Description of the condition

FMS has been defined traditionally as widespread pain that lasts for longer than three months, with pain on palpation at 11 or more of 18 specified tender points (Wolfe 1990). For the International Classification of Diseases ICD‐11 of the World Health Organisation WHO, ​FMS​ was relocated from its legacy ICD‐10 chapter location to a new category block in the ​Symptoms, signs​ chapter, as an ​inclusion term ​under ​Chronic Primary Pain​ (CWP). It is currently coded as an ​inclusion term ​under ​CWP (Code MG30.01). The WHO uses the term fibromyalgia syndrome and not the term fibromyalgia (FM). FMS is defined as a form of CWP (pain in at least 4 of 5 body regions or in at least 3 or 4 body quadrants) associated with sleep disorders, cognitive dysfunction, and somatic symptoms. The symptoms have been present at a similar level for at least three months and are not better accounted for by another diagnosis (Nicholas 2019; World Health Organization 2020).

For a clinical diagnosis, the ACR 1990 classification criteria (Wolfe 1990), the ACR 2010 preliminary diagnostic criteria (Wolfe 2010), the 2011 diagnostic criteria (Wolfe 2011), the 2016 diagnostic criteria (Wolfe 2016), the ACTTION‐APS Pain Taxonomy (AAPT) diagnostic criteria (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) are used (Arnold 2019). Diagnosis is established by a history of the key symptoms and the exclusion of somatic diseases sufficiently explaining the key symptoms (Häuser 2015). FMS symptoms can be assessed by patient's self‐report, via the fibromyalgia criteria and severity scales for clinical and epidemiological studies, a modification of the ACR Preliminary Diagnostic Criteria for Fibromyalgia, the so‐called Fibromyalgia Symptom Questionnaire (Wolfe 2011). The severity of the AAPT criteria of sleep problems or fatigue, or both, are assessed by the physician (Arnold 2019). Clinical guidelines have suggested a clinical work‐up with detailed history taking of a FMS‐like symptom cluster, complete physical examination and some laboratory tests to screen for somatic diseases which can fully explain FMS‐like symptoms and/or might contribute to CWP and fatigue (Fitzcharles 2013, Häuser 2015, Arnold 2019).

A definite aetiology (cause) of this syndrome remains unknown. A model of interacting biological and psychosocial variables in the predisposition, triggering, and development of the chronicity of fibromyalgia symptoms has been suggested (Üceyler 2017). A systematic review of prospective cohort studies in the general population on risk factors of CWP and FMS identified various childhood difficulties (e.g. physical and sexual abuse), female sex (except with pre‐existing medical disorders), older/middle age, smoking, high body mass index, alcohol abstinence, and pre‐existing medical disorders in adulthood. The strongest associations were with sleep disorders, headaches and other pains, depression, and illness behaviour (Creed 2020). Genome‐wide association studies investigated genes potentially involved in FMS pathogenesis highlighting that genetic factors are possibly responsible for up to 50% of the disease susceptibility. Potential candidate genes found associated to FMS are SLC64A4, TRPV2, MYT1L, and NRXN3 (D'Agnelli 2019). Triggering of fibromyalgia symptoms in predisposed persons by inflammatory rheumatic diseases and psychosocial stress (e.g. workplace and family conflicts) is largely ensured whereas the evidence on physical stress (e.g. infections, surgery, accidents) as triggering factors is inconclusive (Häuser 2015).

Several factors are associated with the pathophysiology (functional changes associated with or resulting from disease) of fibromyalgia, but the precise relationship to symptoms of the disorder is unclear (Üceyler 2017). The best established pathophysiological features are those of central sensitisation; that is, augmented pain and sensory processing in the central nervous system (CNS), with increased functional connectivity to pro‐nociceptive brain regions and decreased connectivity to antinociceptive regions, and accompanying changes in CNS neurotransmitters as well as the size and shape of brain regions (Cagnie 2017; Clauw 2014). Other findings include sympathetic nervous system dysfunction (Martínez‐Martínez 2014), increased pro‐inflammatory and reduced anti‐inflammatory cytokine profiles (produced by cells involved in inflammation) (Üceyler 2011), and small fibre pathology (Üceyler 2017).

Fibromyalgia is common. A review indicated a global mean prevalence of 2.7% (range 0.4% to 9.3%), and a mean in the Americas of 3.1%, in Europe of 2.5%, and in Asia of 1.7% (Queiroz 2013). Fibromyalgia is more common in women, with a female to male ratio of 3:1 (4.2%:1.4%). Estimates of prevalence in specific populations vary greatly, but have been reported to be as high as 9% in female textile workers in Turkey and 10% in metalworkers in Brazil (59% in those with repetitive strain injury; Queiroz 2013). The change in diagnostic criteria does not appear to have significantly affected estimates of prevalence (Wolfe 2013, Häuser 2021).

The clinical picture (symptoms, disability) of people meeting FMS criteria is heterogenous. FMS can be associated with mental disorders (mainly anxiety and depressive disorders) and other chronic secondary pain syndromes such as inflammatory rheumatic diseases and osteoarthritis (Fitzcharles 2018). Overlap of FMS and various chronic primary pain syndromes is prevalent, too. The U.S. Congress and National Institutes of Health has recommended to use the term Chronic Overlapping Pain Conditions (COPCs) for pain conditions which involve many organ systems: vulvodynia, temporomandibular disorders, myalgic encephalomyelitis/chronic fatigue syndrome, irritable bowel syndrome, interstitial cystitis/painful bladder syndrome, endometriosis, chronic tension‐type headache, chronic migraine headache and chronic low back pain (Maixner 2016). Prevalence rates for FMS in these various conditions range from 20% to 65% (Fitzcharles 2018). Mild, moderate and severe forms of FMS can be differentiated (Häuser 2018). Symptom severity and the extent of disability of people with FMS is associated with somatic and psychological comorbidities (Häuser 2015), and occupational characteristics such as physically demanding jobs and work tasks (Palstam 2017). Most people with FMS report high disability levels and poor quality of life, along with extensive use of medical care (Häuser 2015). There is often significant disability, with moderate or severe pain experienced for many years (Bennett 2007).

Fibromyalgia symptoms are known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically‐relevant benefit from any one intervention. A range of non‐pharmacological and pharmacological interventions is or may be used, depending on the particular clinical situation and licensed indications of medicines.

A stepwise and graduated approach depending on the key symptoms and the extent of disability is recommended by recent clinical guidelines (Macfarlane 2017; Petzke 2017). Guidelines recommend starting with education, defining realistic goals of therapy (improvement of daily functioning), and non‐pharmacological therapies such as exercise and psychological therapies though evidence of major effectiveness of these is limited (Geneen 2017; Williams 2020). A multidisciplinary approach, combining pharmacological interventions with physical or cognitive interventions, is advocated for severe forms of FMS (Macfarlane 2017; Petzke 2017). Reasons for preferring non‐pharmacological therapies as first line therapies include non‐pharmacological therapies having more ubiquitous clinically relevant effects on FMS symptom domains ‐ pain, sleep disturbance, fatigue, affective symptoms (depression/anxiety), functional deficit and cognitive impairment ‐ and less side effects than medications (Perrot 2014). Positive, yet declining effects of non‐pharmacological therapies such as cognitive‐behavioral therapies (Bernardy 2018), and multicomponent treatments (Arnold 2012), could be demonstrated in follow‐ups after the end of treatment.

Conventional analgesics are usually not effective. Treatment is often by so‐called pain modulators, such as antidepressants like duloxetine and amitriptyline (Häuser 2013; Lunn 2014; Moore 2012a), or antiepileptics like gabapentin or pregabalin (Cooper 2017; Moore 2009; Üceyler 2013, Wiffen 2013). The proportion of people who achieve worthwhile pain relief even with effective interventions (typically at least a 50% reduction in pain intensity; Moore 2013a), is small, generally only 10% to 15% more than with placebo, with number needed to treat for an additional beneficial outcome (NNTB) usually between 6 and 14 (Wiffen 2013). Those who do experience good levels of pain relief with pregabalin also benefit from substantial improvements in other symptoms, such as fatigue, function, sleep, depression, anxiety, and ability to work, with significant improvement in quality of life (Moore 2010b; Moore 2014a; Straube 2011). Fibromyalgia is similar to other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment (Moore 2013b).

Description of the interventions

The exact number and types of pharmacological therapies that might be used for the treatment of fibromyalgia is not known. Medicines from a number of different classes have been used to treat fibromyalgia in clinical practice, and trials and Cochrane Reviews of efficacy are likely to be found covering the following drug classes:

1. antidepressants (e.g. amitriptyline or other tricyclic antidepressants, duloxetine, milnacipran, mirtazapine);

2. antiepileptics (e.g. gabapentin, pregabalin, topiramate);

3. antipsychotics (e.g. quetiapine);

4. cannabinoids (e.g. nabilone);

5. nonsteroidal anti‐inflammatory medicines (NSAIDs, e.g. diclofenac, ibuprofen, naproxen);

6. opioids (e.g. morphine, oxycodone, tramadol).

It is also possible, or even likely, that other pharmacological therapies outside these classes have been tested, and reviews may be available. For the purposes of this overview, we define pharmacological as relating to the use and effects of medicines, and define medicines or medicine as a defined or undefined chemical that is ingested or otherwise introduced into the body.

How the intervention might work

Because of the large range of medicines that might possibly be found for this overview, and because different medicines within a particular class can have different modes of action, no meaningful discussion of how interventions might work is possible here, especially give the unknown aetiology of FMS. As this overview will concentrate on Cochrane Reviews, and each will have its own section on how that particular intervention works, readers are directed to those sections of the individual reviews.

Why it is important to do this overview

The standards used to assess evidence in chronic pain trials have changed substantially, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy. The most important change is the move from using average pain scores, or average change in pain scores, to the number of people who have a large decrease in pain (by at least 50%) and who continue in treatment, ideally in trials of 8 to 12 weeks or longer. Pain intensity reduction of 50% or more has been shown to correlate with improvements in comorbid symptoms, function, and quality of life for people with chronic pain (Conaghan 2015; Moore 2013a; Peloso 2016), and specifically fibromyalgia (Moore 2010b; Straube 2011).

There is now increasing recognition that results based on a small number of small underpowered studies may well give an incorrect or highly imprecise answer to a clinical question. Many studies in chronic pain have historically been relatively small, and analysis of smaller trials in Cochrane Reviews has been criticised (AlBalawi 2013; Roberts 2015). An analysis on the impact of study size in Cochrane Reviews has highlighted this issue, and pointed out that if two adequately powered studies are available, then omitting all underpowered studies makes little or no difference to the result (Turner 2013). The standard Cochrane 'Risk of bias' assessment does not include size, unless added by authors. Some items, like inconsistency or heterogeneity may be a consequence of small size (IntHout 2015; Turner 2013), but in any event, simulation studies demonstrate that the chances of heterogeneity tests accurately detecting true homogeneity or heterogeneity with a small number of small studies is almost random (Gavaghan 2000). Alternative approaches not available in Review Manager 5 software (Review Manager 2020), may offer a way forward in some circumstances (Kulinskaya 2015). There are potentially large effects of random chance when the numbers of events are small (Flather 1997; Moore 1998; Pogue 1997; Pogue 1998). A simulation exercise suggests that, in most circumstances, a minimum data requirement is 250 to 500 events, such as a participant achieving adequate pain relief (Thorlund 2011).

A 1996 survey indicated that 90% of meta‐analyses of analgesic interventions had methodological flaws that could limit their validity, and that meta‐analyses of low quality produced significantly more positive conclusions (Jadad 1996a). Even in good quality Cochrane Reviews, the use of Grading of Recommendations Assessment, Development and Evaluation (GRADE) to summarise the certainty of evidence indicates that fewer than 20% of reviews actually have any high quality evidence (Fleming 2016). Judging systematic review quality is difficult. AMSTAR (A MeaSurement Tool to Assess systematic Reviews) is most often used, and a newer version now exists in AMSTAR‐2 (Shea 2017). This is a generic tool examining what is regarded as best practice in systematic review methodology, and its use in back pain indicated that 86% of systematic reviews provided low or critically low confidence in their results in cannabis‐based medicine reviews for pain (Moore 2020), 90% in exercise therapy for low back pain (Almeida 2020), 99% in bariatrics (Storman 2020), and 100% in spine surgery (Dettori 2020). Cochrane Reviews rated mainly moderate or high confidence (Almeida 2020; Moore 2020).

Beyond the generic, there are also specific criteria important to pain studies, including adequate initial pain for a sensitive assay (Moore 2010a), the importance of patient centred outcomes (Moore 2013a), underestimation of pain by professionals when compared with patients (Seers 2018), and the importance of imputation method in some circumstances (Moore 2012b). These methods have been used for judging the quality of systematic reviews of cannabis‐based medicines (Moore 2020).

This overview will examine how Cochrane Reviews of fibromyalgia meet these criteria as well as summarising the current available knowledge. It aims to set high standards and mark a departure from how overview reviews were conducted previously, and inform on how reporting of Cochrane Reviews on fibromyalgia may be improved.