Abstract
Introduction
Fibromyalgia (FM) is a clinical condition characterised by widespread and persistent pain with insomnia, fatigue, morning stiffness, cognitive symptoms (memory, concentration, attentional problems, mental slowness) and emotional problems (depression and anxiety).1,2 Its estimated prevalence is estimated at 2–4% of the general population.
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FM is a complex syndrome that most likely originates from a multi-axial interaction between psychological, neurological, endocrine and immune systems. A detailed review of these is beyond the scope of this article but a brief summary can be found in the literature (2018).3–6 Of interest here, FM shares with many forms of chronic pain an ill-defined construct. It has been described as an ‘enigma’ that has been under-, over- and mis-diagnosed.
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Hauser
The construct of FM: a historical perspective
The criteria for FM were originally developed in 1990 by the American College of Rheumatology (ACR) to reflect the prevalence of patients who presented to physicians complaining of chronic widespread pain and tender points.
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These criteria reflected the fact that, at that time, the consensus opinion about the pathophysiology of fibromyalgia (i.e. the underlying ‘disease’) was that it was primarily a musculoskeletal disorder. These criteria focussed primarily on the pain. In 2010, the criteria were modified to reflect co-morbid symptoms that contribute to the global suffering (and had been neglected in the past) included secondary symptoms such as depression, poor sleep, cognitive symptoms, and a minimum of three tender regions.
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In 2016 new criteria were introduced, which no longer required the clinician to examine the patient for tender points (the only clinically detectable feature suggesting possibly some underlying muscle abnormality or a feature of sensitisation). This was in response to the fact that most physicians in the United States (US) were making the diagnosis of FM without examining for tender points and thus inappropriately applying the 2010/2011 criteria to their patients.
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Also, the tender point examination was not viewed as a consistent, objective test but having a subjectivity and dependent upon each individual examiner’s opinions and abilities to detect them. The emphasis was on whether the patient had chronic widespread pain (using a scale) and on secondary symptom severity: a purely subjective approach. The results took into account aspects of the pain, impact of the condition on the person and severity. However, the evolution of criteria has not been ‘anchored’ to any pathophysiology or any biomarkers of disease mechanism. An evaluation of the validity of these criteria and the violations of validity analysis can be found in Figure 1 of Appendix A (taken from Kumbhare
Why the present construct of FM is unsatisfactory
One of the major threats to the present approach is that, when the criteria are applied, a highly heterogeneous sample can be obtained.
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This also arises from using criteria that were based upon freely self-reported symptoms and are applied by healthcare practitioners in different countries, socioeconomic groups and, most important, the lack of a reference standard against which the criteria are developed. Kumbhare
The inter-criteria agreements for the 1990 and 2010 FM criteria available in the literature.
FM, fibromyalgia.
The construct of FM: cutting edge of research
To our knowledge, current research suggests that central sensitisation may be an important part of the syndrome’s pathophysiology.15–17 The pattern of expanding pain characterised by hyperalgesia (increased pain in response to normally painful stimuli) and allodynia (pain in response to normally non-painful stimuli) strongly suggested supraspinal rather than purely spinal dysfunction. 18 Moreover, in addition to widespread pain and tenderness, patients experience other symptoms suggestive of central nervous system (CNS) involvement, including fatigue, sleep, mood and memory difficulties, and hyper-sensitivity to sensory stimuli. Specific dynamic quantitative sensory testing (QST) has demonstrated other CNS pain processing abnormalities, including an increase in facilitatory activity (increased wind-up or temporal summation) and decreased descending analgesic activity [conditioned pain modulation (CPM)] as contributory mechanisms to CNS-mediated pain amplification. 19 Ideally, the criteria should include features of this construct.
Possible biomarkers for FM
In the ideal situation, a valid biomarker correlates, both in its level and changes, with clinical outcome. Validation of an outcome measure is far from a simple issue, and proper statistical techniques should be adopted. 20 The same holds for biomarkers. Their validation can be accomplished only by performing a number of therapies on a number of independent cohorts: an enormous work. 21
To make things even more difficult, there are a number of candidate biomarkers for FM. These include blood-borne biomarkers, imaging, neurophysiology measures and polygenomics assessments. A detailed systematic review is beyond the scope of this article. Kumbhare
Potential methodology against current shortcomings
For a better understanding of the FM construct, the key to success is perhaps overcoming the old-established dichotomy between disease and illness. A disease refers to an abnormal biological condition that negatively impacts an organism’s structure or function, 53 whereas illness usually refers to a patient’s personal experience of symptoms or disability.54,55 In chronic pain disorders, the clinical presentation can be an individual combination of manifestations attributable to the ‘disease’ as well as the ‘illness’. However, the prevalent causal flow is not always straightforward. Often, any evidence for a ‘disease’ is missing, so that pain is wrongly considered as ‘all in the mind’ and therefore as non-existing. Recently, however, illness and disease have been claimed to represent the two sides of the same coin: a disease is defined as such (rather than an anomaly) because soon or later, in at least some of the patients, it will lead to an unwanted status of illness; on the other side of the same coin, any psychological states is associated to a specific biological reality, to the least at the level of neural circuitries (the substrate of the recent concept of ‘nociplastic’ pain). 56 A spiraliform, rather than unidirectional causal flow has been advocated in all health conditions, providing the rationale for treatments acting on the biological as well as on the psycho-behavioural sides of the coin. It is left to empirical research discovering which approaches are most effective in the various conditions. 57
In agreement with this perspective, and in order to obtain diagnostic criteria based both on reliable biomarker and a reliable subjective-clinical representation, the following methodology is suggested:
a) Define carefully the construct for each syndrome. This is done by first establishing the content validity required within the construct. Measures of symptoms should comply with the highest metric standards for questionnaires. 58 In any case, for FM the ACR-established clinically based subjective criteria do not adequately consider the current understanding of the pathophysiology for FM. In order to do this with methodological rigor, the development of objective, reliable and clinically feasible biomarkers is necessary. The biomarkers should be a combination of blood-borne biomarkers, neurophysiologic and imaging to appropriately reflect the complexities of the disorder. We would suggest as a start including measures of central sensitisation.
b) Employ the Delphi technique using the existing literature as well as the input from recognised experts would to establish the content validity.
c) Perform analyses on independent cohorts to measure the convergent and discriminant characteristics of the factors associated with the content as identified by the Delphi process described above.
d) Use (a) and (b) to develop the construct. This should be performed by a group of recognised experts and should represent basic science researchers, clinician scientists, clinical epidemiologists.
e) Using the newly agreed upon construct for the disorder a new diagnostic definition and criteria should be created.
f) Diagnostic criteria should then be applied clinically on independent cohorts to assess their impact upon important clinical care outcomes. Once this has been achieved the researchers and academic clinicians may accept it.
g) A decision-tree diagnostic algorithm should be developed, based on the established criteria, and tested with respect to its predictive capacity.
Why solving the FM puzzle might be useful for pain medicine, and medicine in general
Many of the prevalent chronic pain syndromes do not have a reference or ‘gold’ diagnostic standard (either clinical, biological or both) and are classified according to mostly self-standing, subjective ‘criteria’. For example, the International Association for the Study of Pain (IASP)/World Health Organisation (WHO) definition for chronic pain is that of a symptom complex that has been present for at least 3 months. The pain could be characterised as nociceptive, neuropathic or nociplastic (see above). They combine together within a chronic pain patient to result in poor functioning causing disability. 59 Rigorous definition of the ‘illness’ syndromes and valid measures of the constituent variables would steer research efforts towards specific biomarkers, thus fostering the construction of effective diagnostic algorithms. Syndromes of ‘illnesses without disease’ extend well beyond the domain of pain, encompassing most psychiatric conditions, ‘neurofunctional’ motor disorder, 60 dizziness and visceral ‘psychosomatic’ disorders, and other. A better understanding of FM might thus help treating all of these conditions.
Conclusion
Chronic pain conditions are multifactorial and can involve many body systems and their manifestations blur the disease–illness distinction. Furthermore, the construct for most has yet to be appropriately defined and universally accepted. We use FM – a prevalent nociplastic pain syndrome – to demonstrate some of the shortcomings of the past and current methods of diagnosis. We have set out a potential pathway for future research that defines the construct and establishes its content and through the use of Delphi technique develops new criteria which add physiological markers to the current diagnostic methodology. The critical question remains in choosing the correct biomarker. Ideally, this should reflect underlying disease mechanism or critical pathophysiology, be objective, reliable and feasible.
Footnotes
Conflict of interest statement
Ethical statement
Funding
ORCID iD
