Controversies and challenges in fibromyalgia: a review and a proposal

Abstract

Fibromyalgia (FM) is the most commonly encountered chronic widespread pain (CWP) condition in rheumatology. In comparison to inflammatory arthritis (IA), it can seem ill defined with no clear understanding of the pathology and therefore no specific targeted treatment. This inevitably raises controversies and challenges. However, this is an outdated view perpetuated by poor teaching of pain at undergraduate and postgraduate levels, and the perennial problem of advances in relevant cross-speciality knowledge penetrating speciality silos. Research has provided a better understanding of the aetiopathology and FM is now regarded as a centralized pain state. Effective treatment is possible utilizing a multidisciplinary approach combining nonpharmacologic and pharmacologic treatments rooted in a biopsychosocial model. This article will provide a review of the mechanisms, diagnosis and treatment of FM, focus on some ongoing contentious issues and propose a change to the diagnostic terminology.

Keywords

Fibromyalgia chronic widespread pain central sensitisation psychological factors diagnostic criteria

Introduction

Chronic widespread pain (CWP) syndromes have always been a challenge to patient and clinician alike. Every medical speciality has its own version and in rheumatology, fibromyalgia (FM) is the most commonly encountered. Furthermore, they often overlap with each other.^1–3

When a patient is describing their pain experience, the default position of the clinician is to accept this at face value and to avoid imposing personal value judgements. However, the clinician also has to strive to avoid overmedicalization, including medicalizing symptoms and signs including pain that fall within the normal spectrum and thereby ‘creating’ disease, and ignoring psychological factors that may drive symptom presentation and illness behaviour thereby leading to overinvestigation and overtreatment. This also has to be balanced against labelling symptoms and signs as psychological and missing treatable ‘organic’ disease.

These complex factors when dealing with CWP provide the background to some of the controversies and challenges faced when treating FM (see box 1), and to this review.

Box 1.

Challenges and controversies in fibromyalgia.

Controversies
• Whether FM should be considered a discrete entity or part of the CWP spectrum
• Differing clinical diagnostic criteria
• Mind–body dualism in the context of FM
• The WHO pain ladder was not designed for chronic noncancer pain and therefore its use in CWP should be discouraged
Challenges
• While understanding of CWP and FM continues to improve, the precise aetiopathogenesis remains unclear and continues to evolve
• Balancing the need to avoid overinvestigation and overmedicalization against missing other diagnoses or under treatment
• Recognizing the significant role of concurrent psychological diagnoses when present, and confronting the associated stigmatization
• FM in the presence of coexisting disease, for example IA
• Managing patient expectations and recognizing the limitations of the pharmacological treatment, particularly high strength opioids which should be avoided
• Development of services able to provide an individualized approach to FM/CWP rooted in a biopsychosocial model

CWP, chronic widespread pain; FM, fibromyalgia; IA, inflammatory arthritis; WHO, World Health Organization.

Epidemiology

There is ongoing debate whether FM should be considered as a discrete entity or as part of the CWP spectrum (see also ‘Definition and diagnostic criteria’ below). Therefore, the prevalence depends on whether FM or CWP are being investigated and which diagnostic criteria are utilized. The prevalence of CWP varies between 4% and 11% utilizing ‘Manchester’ or other CWP definitions.^4–6 The prevalence of FM in the general population varies between 2% and 8%.^7–10 There is a need for a standard definition of CWP/FM.⁶ The challenge will be how to achieve an expert consensus on the definition and diagnosis of CWP and FM. Meanwhile there will continue to be disparity in research structure and therefore difficulty in comparative research work, and the extent and burden of CWP/FM in the community remains unclear.

Pathogenesis

The overall perception and experience of pain is dependent on a balance of peripheral nociceptive inputs central descending facilitation and inhibition of nociceptive sensory processing, cortical processing and the consequent emotional, psychological, autonomic, hormonal and behavioural response.^1,7,11–14 The understanding of FM has moved away from a predominantly peripheral musculoskeletal pathology towards a centralized pain state within the CWP spectrum. This does not deny the contribution of peripheral nociceptive mechanisms, and it is likely that many different pain mechanisms contribute to the FM/CWP or ‘central’ pain prone phenotype.⁷ It rather emphasizes the role of maladaptive pain amplification through a variety of different mechanisms. The following outlines some of these.

Central pain mechanisms

There is an increasing body of neuroimaging study evidence in CWP and FM, and knowledge of central pain mechanisms; a full review is beyond the scope of this article. There are review articles available for more detailed reading.^15–19

There is evidence for enhanced brain responses to experimental pain stimuli.^20,21 Other work demonstrates altered resting state^22–24 and pain induced functional connectivity.^25,26 Changes in brain morphology have been demonstrated. Grey matter volume changes in several areas have been noted, including cingulofrontal, amygdalae, postcentral gyri, hippocampi, striatal, superior frontal, anterior cingulate and insular.^27–31 Furthermore, decreases in cortical thickness and overall brain volume are more pronounced in patients with longer exposure to FM pain.^28,29,32 There is functional neuroimaging evidence for impaired descending inhibition^28,33 and enhanced ascending facilitation or ‘wind up’.^15,34

Evidence of altered function of brain neurotransmission has been demonstrated, including decreased availability of µ-opioid receptors,³⁵ elevated insular glutamate and reduced γ-aminobutyric acid (GABA),^36,37 and alterations in cerebral glutamate/glutamine, inositol, choline and N-acetylaspartate levels compared with healthy controls.³⁸ Changes in levels of molecules associated with the neurotransmission of pain have been documented in FM. These include increased cerebrospinal fluid substance P, glutamate and nerve growth factor, and decreased serotonin, norepinephrine, dopamine and GABA.^7,11

These neuroplastic structural and functional changes may help to explain the transition from acute to chronic conditions and have implications for rehabilitation.^39,40

Peripheral mechanisms

Peripheral factors are likely to contribute to both the initiation and maintenance of the centralized pain state. These might include subtle inflammatory activity and changes to the inflammatory cytokine network and glial cell activity.⁷ There may be muscle nociceptive factors operating, such as peripheral ischaemia, microtrauma and enhanced nociceptor activity.^14,41

Musculoskeletal factors

Patients with FM often become physically inactive as a consequence of pain, and may develop a maladaptive posture and gait.^42,43 This can become reinforced by fear-avoidance behaviours and kinaesiophobia (fear of movement).^44,45 This may lead to marked physical deconditioning, further deterioration of posture and gait, worsening musculoskeletal fitness and tone with further deterioration in posture, gait and fitness in an ever declining vicious circle. Patients may therefore also present with enthesopathies, bursitis and tendinopathies secondary to maladapted posture, gait and deconditioning, for example trochanteric bursitis. However, the patient with apparent FM and recurrent enthesopathies and possible inflammatory signs or features in their history should prompt further review and investigation as necessary (see ‘Coexisting conditions’ below).

Sleep disturbance

Nonrestorative sleep and fatigue are common and distressing symptoms in FM. Studies demonstrate disruption to stage four non rapid eye movement sleep.⁴⁶ Sleep quality may be a mediator in the relationship between pain and emotional distress in some patients,⁴⁷ and patients with FM and poorer sleep have worse function and quality of life.⁴⁸

Other mechanisms

Other potential mechanisms include dysfunction of the hypothalamic–pituitary axis (HPA). The main HPA abnormalities documented in FM include low free cortisol levels in 24 h urine samples; loss of the normal circadian rhythm with elevated evening cortisol level; insulin-induced hypoglycaemia associated with an overproduction of pituitary adrenocorticotropic hormone (ACTH); low levels of growth hormone; and insufficient adrenal release of glucocorticoids to stimulation by ACTH.¹¹ Although studies have been conflicting, there is evidence for autonomic dysfunction in FM.^26,49 Sympathetic dysfunction has been consistently described and may explain some features.^50,51 Familial aggregation has been noted in FM and family members of patients with FM may also have a history of chronic pain. Therefore genetics may also play a role in susceptibility to chronic pain states through genes that play a role in the transmission and processing of pain.^7,52

Psychological factors

Psychosocial and behavioural issues can contribute to and modify the presentation and treatment of FM. Patients are more likely to suffer depression, anxiety, obsessive–compulsive disorder and post-traumatic stress disorder.^2,3,7 They may have a negative body image perception.^53,54 Catastophizing, reduced self-efficacy, hypervigilance and kinaesiophobia can be additional complicating factors.^2,7,47 The familial aggregation noted above could also be transmitted through modelling and learning. Unfortunately there is still a stigma attached to a psychological label, and patients may be reluctant to admit to such problems or consider psychological approaches. Some doctors may share similar stigmatizing attitudes with the potential result that the patient is overinvestigated, overmedicalized and undertreated psychologically.

In common with other CWP and ‘functional’ syndromes, FM is often subject to the mind–body dualism controversy.^3,55 Many patients with FM would meet the Diagnostic and Statistical Manual for Mental Disorders 5 criteria for somatic symptom disorder, but reliability and validity is questionable.^56,57 The increasing knowledge being gained from cognitive neuroscience is providing new insights into the psychiatric and psychological concepts, and can be used to support either stance. With the neuroscience revolution of the past few decades, it seems increasingly absurd to attempt to dissect a distressed chronic pain patient into either a psychological or organic disease state. If the science has shown us anything, it is that both factors are equally important, and that a biopsychosocial approach is required.^2,58

A more recent challenge is the effect of the internet and mass global communication. There is unlimited access to a wealth of health information and advice, good or bad, true or false. This may reinforce abnormal health beliefs, and patients may come to the clinic with preconceived internet based self diagnoses and demands for inappropriate or dubious treatments. Patients with FM/CWP are more likely to have health-related anxiety, and excessive internet use exacerbating health anxiety has been termed ‘cyberchondria’.^59,60

Definition and diagnostic criteria

The definition of FM continues to evolve reflecting the changes in understanding and shifts in diagnostic criteria. The American College of Rheumatology (ACR) 1990 diagnostic criteria required the presence of pain on both sides of the body and above and below the waist present for at least 3 months, with the presence of at least 11 out of a possible 18 tender points and not better explained by any other disorder.⁶¹ They are not intended to replace the 1990 criteria, but to address the changing face and definition of FMS. The newer 2010 ACR diagnostic criteria⁶² define FM as a CWP condition associated with fatigue, sleep and cognitive disturbance and a variety of somatic symptoms.

Challenges and controversies

Once the technique for tender point testing and their location is known, the 1990 criteria are simple to administer and score.⁶³ However, tender points are not unique to patients with FM and are associated with psychological distress and female sex independent of age.^11,64,65

The 2010 criteria utilizes a widespread pain index and symptom severity scale comprising rating for three symptoms (fatigue, sleep, cognitive) and somatic symptoms.⁶² Forty-one possible somatic symptoms are listed for consideration, but no detail is given on how to rate their presence as mild, moderate or severe, leaving this to the clinician. Some organizations have produced questionnaires for patient self administration, listing the criteria and all 41 somatic symptoms. However, the criteria were not intended for self administration, and the symptom severity score should not be assessed by listing the given examples and creating a tick list. Subsequently Wolfe produced a ‘How to use the new ACR FM diagnostic criteria’ document⁶³ covering these aspects in more detail. A modified version of the 2010 criteria has removed the physician’s estimate of the extent of somatic symptoms and substituted a sum of three specific self-reported symptoms, making it simpler to use and maintaining sensitivity.^66–68 Compared with the 1990 and 2010 criteria, the modified 2010 criteria identify a higher FM prevalence and a greater proportion of men with the condition.⁶⁹

As reflected by the changing ACR criteria, an ongoing controversy is whether FM should be considered as a discrete disorder or is better regarded as part of the spectrum of CWP.^49,70,71 It is well recognized that many chronic pain syndromes have overlapping features with each other,⁷² and many patients with FM may also have other chronic pain syndromes such as irritable bowel syndrome,⁷³ chronic fatigue,⁷⁴ migraine,⁷⁵ craniofacial pain,⁷⁶ chronic pelvic pain⁷⁷ and other chronic regional pain problems.^1,78 The 2010 criteria conceptualize core fibromyalgic symptoms as part of the spectrum of central pain sensitization,⁷ moving the diagnosis of FM towards the CWP continuum. Furthermore neuroimaging studies are providing increasing evidence for changes and dysfunction in central brain structures and mechanisms in FM¹⁵ and CWP.¹⁹

Presentation

There is a female preponderance in FM, which typically presents with chronic widespread musculoskeletal pain. Pain may be described as aching, burning or sore. Patients usually describe sleep disturbance and fatigue. Tactile sensitivity and generalized ‘tenderness’ is often displayed, and there may be complaints of general sensory sensitivity, for example to light, sound, smell etc.⁷⁹ A history of other chronic pain syndromes such as headache, migraine, noncardiac chest pain, heartburn, dysmenorrhoea, and irritable bowel syndrome may be present. Dyscognition or ‘fibro-fog’ is a common complaint.¹ Other symptoms can include paraesthesias, restless legs, morning stiffness, and sensation of tissue swelling.

Examination

The aim of the physical examination is to rule out any other potential conditions and confirm the diagnosis. Therefore, a full general medical examination is required with particular attention to the musculoskeletal system. ‘Red flag’ symptoms and signs suggest alternative diagnoses and require appropriate investigation. These include symptoms of significant weight change, fever, sleep apnoea or signs of significant muscle weakness or wasting, abnormal gait, focal neurological signs, abnormal reflexes, synovitis or joint swelling, rashes, lymphadenopathy and cardiac murmurs.

Depending upon the diagnostic criteria utilized, various questionnaires and a tender point count may need to be administered.

Differential diagnosis

This includes:

inflammatory arthritis (IA) and spondylo-arthropathies,

autoimmune connective tissue disease,

myositis,

myopathies,

primary generalized osteoarthritis,

polymyalgia rheumatica,

hypothyroidism,

malignancies.

Coexisting conditions: considerations and challenges

FM can coexist with other conditions such as osteoarthritis and IA.^11,80–82 Joint hypermobility syndrome is increasingly recognized in the context of FM, and vice versa.^83–89 It can be challenging to both the doctor and patient to work out which aspects of their pain are due to which condition.²³ Patients with IA and FM can be at risk of overtreatment of one condition and undertreatment of the other in either direction, and the patient with FM who subsequently develops an IA may be at risk of delayed diagnosis. Patients with rheumatoid arthritis (RA) and FM have higher Disease Activity Score (DAS28) scores^90,91 and worse outcomes.⁹²

The various inflammatory outcome measures utilized such as DAS28 in RA, Bath Ankylosing Spondylitis Disease Activity Index and Psoriatic Arthritis Response Criteria scores require patient pain ratings and cannot differentiate inflammatory from noninflammatory pain, and clinical judgement is still required.^93–96 In DAS28 scores, the tender count has been noted as a particular issue.^82,93,95,97 A patient with CWP/FM is likely to rate any measures of pain and effect on quality of life measures consistently very highly, particularly if there is associated anxiety or depression.⁹⁷ Therefore patients are at risk of having apparently ‘failed’ a Disease modifying anti-rheumatic drug (DMARD) treatment when in fact it was having a beneficial effect. Expensive DMARD medications may be subject to forms of rationing in some countries. Thus there is the potential for some patients with active IA and CWP which was not recognized to have apparently failed all available biologic medications due to the inadequacy of currently used outcome measures; these patients may run out of treatment options and not be eligible for further biologic treatment. In this scenario, the recognition and treatment of the CWP becomes particularly important.

A challenge in IA clinics is to recognize coexistent FM/CWP so that this can be appropriately managed and considered when completing outcome measures. An index of suspicion should be maintained in the patient with IA when there is a consistently high tender joint count but minimal swollen joint count, very high pain visual analog scale (VAS) but minimal elevation of inflammatory markers.^23,95 A further challenge is to improve outcome measures such that coexistent FM/CWP can be taken into account.

Investigations

Laboratory investigations and imaging are directed towards the exclusion of other conditions according to the history and examination findings. A challenge in CWP/FM is to avoid overinvestigation of polysymptomatology, and multiple referrals feeding into revolving door ‘doctor-shopping’, reinforcement of health anxiety^59,60 and potential iatrogenic harm.^98,99 This has to be balanced against appropriate investigation and referral. This is often particularly difficult for doctors when faced by the demanding patient with several pages printed out from the internet.

Another area of controversy with relevance to FM is vitamin D. Low vitamin D is recognized in association with CWP and FM and there is ongoing debate concerning its potential role.^100,101 It remains unclear what is a normal level of vitamin D, and when it should be replaced or supplemented.^102,103 However, when there is clear vitamin D deficiency there is general consensus that this should be appropriately treated.

Treatment

There are published guidelines for the treatment of FM, the main ones being European League Against Rheumatism (EULAR) 2008, revised 2016,^104,105 American Pain Society (APS) 2005,¹⁰⁶ German Association of the Scientific Medical Societies (AWMF) 2012,^58,107 Israeli¹⁰⁸ and Canadian Pain Society 2013.¹⁰⁹ While there is heterogeneity, they do agree that the main treatment should be multidisciplinary with a nonpharmacologic focus, balancing cautious pharmacologic input when required with patient education and engagement.^7,110–112 There are differences between the guidelines on the strength of recommendations for pharmacologic therapies, and on the types of nonpharmacologic therapies. The recently revised EULAR guidelines note that many recommendations were based upon expert opinion, and in the revision have recommendations underpinned by high-quality reviews and meta-analyses.¹⁰⁵

The following is a summary of treatment strategies (see also Figure 1), and readers are referred to the individual guidelines, which also provide the evidence base for their recommendations.

Figure 1.

Treatment approaches for the patient with FM.

Nonpharmacologic therapies

The most studied nonpharmacologic therapies which are all recommended by the guidelines^105–109 are exercise, patient education and psychological treatment, particularly cognitive behavioural therapy (CBT). All encourage a multidisciplinary approach. Patients with more severe disease and those whose condition fails to respond to initial treatment will need an individualized approach rooted in a holistic biopsychosocial model.

The use of complementary and alternative medicine (CAM) continues to be challenging and controversial, and all the guidelines mention it. The Canadian guidelines encourage patients to discuss CAM, and that the practitioner should be tolerant of disclosure but inform them that there is currently insufficient evidence to recommend CAM for FM. The revised EULAR guidelines provide recommendations based upon available evidence.

Some patients will struggle to make or maintain progress. They may require specialist referral¹¹¹ such as rheumatology, psychology, psychiatry or to a pain clinic for further advice and consideration of an outpatient or inpatient based pain management programme. This provides more intensive input aimed to improve long-term self-managed coping skills.¹¹³

Pharmacologic

The aim is to provide a balance of medications that help the patient to cope with their symptoms, complementing the nonpharmacologic therapies and patient education (Figure 1). The evidence base is poor. Patient expectations should be managed, as although a symptom-based medication approach may ameliorate symptoms, it will not ‘cure’ the pain. Medication will require cautious dose escalation and monitoring of short- and long-term side effects, and discontinuation of ineffective drugs or those with intolerable side effects. Few medications are licensed for FM and many continue to be prescribed off license.

Neuromodulatory medications

These include the antidepressant (tricyclic, selective serotonin norepinephrine uptake inhibitor (SNRI), serotonin selective reuptake inhibitor (SSRI)] and anticonvulsant classes of medications. Amitriptyline has some evidence¹¹⁰ and is recommended in all the guidelines,¹¹⁴ and therefore is worthwhile considering particularly for patients with FM and sleep disturbance. The serotonin norepinephrine uptake inhibitors (SNRIs) have better evidence than SSRIs,⁷ and may benefit from their effect on both serotonin and noradrenaline on the descending modulatory pathways. Gabapentin and pregabalin are also commonly used in FM and CWP.

Analgesic medication

The use of opioids in CWP is an ongoing controversy¹¹⁵ and the guidelines vary in their recommendations. Weak nonopioids such as paracetamol, or paracetamol combined with a weak opioid such as codeine, are often used as adjuvant medication, as per the World Health Organization (WHO) pain ladder. However, this approach has limitations in FM (see below). NSAIDs are often ineffective, and the potential adverse effects of gastrointestinal ulceration and cardiovascular risk have to be considered. Tramadol may be beneficial for some patients but the problems associated with opioid use and its potential interaction with SNRIs to cause the serotonin syndrome must be considered.

Strong opioids are not recommended by the German and EULAR guidelines, discouraged by the Canadian guidelines and only considered if other medicinal and nonmedicinal therapies have been exhausted in the APS guidelines. They are often poorly effective for the pain and there are significant potential long-term adverse effects including increased risk of mortality,^116,117 reduction of testosterone¹¹⁸ and opiate-induced hyperalgesia.¹¹⁹ The WHO pain ladder was designed for cancer pain, and not intended for use in chronic pain. Thus the concept and particularly the opiate rung is not appropriate for CWP/FM.^117,120

If a patient is gaining various medications at increasing doses for little further impact on pain but accruing short- and long-term adverse effects, or is on high-dose strong opioids then referral to a pain clinic should be considered.

Proposal

There is good evidence that FM should be regarded as part of the CWP spectrum. This provides a clearer understanding of the condition, the common overlap with other chronic pain conditions and that it has to be treated accordingly for both the musculoskeletal aspects and in a broader holistic biopsychosocial pain management model. This approach is already being championed internationally with proposals on how to construct and optimize appropriate clinical services for bodily distress syndromes/medically unexplained symptom clinics.¹²¹ The CWP/central sensitization model has implications for the diagnostic labels utilized. It is no longer appropriate to continue diagnosing chronic pain conditions in isolation of each other or their CWP component. This denies the increasing body of research evidence, and potentially denies the patient recognition and treatment of their CWP.

Therefore, a proposal and a challenge to the wider medical community when seeing a patient with CWP is to consider changing the diagnostic terminology from specific isolated chronic pain conditions to a central CWP label with a descriptive subcategory. For example, chronic pain and irritable bowel syndrome become CWP-IBS predominant; a patient with chronic pain, IBS and CFS becomes CWP-IBS, fatigue predominant. Rheumatologists should consider taking a lead and use the diagnosis of CWP-FM predominant. This may set an example for other specialities to follow.

Why is this proposal relevant, and how should it be considered and evaluated? It could be considered as another step in the ongoing evolution of the Descartian mind–body dualism debate that continues to challenge medicine through the ages. If it provides a better description of the patient with CWP/FM and thus allows for a fuller holistic approach to that patient, then it should be seen as relevant to current practice and adopted. Only time and the clinical community on an individual and wider level can determine whether it is something they wish to adopt. Even if this proposal does nothing other than promote further debate, discussion and stimulation of thought when faced by a patient with CWP/FM, it will have been worthwhile.

Conclusion

While the teaching of pain at undergraduate and postgraduate levels remains suboptimal¹²² and rheumatology moves towards an increasing immunological focus, many trainee and experienced rheumatologists can feel overwhelmed when faced by a distressed patient with fibromyalgia. However, there is now much improved understanding of FM and other centralized pain states (see Box 2). Effective treatment is possible utilizing combined nonpharmacologic and pharmacologic approaches rooted in a biopsychosocial model.

Box 2.

Conclusions.

• Central and peripheral mechanisms contribute to the development of FM and other centralized pain states
• Optimal clinical diagnostic criteria remain elusive and continue to evolve
• Psychological conditions when present can significantly influence the presentation and treatment of FM
• Effective treatment is possible utilizing combined nonpharmacologic and pharmacologic approaches rooted in a biopsychosocial model

FM, fibromyalgia.

Footnotes

Acknowledgements

Thanks are due to Dr Piper, Dr Wolman and Professor Ikkos for their review and suggestions.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The author declares that there is no conflict of interest.

References

Yunus

. Fibromyalgia and overlapping disorders: the unifying concept of central sensitivity syndromes. Semin Arthritis Rheum 2007; 36(6): 339–356.

Adams

Turk

. Psychosocial factors and central sensitivity syndromes. Curr Rheumatol Rev 2015; 11(2): 96–108.

Hudson

Pope

. The concept of affective spectrum disorder: relationship to fibromyalgia and other syndromes of chronic fatigue and chronic muscle pain. Baillieres Clin Rheumatol 1994; 8(4): 839–856.

Hunt

Silman

Benjamin

. The prevalence and associated features of chronic widespread pain in the community using the ‘Manchester’ definition of chronic widespread pain. Rheumatology (Oxford) 1999; 38(3): 275–279.

Macfarlane

. Generalized pain, fibromyalgia and regional pain: an epidemiological view. Baillieres Best Pract Res Clin Rheumatol 1999; 13(3): 403–414.

Butler

Landmark

Glette

. Chronic widespread pain – the need for a standard definition. Pain 2016; 157(3): 541–543.

Clauw

. Fibromyalgia: a clinical review. JAMA 2014; 311(15): 1547–1555.

Neumann

Buskila

. Epidemiology of fibromyalgia. Curr Pain Headache Rep 2003; 7(5): 362–368.

Vincent

Lahr

Wolfe

. Prevalence of fibromyalgia: a population-based study in Olmsted County, Minnesota, utilizing the Rochester Epidemiology Project. Arthritis Care Res (Hoboken) 2013; 65(5): 786–792.

10.

Wolfe

Ross

Anderson

. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995; 38(1): 19–28.

11.

Choy

. Fibromyalgia Syndrome, 2nd ed. Oxford Rheumatology Library. Oxford: Oxford University Press, 2015.

12.

Clauw

. Diagnosing and treating chronic musculoskeletal pain based on the underlying mechanism(s). Best Pract Res Clin Rheumatol 2015; 29(1): 6–19.

13.

Smith

Harris

Clauw

. Fibromyalgia: an afferent processing disorder leading to a complex pain generalized syndrome. Pain Physician 2011; 14(2): E217–E245.

14.

Vierck

Jr.

Mechanisms underlying development of spatially distributed chronic pain (fibromyalgia). Pain 2006; 124(3): 242–263.

15.

Cagnie

Coppieters

Denecker

. Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI. Semin Arthritis Rheum 2014; 44(1): 68–75.

16.

Napadow

Harris

. What has functional connectivity and chemical neuroimaging in fibromyalgia taught us about the mechanisms and management of ‘centralized’ pain? Arthritis Res Ther 2014; 16(5): 425.

17.

Nebel

Gracely

. Neuroimaging of fibromyalgia. Rheum Dis Clin North Am 2009; 35(2): 313–327.

18.

Petersel

Dror

Cheung

. Central amplification and fibromyalgia: disorder of pain processing. J Neurosci Res 2011; 89(1): 29–34.

19.

Walitt

Ceko

Gracely

. Neuroimaging of central sensitivity syndromes: key insights from the scientific literature. Curr Rheumatol Rev 2016; 12(1): 55–87.

20.

Cook

Lange

Ciccone

. Functional imaging of pain in patients with primary fibromyalgia. J Rheumatol 2004; 31(2): 364–378.

21.

Gracely

Petzke

Wolf

. Functional magnetic resonance imaging evidence of augmented pain processing in fibromyalgia. Arthritis Rheum 2002; 46(5): 1333–1343.

22.

Napadow

LaCount

Park

. Intrinsic brain connectivity in fibromyalgia is associated with chronic pain intensity. Arthritis Rheum 2010; 62(8): 2545–2555.

23.

Andersson

Svensson

Bergman

. Chronic widespread pain in patients with rheumatoid arthritis and the relation between pain and disease activity measures over the first 5 years. J Rheumatol 2013; 40(12): 1977–1985.

24.

Ichesco

Puiu

Hampson

. Altered resting state connectivity of the insular cortex in individuals with fibromyalgia. J Pain 2014; 15(8): 815–826.e1.

25.

Ichesco

Puiu

Hampson

. Altered fMRI resting-state connectivity in individuals with fibromyalgia on acute pain stimulation. Eur J Pain 2016; 20(7): 1079–1089.

26.

Kim

Loggia

Cahalan

. The somatosensory link in fibromyalgia: functional connectivity of the primary somatosensory cortex is altered by sustained pain and is associated with clinical/autonomic dysfunction. Arthritis Rheumatol 2015; 67(5): 1395–1405.

27.

Burgmer

Gaubitz

Konrad

. Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia. Psychosom Med 2009; 71(5): 566–573.

28.

Jensen

Srinivasan

Spaeth

. Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia pain. Arthritis Rheum 2013; 65(12): 3293–3303.

29.

Kuchinad

Schweinhardt

Seminowicz

. Accelerated brain gray matter loss in fibromyalgia patients: premature aging of the brain? J Neurosci 2007; 27(15): 4004–4007.

30.

Schmidt-Wilcke

Luerding

Weigand

. Striatal grey matter increase in patients suffering from fibromyalgia – a voxel-based morphometry study. Pain 2007; 132(Suppl. 1): S109–S116.

31.

Lutz

Jäger

de Quervain

. White and gray matter abnormalities in the brain of patients with fibromyalgia: a diffusion-tensor and volumetric imaging study. Arthritis Rheum 2008; 58(12): 3960–3969.

32.

Bernardy

Füber

Köllner

. Efficacy of cognitive-behavioral therapies in fibromyalgia syndrome – a systematic review and metaanalysis of randomized controlled trials. J Rheumatol 2010; 37(10): 1991–2005.

33.

Jensen

Kosek

Petzke

. Evidence of dysfunctional pain inhibition in fibromyalgia reflected in rACC during provoked pain. Pain 2009; 144(1–2): 95–100.

34.

Staud

Price

Robinson

. Maintenance of windup of second pain requires less frequent stimulation in fibromyalgia patients compared to normal controls. Pain 2004; 110(3): 689–696.

35.

Harris

Clauw

Scott

. Decreased central mu-opioid receptor availability in fibromyalgia. J Neurosci 2007; 27(37): 10000–10006.

36.

Foerster

Petrou

Edden

. Reduced insular gamma-aminobutyric acid in fibromyalgia. Arthritis Rheum 2012; 64(2): 579–583.

37.

Harris

Sundgren

Craig

. Elevated insular glutamate in fibromyalgia is associated with experimental pain. Arthritis Rheum 2009; 60(10): 3146–3152.

38.

Fayed

Garcia-Campayo

Magallón

. Localized 1H-NMR spectroscopy in patients with fibromyalgia: a controlled study of changes in cerebral glutamate/glutamine, inositol, choline, and N-acetylaspartate. Arthritis Res Ther 2010; 12(4): R134.

39.

Flor

. Cortical reorganisation and chronic pain: implications for rehabilitation. J Rehabil Med 2003; (Suppl. 41): 66–72.

40.

Pelletier

Higgins

Bourbonnais

. Is neuroplasticity in the central nervous system the missing link to our understanding of chronic musculoskeletal disorders? BMC Musculoskelet Disord 2015; 16: 25.

41.

Staud

Weyl

Bartley

. Analgesic and anti-hyperalgesic effects of muscle injections with lidocaine or saline in patients with fibromyalgia syndrome. Eur J Pain 2014; 18(6): 803–812.

42.

Vaillant

Pissety

Martinez

. Subjects with fibromyalgia syndrome have a reduction of balance performance. Ann Phys Rehabil Med 2016; (Suppl. 59): e111–e112.

43.

Heredia-Jimenez

Orantes-Gonzalez

Soto-Hermoso

. Variability of gait, bilateral coordination, and asymmetry in women with fibromyalgia. Gait Posture 2016; 45: 41–44.

44.

Palstam

Larsson

Löfgren

. Decrease of fear avoidance beliefs following person-centered progressive resistance exercise contributes to reduced pain disability in women with fibromyalgia: secondary exploratory analyses from a randomized controlled trial. Arthritis Res Ther 2016; 18(1): 116.

45.

Nijs

Roussel

Van Oosterwijck

. Fear of movement and avoidance behaviour toward physical activity in chronic-fatigue syndrome and fibromyalgia: state of the art and implications for clinical practice. Clin Rheumatol 2013; 32(8): 1121–1129.

46.

Moldofsky

. The significance, assessment, and management of nonrestorative sleep in fibromyalgia syndrome. CNS Spectr 2008; 13(Suppl. 5): 22–26.

47.

Miro

Martínez

Sánchez

. When is pain related to emotional distress and daily functioning in fibromyalgia syndrome? The mediating roles of self-efficacy and sleep quality. Br J Health Psychol 2011; 16(4): 799–814.

48.

Liedberg

Bjork

Borsbo

. Self-reported nonrestorative sleep in fibromyalgia – relationship to impairments of body functions, personal function factors, and quality of life. J Pain Res 2015; 8: 499–505.

49.

Cohen

. Is fibromyalgia a distinct clinical entity? The disapproving rheumatologist’s evidence. Baillieres Best Pract Res Clin Rheumatol 1999; 13(3): 421–425.

50.

Eisinger

. Dysautonomia, fibromyalgia and reflex dystrophy. Arthritis Res Ther 2007; 9(4): 105.

51.

Martinez-Lavin

. Biology and therapy of fibromyalgia. Stress, the stress response system, and fibromyalgia. Arthritis Res Ther 2007; 9(4): 216.

52.

Ablin

Buskila

. Update on the genetics of the fibromyalgia syndrome. Best Pract Res Clin Rheumatol 2015; 29(1): 20–28.

53.

Akkaya

Atalay

. Relationship between the body image and level of pain, functional status, severity of depression, and quality of life in patients with fibromyalgia syndrome. Clin Rheumatol 2012; 31(6):983–988.

54.

Boyington

Schoster

Callahan

. Comparisons of body image perceptions of a sample of black and white women with rheumatoid arthritis and fibromyalgia in the US. Open Rheumatol J 2015; 9: 1–7.

55.

Merskey

. Social influences on the concept of fibromyalgia. CNS Spectr 2008; 13(Suppl. 5): 18–21.

56.

Hauser

Henningsen

. Fibromyalgia syndrome: a somatoform disorder? Eur J Pain 2014; 18(8): 1052–1059.

57.

Wolfe

Walitt

Katz

. Symptoms, the nature of fibromyalgia, and Diagnostic and Statistical Manual 5 (DSM-5) defined mental illness in patients with rheumatoid arthritis and fibromyalgia. PLoS One 2014; 9(2): e88740.

58.

Hauser

Arnold

Eich

. Management of fibromyalgia syndrome – an interdisciplinary evidence-based guideline. Ger Med Sci 2008; 6: Doc14.

59.

Fergus

. Cyberchondria and intolerance of uncertainty: examining when individuals experience health anxiety in response to Internet searches for medical information. Cyberpsychol Behav Soc Netw 2013; 16(10): 735–739.

60.

Fergus

Dolan

. Problematic internet use and internet searches for medical information: the role of health anxiety. Cyberpsychol Behav Soc Netw 2014; 17(12): 761–765.

61.

Wolfe

Smythe

Yunus

. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990; 33(2): 160–172.

62.

Wolfe

Clauw

Fitzcharles

. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken) 2010; 62(5): 600–610.

63.

Wolfe

. How to use the new American College of Rheumatology fibromyalgia diagnostic criteria [letter]. Arthritis Care Res (Hoboken) 2011; 63(7): 1073–1074.

64.

Wolfe

. The relation between tender points and fibromyalgia symptom variables: evidence that fibromyalgia is not a discrete disorder in the clinic. Ann Rheum Dis 1997; 56(4): 268–271.

65.

Brown

Mulveya

Cordingleya

. The relationship between psychological distress and multiple tender points across the adult lifespan. Arch Gerontol Geriatr 2016; 63: 102–107.

66.

Wolfe

Clauw

Fitzcharles

. Fibromyalgia criteria and severity scales for clinical and epidemiological studies: a modification of the ACR preliminary diagnostic criteria for fibromyalgia. J Rheumatol 2011; 38(6): 1113–1122.

67.

Bennett

Friend

Marcus

. 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(9): 1364–1373.

68.

Ferrari

Russell

. A questionnaire using the modified 2010 American College of Rheumatology criteria for fibromyalgia: specificity and sensitivity in clinical practice. J Rheumatol 2013; 40(9): 1590–1595.

69.

Jones

Atzeni

Beasley

. The prevalence of fibromyalgia in the general population: a comparison of the American College of Rheumatology 1990, 2010, and modified 2010 classification criteria. Arthritis Rheumatol 2015; 67(2): 568–575.

70.

Fitzcharles

. Is fibromyalgia a distinct clinical entity? The approving rheumatologist’s evidence. Baillieres Best Pract Res Clin Rheumatol 1999; 13(3): 437–443.

71.

Makela

. Is fibromyalgia a distinct clinical entity? The epidemiologist’s evidence. Baillieres Best Pract Res Clin Rheumatol 1999; 13(3): 415–419.

72.

Aaron

Buchwald

. A review of the evidence for overlap among unexplained clinical conditions. Ann Intern Med 2001; 134(9 Pt 2): 868–881.

73.

Kibune Nagasako

Garcia Montes

Silva Lorena

. Irritable bowel syndrome subtypes: clinical and psychological features, body mass index and comorbidities. Rev Esp Enferm Dig 2016; 108(2): 59–64.

74.

Schmaling

Betterton

. Neurocognitive complaints and functional status among patients with chronic fatigue syndrome and fibromyalgia. Qual Life Res 2015; 25(5): 1257–1263.

75.

de Tommaso

Sciruicchio

. Migraine and central sensitization: clinical features, main comorbidities and therapeutic perspectives. Curr Rheumatol Rev 2015; 12(2): 113–126.

76.

Di Venere

Corsalini

Stefanachi

. Quality of life in fibromyalgia patients with craniomandibular disorders. Open Dent J 2015; 9: 9–14.

77.

Sanses

Chelimsky

McCabe

. The pelvis and beyond: musculoskeletal tender points in women with chronic pelvic pain. Clin J Pain 2015; 32(8): 659–665.

78.

Williams

Clauw

. Understanding fibromyalgia: lessons from the broader pain research community. J Pain 2009; 10(8): 777–791.

79.

Wilbarger

Cook

. Multisensory hypersensitivity in women with fibromyalgia: implications for well being and intervention. Arch Phys Med Rehabil 2011; 92(4): 653–656.

80.

Haliloglu

Carlioglu

Akdeniz

. Fibromyalgia in patients with other rheumatic diseases: prevalence and relationship with disease activity. Rheumatol Int 2014; 34(9): 1275–1280.

81.

Atzeni

Cazzola

Benucci

. Chronic widespread pain in the spectrum of rheumatological diseases. Best Pract Res Clin Rheumatol 2011; 25(2): 165–171.

82.

Coury

Rossat

Tebib

. Rheumatoid arthritis and fibromyalgia: a frequent unrelated association complicating disease management. J Rheumatol 2009; 36(1): 58–62.

83.

Acasuso-Diaz

Collantes-Estevez

. Joint hypermobility in patients with fibromyalgia syndrome. Arthritis Care Res 1998; 11(1): 39–42.

84.

Fitzcharles

. Is hypermobility a factor in fibromyalgia? J Rheumatol 2000; 27(7): 1587–1589.

85.

Holman

. Is hypermobility a factor in fibromyalgia? J Rheumatol 2002; 29(2): 396–398.

86.

Karaaslan

Haznedaroglu

Ozturk

. Joint hypermobility and primary fibromyalgia: a clinical enigma. J Rheumatol 2000; 27(7): 1774–1776.

87.

Ofluoglu

Gunduz

Kul-Panza

. Hypermobility in women with fibromyalgia syndrome. Clin Rheumatol 2006; 25(3): 291–293.

88.

Sendur

Gurer

Bozbas

. The frequency of hypermobility and its relationship with clinical findings of fibromyalgia patients. Clin Rheumatol 2007; 26(4): 485–487.

89.

Ting

Hashkes

Schikler

. The role of benign joint hypermobility in the pain experience in Juvenile Fibromyalgia: an observational study. Pediatr Rheumatol Online J 2012; 10(1): 16.

90.

Abbasi

Haidri

. Fibromyalgia complicating disease management in rheumatoid arthritis. J Coll Physicians Surg Pak 2014; 24(6): 424–427.

91.

Zammurrad

Munir

Farooqi

. Disease activity score in rheumatoid arthritis with or without secondary fibromyalgia. J Coll Physicians Surg Pak 2013; 23(6): 413–417.

92.

Duran

Combe

Niu

. The effect on treatment response of fibromyalgic symptoms in early rheumatoid arthritis patients: results from the ESPOIR cohort. Rheumatology (Oxford) 2015; 54(12): 2166–2170.

93.

Makinen

Hannonen

. How to assess patients with rheumatoid arthritis and concomitant fibromyalgia? J Rheumatol 2009; 36(1): 9–11.

94.

Taylor

Harrison

Highton

. Disease Activity Score 28-ESR bears a similar relationship to treatment decisions across different rheumatologists, but misclassification is too frequent to replace physician judgement. Rheumatology (Oxford) 2008; 47(4): 514–518.

95.

Ton

Bakker

Verstappen

. Look beyond the disease activity score of 28 joints (DAS28): tender points influence the DAS28 in patients with rheumatoid arthritis. J Rheumatol 2012; 39(1): 22–27.

96.

Wolfe

. Fibromyalgianess. Arthritis Rheum 2009; 61(6): 715–716.

97.

Leeb

Andel

Sautner

. The DAS28 in rheumatoid arthritis and fibromyalgia patients. Rheumatology (Oxford) 2004; 43(12): 1504–1507.

98.

Clarke

. Management of chronic pain. Can Fam Physician 1989; 35: 315–319.

99.

Rowlingson

Hamill

. Organization of a multidisciplinary pain center. Mt Sinai J Med 1991; 58(3): 267–272.

100.

Hsiao

Hung

Chang

. Is serum hypovitaminosis D associated with chronic widespread pain including fibromyalgia? A meta-analysis of observational studies. Pain Physician 2015; 18(5): E877–E887.

101.

McCabe

Pye

Mc Beth

. Low vitamin D and the risk of developing chronic widespread pain: results from the European male ageing study. BMC Musculoskelet Disord 2016; 17: 32.

102.

Binkley

Wiebe

. Clinical controversies in vitamin D: 25(OH)D measurement, target concentration, and supplementation. J Clin Densitom 2013; 16(4): 402–408.

103.

Stokes

Lammert

. Vitamin D supplementation: less controversy, more guidance needed. F1000Res 2016; 5.

104.

Carville

Arendt-Nielsen

Bliddal

. EULAR evidence-based recommendations for the management of fibromyalgia syndrome. Ann Rheum Dis 2008; 67(4): 536–541.

105.

Macfarlane

Kronisch

Dean

. EULAR revised recommendations for the management of fibromyalgia.Annals of the Rheumatic Diseases 2016;In press.

106.

Burckhardt

Goldenberg

Crofford

. Guideline for the management of fibromyalgia syndrome pain in adults and children, APS clinical practice guidelines series, no. 4. Glenview, IL: American Pain Society.

107.

Eich

Häuser

Arnold

. Fibromyalgia syndrome. Definition, classification, clinical diagnosis and prognosis. Schmerz 2012; 26(3): 247–258.

108.

Ablin

Amital

Ehrenfeld

. Guidelines for the diagnosis and treatment of the fibromyalgia syndrome. Harefuah 2013; 152(12): 742–747, 751, 750.

109.

Fitzcharles

Ste-Marie

Goldenberg

. 2012 Canadian guidelines for the diagnosis and management of fibromyalgia syndrome: executive summary. Pain Res Manag 2013; 18(3): 119–126.

110.

Angel Garcia

Martinez Nicolas

Saturno Hernandez

. Clinical approach to fibromyalgia: synthesis of evidence-based recommendations, a systematic review. Rheumatol Clin 2015; 12(2): 65–71.

111.

Goldenberg

Burckhardt

Crofford

. Management of fibromyalgia syndrome. JAMA 2004; 292(19): 2388–2395.

112.

Hauser

Thieme

Turk

. Guidelines on the management of fibromyalgia syndrome – a systematic review. Eur J Pain 2010; 14(1): 5–10.

113.

Society

. Guidelines for pain management programmes for adults: an evidence-based review prepared on behalf of the British Pain Society. London: The British Pain Society, 2013.

114.

Dymon

. Fibromyalgia, in Ambulatort Care Self Assessment Program ACSAP Book 1 – Neurological and Psychiatric Care. American College of Clinical Pharmacy, 2015, pp. 5–15.

115.

Hauser

Petzke

Radbruch

. The opioid epidemic and the long-term opioid therapy for chronic noncancer pain revisited: a transatlantic perspective. Pain Manag 2016; 6(3): 249–263.

116.

Rudd

Aleshire

Zibbell

. Increases in drug and opioid overdose deaths – United States, 2000–2014. MMWR Morb Mortal Wkly Rep 2016; 64(50–51): 1378–1382.

117.

Ray

Chung

Murray

. Prescription of long-acting opioids and mortality in patients with chronic noncancer pain. JAMA 2016; 315(22): 2415–2423.

118.

Huang

Travison

Maggio

. Effects of testosterone replacement on metabolic and inflammatory markers in men with opioid-induced androgen deficiency. Clin Endocrinol (Oxf) 2016; 85(2): 232–238.

119.

Pryzbylkowski

. Opioid induced hyperalgesia. Pain Med 2015; 16(Suppl. 1): S32–S36.

120.

Ballantyne

Kalso

Stannard

. WHO analgesic ladder: a good concept gone astray. BMJ 2016; 352: i20.

121.

Creed

Henningsen

Byng

. Achieving optimal treatment organisation in different countries – suggestions for service development applicable across different healthcare systems. In: Creed

Henningsen

Fink

(eds) Medically unexplained symptoms, somatisation and bodily distress: developing better clinical services. Cambridge: Cambridge University Press, 2011, pp. 236–253.

122.

Briggs

Battelli

Gordon

. Current pain education within undergraduate medical studies across Europe: Advancing the Provision of Pain Education and Learning (APPEAL) study. BMJ Open 2015; 5(8): e006984.