Description of the condition

Fibromyalgia has been traditionally defined 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). In the International Classification of Diseases (ICD‐11), ​maintained by the World Health Organization (WHO), fibromyalgia syndrome 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 widespread pain​ (CWP). It is currently coded as an ​inclusion term ​under ​CWP (Code MG30.01). WHO uses the term 'fibromyalgia syndrome' and not 'fibromyalgia'. In agreement with the ICD‐11, we will use the term 'fibromyalgia syndrome' (FMS) in this review. 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; WHO 2020).

For a clinical diagnosis, the following diagnostic criteria are most frequently used:

• the ACR (American College of Rheumatology) 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); and

• the ACTTION‐APS Pain Taxonomy (AAPT) diagnostic criteria (Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Network public‐private partnership with the US Food and Drug Administration and the American Pain Society) (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, also known as the Fibromyalgia Symptom Questionnaire (Wolfe 2011). The severity of the AAPT criteria of sleep problems and/or fatigue are physician assessed (Arnold 2019). Clinical guidelines have suggested a clinical work‐up with detailed history taking of a FMS‐like symptom cluster, complete physical examination, and laboratory tests to screen for somatic diseases that can fully explain FMS‐like symptoms and/or might contribute to CWP and fatigue (Fitzcharles 2013; Häuser 2015; Arnold 2019).

The 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 may be responsible for up to 50% of the disease susceptibility. Potential candidate genes found to be associated with FMS are solute carrier family 6 member 4 (SLC6A4), transient receptor potential cation channel subfamily V member 2 (TRPV2), myelin transcription factor 1 like (MYT1L), and neurexin 3 (NRXN3) (D'Agnelli 2019). Triggering of FMS symptoms in predisposed individuals by inflammatory rheumatic diseases and psychosocial stress (e.g. workplace and family conflicts) is largely ensured by prospective cohort studies, whereas 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 FMS (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 2014). Other findings include sympathetic nervous system dysfunction (Martinez‐Martinez 2014), increased pro‐inflammatory and reduced anti‐inflammatory cytokine profiles (produced by cells involved in inflammation) (Üceyler 2011), and small‐fibre pathology (Grayston 2019), which can be detected in subgroup of patients.

FMS is common; numerous studies have investigated prevalence in different settings and countries. The Queiroz 2013 review gives a global mean prevalence of 2.7% (range 0.4% to 9.3%) and a mean of 3.1% in the Americas, 2.5% in Europe, and 1.7% in Asia. FMS 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, 10% in metalworkers in Brazil, and 59% in individuals with repetitive strain injury (Queiroz 2013). The change from ACR 1990 classification criteria to the 2011 and 2016 diagnostic criteria for clinical diagnosis does not appear to have affected estimates of prevalence (Wolfe 2013; Häuser 2021). By switching from the tender point count as a diagnostic criterion (ACR 1990 classification criteria) to symptom‐based diagnosis based on the 2011 or 2016 diagnostic criteria, more men meet the FMS criteria (Wolfe 2013). Determining the incidence of FMS is problematic. A study utilising a US‑based large insurance claims database for ‘new’ FMS cases found that the age‐adjusted (to the US population) rate for ‘new’ FMS was 6.88 cases per 1000 person‐years for men and 11.28 cases per 1000 person‐years for women between 1997 and 2002 (Weir 2006).

The clinical presentation (i.e. symptoms, disability) of people meeting FMS 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). The overlap of FMS and various chronic primary pain syndromes is prevalent. The US Congress and National Institutes of Health have recommended using the term 'chronic overlapping pain conditions' (COPCs) for pain conditions that 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 by the severity of symptoms and of disability (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 in secondary and tertiary medical care report high disability levels and poor health‐related quality of life, along with extensive use of medical care (Häuser 2015).

Description of the interventions

FMS symptoms are known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention (Häuser 2015). Recent clinical guidelines recommend a stepwise and graduated approach depending on the key symptoms and the extent of disability (Macfarlane 2017; Petzke 2017), starting with education, defining realistic goals of treatment (improvement of daily functioning), and non‐pharmacological intervention such as exercise and psychological therapies. A multidisciplinary approach combining pharmacological therapies with non‐pharmacological (i.e. physical or cognitive interventions) interventions is advocated for severe forms of FMS (Macfarlane 2017; Petzke 2017). The following reasons were given for preferring non‐pharmacological interventions over medications as first‐line treatments in recent guidelines (Macfarlane 2017; Petzke 2017): non‐pharmacological interventions have more ubiquitous clinically relevant effects on FMS symptom domains (pain, sleep disturbance, fatigue, affective symptoms (depression/anxiety), functional deficit, and cognitive impairment) and fewer side effects than medications (Perrot 2014), and the potential reductions of FMS symptoms by pharmacological therapies on FMS symptoms are limited to the time of treatment (Saxe 2012). In contrast, positive (whilst declining) effects of non‐pharmacological therapies such as cognitive‐behavioural therapies, Bernardy 2018, and multicomponent treatments, Arnold 2012b, could be demonstrated in follow‐up after end of treatment.

The precise number and types of non‐pharmacological therapies that might be used for the treatment of FMS is not known. Surveys conducted of people with FMS have found they use multiple non‐pharmacological interventions (Bennett 2007; Häuser 2012). To date, there is not an internationally accepted definition and classification of non‐pharmacological interventions. We will use the definition of another Cochrane Review, which defined non‐pharmacological interventions as experimental (pain) therapies that do not involve taking medicine or any other active substance (Boldt 2014). Eligible therapies included surgical interventions, exercise training (i.e. aerobic exercise), acupuncture, massage, joint mobilisation (i.e. osteopathy), relaxation training, thermotherapy (warm or cold pack application), transcutaneous electrical nerve stimulation (TENS), magnetic field therapy, brain stimulation, and psychological or behavioural therapies (Boldt 2014).

We assume we will find Cochrane Reviews covering the following types of non‐pharmacological interventions (in alphabetical order).

• Acupuncture

• Brain stimulation

• Body/mind interventions (i.e. Tai Chi)

• Dietary interventions

• Exercise training

• Psychological therapies

It is very likely that other non‐pharmacological therapies outside the ones listed above have been tested for which non‐Cochrane Reviews may be available.

How the intervention might work

Given the large number of non‐pharmacological therapies that may be found for this overview, and that different non‐pharmacological therapies can have different modes of action, no meaningful discussion of how interventions might work is possible here. 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

In view of the many non‐pharmacological therapies used for FMS, this overview of Cochrane Reviews aims to present the evidence of benefits and harms of selected non‐pharmacological interventions to people with FMS and healthcare providers. This overview also aims to highlight potential limitations of Cochrane systematic reviews on non‐pharmacological interventions of FMS.

• Most studies of people with FMS reported the outcomes (e.g. pain intensity, health‐related quality of life) as mean values. However, the standards used to assess evidence in chronic pain trials have changed substantially in the last 10 years. 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 substantial (by at least 50%) or a moderate (by at least 30%) decrease in pain and who continue in treatment, ideally in trials of 8 to 12 weeks or longer. In addition, responder criteria for other FMS‐associated symptoms than pain such as sleep problems, fatigue, and reduced health‐related quality of life and the use of combined responder criteria (e.g. predefined reduction of pain and sleep problems and global impression of improvement) has been suggested by expert panels (Arnold 2012a). We are therefore interested in assessing if systematic reviews have analysed responders outcomes as described above.

• The selection of an adequate control group for non‐pharmacological therapies is a matter of debate. Double‐blind procedures as with drugs can be realised for technical non‐pharmacological therapies such as brain stimulation or acupuncture, but not for non‐technical therapies such as exercise or psychological therapies (Enck 2019). For these therapies, treatment as usual or waiting‐list control is frequently used as a control group. In most of these studies, participants in these control groups receive less care by less experienced and/or engaged therapists than the intervention tested (Bernardy 2018). Whilst these control groups might reflect clinical practice, they do not permit differentiation of the specific and non‐specific effects of the intervention tested (Enck 2019). We are therefore interested in assessing how systematic reviews have managed synthesis of the evidence according to the type of control group.

• Many prior non‐pharmacological trials have not systematically assessed adverse events (Sharpe 2020). We are therefore interested in assessing if systematic reviews have analysed the methods of assessment and the frequency of adverse events in the studies analysed.

• As noted in Description of the condition, most people diagnosed with FMS meet the criteria of mental disorders and other chronic pain syndromes (Häuser 2015). The exclusion criteria of pharmacological studies in FMS are strict due to the requirements of drug agencies and raise concerns about the external validity of study findings (Welsch 2018). We are therefore interested in assessing if systematic reviews have reported the inclusion and exclusion criteria of the studies analysed and have discussed the generalisability of the results on individuals with FMS in clinical practice.

• The use of GRADE, Schünemann 2021, to summarise the quality of the 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. Its use in back pain indicated that the following percentages of systematic reviews provided low or critically low confidence in their results: 86% in cannabis‐based medicine reviews for pain (Moore 2020); 90% in exercise therapy for low back pain (Almeida 2020); and 100% in spine surgery (Dettori 2020). Cochrane Reviews rated mainly moderate or high confidence using AMSTAR‐2 (Almeida 2020; Moore 2020). We will therefore use AMSTAR‐2 to assess the methodological quality of Cochrane Reviews on non‐pharmacological therapies for FMS.