factors in all individuals with these conditions.
      • Adler GK
      • Kinsley BT
      • Hurwitz S
      • Mossey CJ
      • Goldenberg DL
      Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome.
      • Cohen H
      • Neumann L
      • Shore M
      • Amir M
      • Cassuto Y
      • Buskila D
      Autonomic dysfunction in patients with fibromyalgia: Application of power spectral analysis of heart rate variability [see comments].
      ,
      • Crofford LJ
      • Pillemer SR
      • Kalogeras KT
      • Cash JM
      • Michelson D
      • Kling MA
      • Sternberg EM
      • Gold PW
      • Chrousos GP
      • Wilder RL
      Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia.
      • Demitrack MA
      • Crofford LJ
      Evidence for and pathophysiologic implications of hypothalamic- pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.
      ,
      • Martinez-Lavin M
      • Hermosillo AG
      • Rosas M
      • Soto ME
      Circadian studies of autonomic nervous balance in patients with fibromyalgia: A heart rate variability analysis.
      • Qiao ZG
      • Vaeroy H
      • Morkrid L
      Electrodermal and microcirculatory activity in patients with fibromyalgia during baseline, acoustic stimulation and cold pressor tests.
      Although most agree that the core symptoms of FM are likely because of changes in the central nervous system, peripheral factors also play an important role in both the pathogenesis and treatment of FM. For example, some elements of the processes of central sensitization can be worsened or driven by ongoing nociceptive input. Thus, it is likely that the many individuals with FM that also have comorbid conditions causing ongoing peripheral nociceptive input (eg, myofascial pain, osteoarthritis, obesity
      • Dias DN
      • Marques MA
      • Bettini SC
      • Paiva ED
      Prevalence of fibromyalgia in patients treated at the bariatric surgery outpatient clinic of Hospital de Clinicas do Parana - Curitiba.
      ) would potentially benefit from therapies aimed at reducing the peripheral drive of central sensitization, as has been shown in a short-term study.
      • Affaitati G
      • Costantini R
      • Fabrizio A
      • Lapenna D
      • Tafuri E
      • Giamberardino MA
      Effects of treatment of peripheral pain generators in fibromyalgia patients.
      In fact, one of the major areas of study needed for these conditions is to try to differentiate which individuals have these phenomena that are being driven from the central nervous system and which may be driven by ongoing peripheral nociceptive input.
      Although the prevailing view is that FM is not an autoimmune disorder and that classic anti-inflammatory agents are not of benefit in this condition, there are some data suggesting that the immune system may be playing a role in its pathogenesis.
      • Gur A
      • Oktayoglu P
      Status of immune mediators in fibromyalgia.
      Some have speculated that diet or obesity could contribute to this low-grade inflammation in FM and might be a potential target for therapy, and others have posited that this may provide evidence of microglia involvement in FM. There is also a current ongoing controversy regarding the meaning of finding decreased intra-epidermal nerve fiber density (ie, small-fiber neuropathy) in FM. There is no question that this has been shown in several studies
      • Clauw DJ
      What is the meaning of “small fiber neuropathy” in fibromyalgia?.
      • Doppler K
      • Rittner HL
      • Deckart M
      • Sommer C
      Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia.
      ,
      • Kim SH
      • Kim DH
      • Oh DH
      • Clauw DJ
      Characteristic electron microscopic findings in the skin of patients with fibromyalgia: Preliminary study.
      ; however, it might be that this is a nonspecific finding that has now been noted in >50 different pain and nonpain conditions.
      • Clauw DJ
      What is the meaning of “small fiber neuropathy” in fibromyalgia?.

      Discussion

      A new diagnostic framework was established by the AAPT to improve the diagnosis of chronic pain disorders. The AAPT Fibromyalgia Working Group addressed the current state of FM criteria for diagnosis and determined that an alternative to existing criteria might improve the identification of FM patients. The ACR 1990 classification criteria for FM was considered to be impractical for use owing to problems related to the tender point exam, which was difficult to perform and standardize in clinical settings. The tender point exam was also biased toward women, who are more sensitive to a tender point exam than men, and was not an accurate measure of hyperalgesia due to influence by subjective distress.
      • Gracely RH
      • Grant MA
      • Giesecke T
      Evoked pain measures in fibromyalgia.
      The ACR 2010/2011/2016 criteria eliminated the tender point exam and instead defined FM as a multi-symptom disorder. The appearance of the 2010 criteria created some controversy and confusion, and since 2010, alternative approaches to the diagnosis of FM have been proposed. The challenge shared by all attempts to define criteria for FM is that there is no gold standard for FM diagnosis. Until the pathophysiology is better understood and biomarkers are identified, the diagnosis relies on patient report and clinical assessment. Although the criteria published to date seem to identify a similar group of patients, the goal of the Fibromyalgia Working Group members was to make the diagnosis of FM practical for clinicians and useful for researchers, and to capture the key symptoms of the disorder. The AAPT taxonomy offers a new approach by defining core criteria and including other associated symptoms and signs, comorbidities, and impact on function in other dimensions. This taxonomy allows the clinician and researcher to focus on a more limited number of core symptoms for diagnosis, while allowing the many other associated symptoms and signs to be included in dimension 2, which will support the diagnosis of FM.
      Based on consensus meetings and analyses of several population-based studies to assess definitions of widespread pain and determine the best combination of pain and symptoms to identify FM patients, the Fibromyalgia Working Group developed new criteria for FM in dimension 1. The group determined that widespread pain was the core symptom of FM and, as in the ACR 1990 criteria, all patients should meet this criterion. Based on the results of the data analysis of multiple population based studies and other studies,
      • Coggon D
      • Ntani G
      • Palmer KT
      • Felli VE
      • Harari R
      • Barrero LH
      • Felknor SA
      • Gimeno D
      • Cattrell A
      • Vargas-Prada S
      • Bonzini M
      • Solidaki E
      • Merisalu E
      • Habib RR
      • Sadeghian F
      • Masood Kadir M
      • Warnakulasuriya SS
      • Matsudaira K
      • Nyantumbu B
      • Sim MR
      • Harcombe H
      • Cox K
      • Marziale MH
      • Sarquis LM
      • Harari F
      • Freire R
      • Harari N
      • Monroy MV
      • Quintana LA
      • Rojas M
      • Salazar Vega EJ
      • Harris EC
      • Serra C
      • Martinez JM
      • Delclos G
      • Benavides FG
      • Carugno M
      • Ferrario MM
      • Pesatori AC
      • Chatzi L
      • Bitsios P
      • Kogevinas M
      • Oha K
      • Sirk T
      • Sadeghian A
      • Peiris-John RJ
      • Sathiakumar N
      • Wickremasinghe AR
      • Yoshimura N
      • Kelsall HL
      • Hoe VC
      • Urquhart DM
      • Derrett S
      • McBride D
      • Herbison P
      • Gray A
      Patterns of multisite pain and associations with risk factors.
      the group selected MSP with a minimum number of required sites regardless of their anatomical distribution (instead of the ACR 1990 widespread pain criteria) (Fig 1).
      Although pain is the main symptom of FM, other symptoms are reported to be clinically significant by patients and are sometimes more disabling than pain. The new AAPT diagnostic criteria include 2 other symptoms, fatigue and sleep problems, which are most commonly reported by FM patients. Based on the results of the analysis of multiple population-based studies, the presence of MSP in combination with moderate to severe fatigue or sleep problems was sufficient to identify the FM patients. This simplified the criteria so that no scoring of associated symptoms was required. Sleep problems identified by FM patient include difficulty falling and staying asleep and unrefreshing sleep—any or all of these problems can be considered when assessing sleep problems. Similarly, fatigue may include mental and/or physical fatigue. Although the analyses of data from the population-based studies offered several approaches to FM diagnosis, the working group consensus was to focus on at least 6 of 9 sites of pain in combination with either fatigue or sleep problems to allow some flexibility (although most patients will have both sleep problems and fatigue, there are some patients who report only 1 of the symptoms). Relegating other symptom domains and signs to dimension 2 allows them to be considered when evaluating a patient but not be required for diagnosis.
      The main goal of the AAPT Fibromyalgia Working Group was to develop the AAPT dimensions for FM. In the process, the group devised new core criteria for the diagnosis of FM with the support of analyses of data from a large-scale population-based post hoc study.
      • Dean LE
      • Arnold L
      • Crofford L
      • Bennett R
      • Goldenberg D
      • Fitzcharles MA
      • Paiva ES
      • Staud R
      • Clauw D
      • Sarzi-Puttini P
      • Jones GT
      • Ayorinde A
      • Fluss E
      • Beasley M
      • Macfarlane GJ
      Impact of moving from a widespread to multisite pain definition on other fibromyalgia symptoms.
      There are several limitations to using this approach to identify core symptoms of FM. as detailed in Dean et al
      • Dean LE
      • Arnold L
      • Crofford L
      • Bennett R
      • Goldenberg D
      • Fitzcharles MA
      • Paiva ES
      • Staud R
      • Clauw D
      • Sarzi-Puttini P
      • Jones GT
      • Ayorinde A
      • Fluss E
      • Beasley M
      • Macfarlane GJ
      Impact of moving from a widespread to multisite pain definition on other fibromyalgia symptoms.
      In developing the new diagnostic criteria, we attempted to approximate the generally accepted prevalence of FM in the analyses. This would seem to present a logical conundrum for a new diagnostic system. Nevertheless, the prevalence proportions typically reported using the ACR 1990 criteria for FM are considered to have face validity, which seemed a reasonable reference point to adopt. MSP was defined here to identify a population with similar prevalence to CWP, and the resulting overlap may limit the ability to detect differences between the 2 groups. The overlap demonstrated was 60 to 76%, with a substantial number of individuals exclusive to 1 group and with differences in pain chronicity between definitions. This indicates that the similarities demonstrated between the MSP and CWP definitions and their relationship to other symptoms associated with FM cannot be attributed solely to the overlap of individuals.
      To assess the relationship between pain and the other associated symptoms of FM, bivariate analyses were conducted across multiple study populations. A fully adjusted model, containing all predictors, could not be performed, as no single study contained all measures. Although this did not prevent the study from assessing these relationships individually, future studies evaluating these in the context of the other symptoms would be beneficial.
      CWP was assessed using 4-view body manikins, present across all study populations, primarily because the 2011 modification of the 2010 FM criteria was not present in any of the studies used. The use of a body manikin has become 1 standard way to collect information from subjects on their sites of pain, and has been shown to have construct validity and to be reliable.
      • van den Hoven LH
      • Gorter KJ
      • Picavet HS
      Measuring musculoskeletal pain by questionnaires: The manikin versus written questions.
      There has been variability in how authors have defined CWP; but, the greatest consistency has come in the use of the definition of CWP within the ACR 1990 criteria for fibromyalgia. However, because these criteria did not specify how they should be operationalized, there is still possible variation.
      • Macfarlane GJ
      • Barnish MS
      • Jones GT
      Persons with chronic widespread pain experience excess mortality: Longitudinal results from UK Biobank and meta-analysis.
      • Steingrimsdottir OA
      • Landmark T
      • Macfarlane GJ
      • Nielsen CS
      Defining chronic pain in epidemiological studies: A systematic review and meta-analysis.
      Despite the difference in the methods of ascertaining pain, the resulting number of pain sites needed to define MSP is consistent with other studies.
      • Wolfe F
      Pain extent and diagnosis: Development and validation of the regional pain scale in 12,799 patients with rheumatic disease.
      Despite these limitations, the analyses demonstrated that the features of FM could be defined in multiple ways. The consensus of the AAPT working group was to simplify the diagnostic criteria to facilitate the identification of FM in clinical practice and for the purpose of research. We concluded that chronic pain remains the core symptom of FM, and 2 key associated symptoms (fatigue and sleep disturbance) are important in understanding and treating FM. The AAPT working group considered the question of whether to require both fatigue and sleep disturbance in dimension 1. However, based on the clinical experience of the working group members, individuals with FM may at a single point in time have either fatigue or sleep disturbance; although, if they are followed longitudinally, they typically develop both problems over time.
      We gathered a group of international clinical and research experts in the field of FM to have broad input in the process. However, the resulting development of the 5 dimensions will need to be assessed by other groups, and the core diagnostic criteria will require further study and validation. We believe that the criteria will be useful across all clinical settings, including primary, secondary, and tertiary practices, but will also require additional study. A global alignment of taxonomy for pain disorders is an important long-term goal. The AAPT is multidimensional, which makes it unique compared with other existing and in-development diagnostic criteria. We hope that this multidimensional approach will increase the value of the AAPT for both clinical research and clinical practice. Additional studies are needed to assess the prevalence of FM using the new definition. We have cited many of the key studies relevant to the development of the dimensions; however, owing to the rapidly evolving field, the vast literature on FM, and limitations of space, many studies could not be included in our review. In addition, the review of the literature was not intended to be at the level of a systematic review, but rather to support the consensus discussions and develop the dimensions. Revisions of the dimensions will also be required as research continues and our understanding of the pathophysiology of FM and chronic pain improves.

      Supplementary Data

      Supplementary data related to this article can be found at https://dx.doi.org/10.1016/j.jpain.2018.10.008.

      References

        • Aaron LA
        • Buchwald D
        A review of the evidence for overlap among unexplained clinical conditions.
        Ann Intern Med. 2001; 134: 868-881
        • Aaron LA
        • Burke MM
        • Buchwald D
        Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder.
        Arch Intern Med. 2000; 160: 221-227
        • Adams EH
        • McElroy HJ
        • Udall M
        • Masters ET
        • Mann RM
        • Schaefer CP
        • Cappelleri JC
        • Clair AG
        • Hopps M
        • Daniel SR
        • Mease P
        • Silverman SL
        • Staud R
        Progression of fibromyalgia: Results from a 2-year observational fibromyalgia and chronic pain study in the US.
        J Pain Res. 2016; 9: 325-336
        • Adler GK
        • Kinsley BT
        • Hurwitz S
        • Mossey CJ
        • Goldenberg DL
        Reduced hypothalamic-pituitary and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome.
        Am J Med. 1999; 106: 534-543
        • 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. 2011; 15: 61-69
        • Alagiri M
        • Chottiner S
        • Ratner V
        • Slade D
        • Hanno PM
        Interstitial cystitis: Unexplained associations with other chronic disease and pain syndromes.
        Urology. 1997; 49: 52-57
        • Arnold LM
        • Clauw DJ
        • McCarberg BH
        • FibroCollaborative
        Improving the recognition and diagnosis of fibromyalgia.
        Mayo Clin Proc. 2011; 86: 457-464
        • Arnold LM
        • Fan J
        • Russell IJ
        • Yunus MB
        • Khan MA
        • Kushner I
        • Olson JM
        • Iyengar SK
        The fibromyalgia family study: a genome-wide linkage scan study.
        Arthritis Rheum. 2013; 65: 1122-1128
        • Arnold LM
        • Hudson JI
        • Hess EV
        • Ware AE
        • Fritz DA
        • Auchenbach MB
        • Starck LO
        • Keck Jr, PE
        Family study of fibromyalgia.
        Arthritis Rheum. 2004; 50: 944-952
        • Arnold LM
        • Hudson JI
        • Keck PE
        • Auchenbach MB
        • Javaras KN
        • Hess EV
        Comorbidity of fibromyalgia and psychiatric disorders.
        J Clin Psychiatry. 2006; 67: 1219-1225
        • Arnold LM
        • Stanford SB
        • Welge JA
        • Crofford LJ
        Development and testing of the fibromyalgia diagnostic screen for primary care.
        J Womens Health (Larchmt). 2012; 21: 231-239
        • Arnold LM
        • Williams DA
        • Hudson JI
        • Martin SA
        • Clauw DJ
        • Crofford LJ
        • Wang F
        • Emir B
        • Lai C
        • Zablocki R
        • Mease PJ
        Development of responder definitions for fibromyalgia clinical trials.
        Arthritis Rheum. 2012; 64: 885-894
        • Atherton K
        • Fuller E
        • Shepherd P
        • Strachan DP
        • Power C
        Loss and representativeness in a biomedical survey at age 45 years: 1958 British birth cohort.
        J Epidemiol Community Health. 2008; 62: 216-223
        • Atzeni F
        • Cazzola M
        • Benucci M
        • Di Franco M
        • Salaffi F
        • Sarzi-Puttini P
        Chronic widespread pain in the spectrum of rheumatological diseases.
        Best Pract Res Clin Rheumatol. 2011; 25: 165-171
        • Ayorinde AA
        • Bhattacharya S
        • Druce KL
        • Jones GT
        • Macfarlane GJ
        Chronic pelvic pain in women of reproductive and post-reproductive age: A population-based study.
        Eur J Pain. 2017; 21: 445-455
        • Bennett RM
        • Friend R
        • Marcus D
        • Bernstein C
        • Han BK
        • Yachoui R
        • Deodhar A
        • Kaell A
        • Bonafede P
        • Chino A
        • Jones KD
        Criteria for the diagnosis of fibromyalgia: Validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria.
        Arthritis Care Res (Hoboken). 2014; 66: 1364-1373
        • Bennett RM
        • Jones J
        • Turk DC
        • Russell IJ
        • Matallana L
        An internet survey of 2,596 people with fibromyalgia.
        BMC Musculoskelet Disord. 2007; 8: 27
        • Berger A
        • Dukes E
        • Martin S
        • Edelsberg J
        • Oster G
        Characteristics and healthcare costs of patients with fibromyalgia syndrome.
        Int J Clin Pract. 2007; 61: 1498-1508
        • Berna C
        • Leknes S
        • Holmes EA
        • Edwards RR
        • Goodwin GM
        • Tracey I
        Induction of depressed mood disrupts emotion regulation neurocircuitry and enhances pain unpleasantness.
        Biol Psychiatry. 2010; 67: 1083-1090
        • Bradley LA
        Psychiatric comorbidity in fibromyalgia.
        Curr Pain Headache Rep. 2005; 9: 79-86
        • Branco JC
        • Bannwarth B
        • Failde I
        • Abello Carbonell J
        • Blotman F
        • Spaeth M
        • Saraiva F
        • Nacci F
        • Thomas E
        • Caubere JP
        • Le Lay K
        • Taieb C
        • Matucci-Cerinic M
        Prevalence of fibromyalgia: A survey in five European countries.
        Semin Arthritis Rheum. 2010; 39: 448-453
        • Brazier JE
        • Harper R
        • Jones NM
        • O'Cathain A
        • Thomas KJ
        • Usherwood T
        • Westlake L
        Validating the SF-36 health survey questionnaire: New outcome measure for primary care.
        BMJ. 1992; 305: 160-164
        • Brummett CM
        • Goesling J
        • Tsodikov A
        • Meraj TS
        • Wasserman RA
        • Clauw DJ
        • Hassett 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
        • Buskila D
        Pediatric fibromyalgia.
        Rheum Dis Clin North Am. 2009; 35: 253-261
        • Buskila D
        • Atzeni F
        • Sarzi-Puttini P
        Etiology of fibromyalgia: The possible role of infection and vaccination.
        Autoimmun Rev. 2008; 8: 41-43
        • Buskila D
        • Neumann L
        • Vaisberg G
        • Alkalay D
        • Wolfe F
        Increased rates of fibromyalgia following cervical spine injury. A controlled study of 161 cases of traumatic injury [see comments].
        Arthritis Rheum. 1997; 40: 446-452
        • Buskila D
        • Press J
        • Gedalia A
        • Klein M
        • Neumann L
        • Boehm R
        • Sukenik S
        Assessment of nonarticular tenderness and prevalence of fibromyalgia in children.
        J Rheumatol. 1993; 20: 368-370
        • Buskila D
        • Sarzi-Puttini P
        • Ablin JN
        The genetics of fibromyalgia syndrome.
        Pharmacogenomics. 2007; 8: 67-74
        • Buskila D
        • Shnaider A
        • Neumann L
        • Zilberman D
        • Hilzenrat N
        • Sikuler E
        Fibromyalgia in hepatitis C virus infection. Another infectious disease relationship.
        Arch Intern Med. 1997; 157: 2497-2500
        • Calandre EP
        • Navajas-Rojas MA
        • Ballesteros J
        • Garcia-Carrillo J
        • Garcia-Leiva JM
        • Rico-Villademoros F
        Suicidal ideation in patients with fibromyalgia: A cross-sectional study.
        Pain Pract. 2015; 15: 168-174
        • Castori M
        • Morlino S
        • Celletti C
        • Ghibellini G
        • Bruschini M
        • Grammatico P
        • Blundo C
        • Camerota F
        Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.
        Am J Med Genet A. 2013; 161A: 2989-3004
        • Chalder T
        • Berelowitz G
        • Pawlikowska T
        • Watts L
        • Wessely S
        • Wright D
        • Wallace EP
        Development of a fatigue scale.
        J Psychosom Res. 1993; 37: 147-153
        • Choi BY
        • Oh HJ
        • Lee YJ
        • Song YW
        Prevalence and clinical impact of fibromyalgia in patients with primary Sjogren's syndrome.
        Clin Exp Rheumatol. 2016; 34: S9-S13
        • Choy E
        • Perrot S
        • Leon T
        • Kaplan J
        • Petersel D
        • Ginovker A
        • Kramer E
        A patient survey of the impact of fibromyalgia and the journey to diagnosis.
        BMC Health Serv Res. 2010; 10: 102
        • Ciampi de Andrade D
        • Maschietto M
        • Galhardoni R
        • Gouveia G
        • Chile T
        • Victorino Krepischi AC
        • Dale CS
        • Brunoni AR
        • Parravano DC
        • Cueva Moscoso AS
        • Raicher I
        • Kaziyama HHS
        • Teixeira MJ
        • Brentani HP
        Epigenetics insights into chronic pain: DNA hypomethylation in fibromyalgia-a controlled pilot-study.
        Pain. 2017; 158: 1473-1480
        • Clark P
        • Burgos-Vargas R
        • Medina-Palma C
        • Lavielle P
        • Marina FF
        Prevalence of fibromyalgia in children: A clinical study of Mexican children.
        J Rheumatol. 1998; 25: 2009-2014
        • Clark S
        • Tindall E
        • Bennett RM
        A double blind crossover trial of prednisone versus placebo in the treatment of fibrositis.
        J Rheumatol. 1985; 12: 980-983
        • Clauw DJ
        What is the meaning of “small fiber neuropathy” in fibromyalgia?.
        Pain. 2015; 156: 2115-2116
        • 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
        • Clauw DJ
        • Schmidt M
        • Radulovic D
        • Singer A
        • Katz P
        • Bresette J
        The relationship between fibromyalgia and interstitial cystitis.
        J Psychiatr Res. 1997; 31: 125-131
        • Coggon D
        • Ntani G
        • Palmer KT
        • Felli VE
        • Harari R
        • Barrero LH
        • Felknor SA
        • Gimeno D
        • Cattrell A
        • Vargas-Prada S
        • Bonzini M
        • Solidaki E
        • Merisalu E
        • Habib RR
        • Sadeghian F
        • Masood Kadir M
        • Warnakulasuriya SS
        • Matsudaira K
        • Nyantumbu B
        • Sim MR
        • Harcombe H
        • Cox K
        • Marziale MH
        • Sarquis LM
        • Harari F
        • Freire R
        • Harari N
        • Monroy MV
        • Quintana LA
        • Rojas M
        • Salazar Vega EJ
        • Harris EC
        • Serra C
        • Martinez JM
        • Delclos G
        • Benavides FG
        • Carugno M
        • Ferrario MM
        • Pesatori AC
        • Chatzi L
        • Bitsios P
        • Kogevinas M
        • Oha K
        • Sirk T
        • Sadeghian A
        • Peiris-John RJ
        • Sathiakumar N
        • Wickremasinghe AR
        • Yoshimura N
        • Kelsall HL
        • Hoe VC
        • Urquhart DM
        • Derrett S
        • McBride D
        • Herbison P
        • Gray A
        Patterns of multisite pain and associations with risk factors.
        Pain. 2013; 154: 1769-1777
        • Cohen H
        • Neumann L
        • Shore M
        • Amir M
        • Cassuto Y
        • Buskila D
        Autonomic dysfunction in patients with fibromyalgia: Application of power spectral analysis of heart rate variability [see comments].
        Semin Arthritis Rheum. 2000; 29: 217-227
        • Cook DB
        • Lange G
        • Ciccone DS
        • Liu WC
        • Steffener J
        • Natelson BH
        Functional imaging of pain in patients with primary fibromyalgia.
        J Rheumatol. 2004; 31: 364-378
        • Craig AD
        Interoception: The sense of the physiological condition of the body.
        Curr Opin Neurobiol. 2003; 13: 500-505
        • Craig AD
        Human feelings: Why are some more aware than others?.
        Trends Cogn Sci. 2004; 8: 239-241
        • Crofford LJ
        The hypothalamic-pituitary-adrenal stress axis in fibromyalgia and chronic fatigue syndrome.
        Zeitschrift fur Rheumatologie. 1998; 57: 67-71
        • Crofford LJ
        • Pillemer SR
        • Kalogeras KT
        • Cash JM
        • Michelson D
        • Kling MA
        • Sternberg EM
        • Gold PW
        • Chrousos GP
        • Wilder RL
        Hypothalamic-pituitary-adrenal axis perturbations in patients with fibromyalgia.
        Arthritis Rheum. 1994; 37: 1583-1592
        • Dean LE
        • Arnold L
        • Crofford L
        • Bennett R
        • Goldenberg D
        • Fitzcharles MA
        • Paiva ES
        • Staud R
        • Clauw D
        • Sarzi-Puttini P
        • Jones GT
        • Ayorinde A
        • Fluss E
        • Beasley M
        • Macfarlane GJ
        Impact of moving from a widespread to multisite pain definition on other fibromyalgia symptoms.
        Arthritis Care Res (Hoboken). 2017; 69: 1878-1886
        • Dehghan M
        • Schmidt-Wilcke T
        • Pfleiderer B
        • Eickhoff SB
        • Petzke F
        • Harris RE
        • Montoya P
        • Burgmer M
        Coordinate-based (ALE) meta-analysis of brain activation in patients with fibromyalgia.
        Hum Brain Mapp. 2016; 37: 1749-1758
        • Demitrack MA
        • Crofford LJ
        Evidence for and pathophysiologic implications of hypothalamic- pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome.
        Ann N.Y. Acad Sci. 1998; 840: 684-697
        • Di Stefano G
        • Celletti C
        • Baron R
        • Castori M
        • Di Franco M
        • La Cesa S
        • Leone C
        • Pepe A
        • Cruccu G
        • Truini A
        • Camerota F
        Central sensitization as the mechanism underlying pain in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type.
        Eur J Pain. 2016; 20: 1319-1325
        • Dias DN
        • Marques MA
        • Bettini SC
        • Paiva ED
        Prevalence of fibromyalgia in patients treated at the bariatric surgery outpatient clinic of Hospital de Clinicas do Parana - Curitiba.
        Rev Bras Reumatol. 2017; 57: 425-430
        • Diatchenko L
        • Fillingim RB
        • Smith SB
        • Maixner W
        The phenotypic and genetic signatures of common musculoskeletal pain conditions.
        Nat Rev Rheumatol. 2013; 9: 340-350
        • Dohrenbusch R
        • Sodhi H
        • Lamprecht J
        • Genth E
        Fibromyalgia as a disorder of perceptual organization? An analysis of acoustic stimulus processing in patients with widespread pain.
        Zeitschrift Fur Rheumatologie. 1997; 56: 334-341
        • Doppler K
        • Rittner HL
        • Deckart M
        • Sommer C
        Reduced dermal nerve fiber diameter in skin biopsies of patients with fibromyalgia.
        Pain. 2015; 156: 2319-2325
        • Dreyer L
        • Kendall S
        • Danneskiold-Samsoe B
        • Bartels EM
        • Bliddal H
        Mortality in a cohort of Danish patients with fibromyalgia: Increased frequency of suicide.
        Arthritis Rheum. 2010; 62: 3101-3108
        • Egloff N
        • von Kanel R
        • Muller V
        • Egle UT
        • Kokinogenis G
        • Lederbogen S
        • Durrer B
        • Stauber S
        Implications of proposed fibromyalgia criteria across other functional pain syndromes.
        Scand J Rheumatol. 2015; 44: 416-424
        • Epstein SA
        • Kay GG
        • Clauw DJ
        • Heaton R
        • Klein D
        • Krupp L
        • Kuck J
        • Leslie V
        • Masur D
        • Wagner M
        • Waid R
        • Zisook S
        Psychiatric disorders in patients with fibromyalgia. A multicenter investigation.
        Psychosomatics. 1999; 40: 57-63
        • Fan A
        • Pereira B
        • Tournadre A
        • Tatar Z
        • Malochet-Guinamand S
        • Mathieu S
        • Couderc M
        • Soubrier M
        • Dubost JJ
        Frequency of concomitant fibromyalgia in rheumatic diseases: Monocentric study of 691 patients.
        Semin Arthritis Rheum. 2017; 47: 129-132
        • Felson DT
        • Goldenberg DL
        The natural history of fibromyalgia.
        Arthritis Rheum. 1986; 29: 1522-1526
        • Fillingim RB
        • Bruehl S
        • Dworkin RH
        • Dworkin SF
        • Loeser JD
        • Turk DC
        • Widerstrom-Noga E
        • Arnold L
        • Bennett R
        • Edwards RR
        • Freeman R
        • Gewandter J
        • Hertz S
        • Hochberg M
        • Krane E
        • Mantyh PW
        • Markman J
        • Neogi T
        • Ohrbach R
        • Paice JA
        • Porreca F
        • Rappaport BA
        • Smith SM
        • Smith TJ
        • Sullivan MD
        • Verne GN
        • Wasan AD
        • Wesselmann U
        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
        • Fitzcharles MA
        • Ste-Marie PA
        • Rampakakis E
        • Sampalis JS
        • Shir Y
        Disability in fibromyalgia associates with symptom severity and occupation characteristics.
        J Rheumatol. 2016; 43: 931-936
        • Fluss E
        • Bond CM
        • Jones GT
        • Macfarlane GJ
        The re-evaluation of the measurement of pain in population-based epidemiological studies: The SHAMA study.
        Br J Pain. 2015; 9: 134-141
        • Foerster BR
        • Petrou M
        • Edden RA
        • Sundgren PC
        • Schmidt-Wilcke T
        • Lowe SE
        • Harte SE
        • Clauw DJ
        • Harris RE
        Reduced insular gamma-aminobutyric acid in fibromyalgia.
        Arthritis Rheum. 2012; 64: 579-583
        • Forseth KO
        • Gran JT
        • Husby G
        A population study of the incidence of fibromyalgia among women aged 26-55 yr.
        Br J Rheumatol. 1997; 36: 1318-1323
        • Fukuda K
        • Dobbins JG
        • Wilson LJ
        • Dunn RA
        • Wilcox K
        • Smallwood D
        An epidemiologic study of fatigue with relevance for the chronic fatigue syndrome.
        J Psychiatr Res. 1997; 31: 19-29
        • Fukuda K
        • Nisenbaum R
        • Stewart G
        • Thompson WW
        • Robin L
        • Washko RM
        • Noah DL
        • Barrett DH
        • Randall B
        • Herwaldt BL
        • Mawle AC
        • Reeves WC
        Chronic multisymptom illness affecting Air Force veterans of the Gulf War.
        JAMA. 1998; 280: 981-988
        • Geisser ME
        • Glass JM
        • Rajcevska LD
        • Clauw DJ
        • Williams DA
        • Kileny PR
        • Gracely RH
        A psychophysical study of auditory and pressure sensitivity in patients with fibromyalgia and healthy controls.
        J Pain. 2008; 9: 417-422
        • Geisser ME
        • Strader Donnell C
        • Petzke F
        • Gracely RH
        • Clauw DJ
        • Williams DA
        Comorbid somatic symptoms and functional status in patients with fibromyalgia and chronic fatigue syndrome: Sensory amplification as a common mechanism.
        Psychosomatics. 2008; 49: 235-242
        • Glass JM
        Review of cognitive dysfunction in fibromyalgia: A convergence on working memory and attentional control impairments.
        Rheum Dis Clin North Am. 2009; 35: 299-311
        • Glass JM
        • Williams DA
        • Fernandez-Sanchez ML
        • Kairys A
        • Barjola P
        • Heitzeg MM
        • Clauw DJ
        • Schmidt-Wilcke T
        Executive function in chronic pain patients and healthy controls: Different cortical activation during response inhibition in fibromyalgia.
        J Pain. 2011; 12: 1219-1229
        • Goldberg DP
        The detection of psychiatric illness by questionnaire; a technique for the identification and assessment of non-psychotic psychiatric illness.
        Oxford University Press, London1972
        • Gota CE
        • Kaouk S
        • Wilke WS
        Fibromyalgia and obesity: The association between body mass index and disability, depression, history of abuse, medications, and comorbidities.
        J Clin Rheumatol. 2015; 21: 289-295
        • Gracely RH
        • Grant MA
        • Giesecke T
        Evoked pain measures in fibromyalgia.
        Best Pract Res Clin Rheumatol. 2003; 17: 593-609
        • 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
        • Granges G
        • Zilko P
        • Littlejohn GO
        Fibromyalgia syndrome: Assessment of the severity of the condition 2 years after diagnosis.
        J Rheumatol. 1994; 21: 523-529
        • Gur A
        • Oktayoglu P
        Status of immune mediators in fibromyalgia.
        Curr Pain Headache Rep. 2008; 12: 175-181
        • Guymer EK
        • Littlejohn GO
        • Brand CK
        • Kwiatek RA
        Fibromyalgia onset has a high impact on work ability in Australians.
        Intern Med J. 2016; 46: 1069-1074
        • Hadker N
        • Garg S
        • Chandran AB
        • Crean SM
        • McNett M
        • Silverman SL
        Primary care physicians’ perceptions of the challenges and barriers in the timely diagnosis, treatment and management of fibromyalgia.
        Pain Res Manag. 2011; 16: 440-444
        • Haliloglu S
        • Carlioglu A
        • Akdeniz D
        • Karaaslan Y
        • Kosar A
        Fibromyalgia in patients with other rheumatic diseases: Prevalence and relationship with disease activity.
        Rheumatol Int. 2014; 34: 1275-1280
        • Harris RE
        Elevated excitatory neurotransmitter levels in the fibromyalgia brain.
        Arthritis Res Ther. 2010; 12: 141
        • Harris RE
        • Clauw DJ
        How do we know that the pain in fibromyalgia is "real"?.
        Curr Pain Headache Rep. 2006; 10: 403-407
        • Harris RE
        • Clauw DJ
        • Scott DJ
        • McLean SA
        • Gracely RH
        • Zubieta JK
        Decreased central mu-opioid receptor availability in fibromyalgia.
        J Neurosci. 2007; 27: 10000-10006
        • Harris RE
        • Napadow V
        • Huggins JP
        • Pauer L
        • Kim J
        • Hampson J
        • Sundgren PC
        • Foerster B
        • Petrou M
        • Schmidt-Wilcke T
        • Clauw DJ
        Pregabalin rectifies aberrant brain chemistry, connectivity, and functional response in chronic pain patients.
        Anesthesiology. 2013; 119: 1453-1464
        • Hays RD
        • Bjorner JB
        • Revicki DA
        • Spritzer KL
        • Cella D
        Development of physical and mental health summary scores from the patient-reported outcomes measurement information system (PROMIS) global items.
        Qual Life Res. 2009; 18: 873-880
        • Hazes JM
        • Hayton R
        • Silman AJ
        A reevaluation of the symptom of morning stiffness.
        J Rheumatol. 1993; 20: 1138-1142