By Nancy J. Selfridge, MD

Associate Professor and Chair, Department of Clinical Medicine and Assistant Dean of Clinical Science, Ross University School of Medicine, Commonwealth of Dominica, West Indies

Dr. Selfridge reports no financial relationships relevant to this field of study.

Summary Points

  • Fibromyalgia diagnosis may be aided by newer criteria screening tools, but accurate diagnosis continues to require a thorough clinical evaluation beginning with a medical history and physical examination.
  • Multiple neurobiological, endocrine, and immunologic abnormalities have been documented in fibromyalgia patients, indicating that it is not merely a psychological or psychosomatic disorder.
  • Integrative interventions with best evidence of efficacy in systematic reviews are alternative exercise, hydrotherapy and balneotherapy, massage therapies, and repetitive transcranial magnetic stimulation. Treatment plans must be highly individualized and balance efficacy with safety, cost, accessibility, and patient preference.

 

Although fibromyalgia (FM) remains a challenging management problem in clinical medicine, significant progress has been made in the last 5 years in terms of identifying underlying neurobiological abnormalities, which may one day elucidate the pathophysiology of the disorder. Diagnostic criteria continue to be refined and debated. Wolfe’s 2010 preliminary criteria were modified in 2011 (2011modcr).1 These modified criteria have been validated repeatedly, and Bennett et al recently formulated a set of alternative criteria that compare favorably with the 2011modcr tool.2 Both have demonstrated excellent sensitivity and specificity compared to the “gold standard” 1990 American College of Rheumatology (ACR) criteria. Both are also better suited for identifying patients for clinical and epidemiological research. They can be administered via patient survey and do not require a tender point count, which was difficult for physicians to perform reliably. Although these newer tools can be helpful in identifying patients with fibromyalgia, both Wolf and Bennett stress that an accurate clinical diagnosis should never be made on the basis of these sets of criteria alone. Patients deserve a thorough medical history and physical examination, a process that also forms the foundation of relationship-centered care. The three sets of diagnostic criteria are compared in Table 1.2,3,4,5

Table 1: A Comparison of Fibromyalgia Diagnostic Criteria

 

1990 ACR Criteria

2011 Modified Criteria

2013 Alternative Criteria

Assessment of tender areas

18 tender points assessed on physical exam by physician

WPI score (0-19): report of pain or tenderness at 19 different sites for > 3 months

PLI score (0-28): pain at 28 different sites for > 3 months

Assessment of key symptoms

Widespread pain > 3 months duration

SSS score (0-12): Sleep, fatigue, and cognition scored for severity (1-3) over past week; headache, depression, and abdominal pain scored for presence or absence (0-1) over past 6 months

SIQR score (0-50): Pain, energy, stiffness, sleep, depression, anxiety, memory problems tenderness to touch, balance, and environmental sensitivity all scored for severity (0-10) and total divided by 2

Source of data

Physician assessment

Patient survey

Patient survey

Qualifying criteria:
FM likely
§

History of widespread pain > 3 months’ duration and 11/18 tender points on physical examination

WPI > 7; SSS 5 or

WPI 3-6; SSS 9 or

WPI + SSS 13

PLI 17; SIQR 21 or

PLI + SIQR 44

Performance

Sensitivity 84.4%

Specificity 81.1%

Sensitivity 83%

Specificity 67%

Sensitivity 81%

Specificity 80%

§For accurate clinical diagnosis, full clinical assessment is necessary to ensure that symptoms cannot be fully explained by another
co-existing condition

WPI: Widespread Pain Index; SSS: Symptom Severity Score; PLI: Pain Location Inventory; SIQR: Revised Symptom Impact Questionnaire

 

Pathophysiology

The past 5 years have yielded a plethora of translational research concerning neurobiological mechanisms of chronic pain. The underlying pathology of FM is now acknowledged to be central pain sensitization, and many abnormalities in functional connectivity have been documented in areas of the brain associated with pain processing.6-11 Of particular interest is the fact that many of these areas have also been associated with difficult emotional states and emotional regulation (amygdala, anterior cingulate cortex, hippocampus). Thus, we have some rudimentary explanations for observations that FM patients often struggle with the affective dimensions of their pain condition, even when they are not co-morbidly depressed. In about 20% of FM patients, there is biopsy evidence of small fiber neuropathy.12 Although routine biopsy is not considered standard care, clinicians would be wise to follow the evolution of clinical guidelines for changes concerning FM assessment in this regard.

Multiple neuroendocrine and immunological abnormalities have been reported in FM.13-20 Although the precise etiology and pathophysiologic mechanism of FM remains obscure, there is currently so much evidence supporting neurobiological and hormonal derangements in FM patients that it is no longer tenable for physicians to be dismissive of FM as a “real” condition or to believe that it is of purely psychological origins. A 2010 survey of Canadian primary care physicians and specialists found that 23% and 12% of these practitioners, respectively, characterized FM patients as malingers.21 Patients experience these attitudes as invalidating, and these messages generate mistrust; invalidation by and mistrust in the physician are associated with poorer quality of life for patients.22 Table 2 provides examples of some of the pathological findings recently discovered in FM patients.

Table 2: Examples of Pathological Findings in Fibromyalgia Patients

Neurophysiological

  • Reduced levels of hippocampal n-acetyl aspartate
  • Elevated levels of glutamate:
    • posterior insula
    • amygdala,
    • posterior cingulate
    • ventral lateral prefrontal cortex
  • Reduced levels of GABA
    • Anterior insula
  • Altered functional connectivity between
    • Insula
    • DMN€
    • EAN§
  • Reduced resting connectivity within somatosensory cortex
  • Increased functional connectivity between
    • Somatosensory cortex
    • DMN€
  • Small fiber neuropathy (20%)

Neuroendocrine

  • Elevated CSF substance P
  • Impaired growth hormone secretion in response to exercise
  • Excessive sympathetic autonomic tone
  • Reduced IGF-1 levels

Immunologic

  • Elevated CFS Interleukin-8
  • Altered lymphocyte corticosteroid receptors
  • Decreased T cell activation marker expression

 

FM Management

As no single intervention is effective for all FM patients, treatment plans are best tailored to individual patients based on preferences and responses to treatments. Mainstays of conventional therapy include treatment of comorbid depression (present in up to 30% of patients) and disordered sleep, regular exercise, and judicious trials of medications, starting with a tricyclic agent and progressing to serotonin and norepinephrine reuptake inhibitors and anticonvulsants, some of which have been shown to be beneficial for managing FM symptoms. Medication efficacy is disappointing: 50% of patients improve by 30%.3,23 Although statistically better than placebo, side effects from pharmacotherapy are common and any improvement in FM symptoms must be weighed against side effects causing reduced quality of life. Thus, prescription medication is not absolutely necessary to manage FM; non-pharmacological therapies, including some integrative medicine modalities, can work as well or better.24 Recent research on integrative modalities will be reviewed here, focusing on systematic reviews and meta-analyses.

Nutrition, Supplements, and Botanicals

In a recent systematic review of FM and nutrition, no single dietary intervention has been shown to be consistently effective for FM symptoms. However, patients with FM who are obese have more severe symptoms and lower quality of life; weight loss through energy-restricted diet and bariatric surgery have resulted in improvement in symptoms and quality of life.25 No nutritional supplements or botanicals show consistent strong evidence of efficacy for improving FM symptoms. However, FM patients have been shown in some studies to have evidence of increased oxidative stress, suggesting that investigating the impact of nutritional antioxidant strategies on FM symptoms would be valuable. Although research evidence is inconclusive, some studies suggest that gluten avoidance may be beneficial. Similarly, avoidance of excitotoxins (aspartame, monosodium glutamate) has demonstrated mixed results. These two dietary strategies require additional research to ascertain their efficacy in improving FM symptoms.

Alternative Exercise

Although aerobic exercise is considered an essential component of FM treatment and has consistently shown sustained benefit for FM symptoms, studies have been plagued by high attrition. About 80% of research on exercise for FM has explored aerobic or mixed conventional exercise programs.26 Patients often experience severe post-exercise pain even when exercise is appropriate for fitness level, likely manifestations of impaired growth hormone secretion and abnormal inflammatory mediator response noted in research. This is a significant management challenge facing the clinician trying to write an exercise prescription for the FM patient. Thus, alternative forms of exercise might be uniquely beneficial for this population.

Bidonde et al evaluated the efficacy of aquatic exercise for FM for a Cochrane review.27 Sixteen studies involving 881 patients were included for analysis, and authors cited lack of confidence in outcomes due to poor study design and methodological flaws. Compared to non-exercising controls, aquatic exercisers reported improvements in multidimensional function (mean difference [MD] -5.97; 95% confidence interval [CI], -9.06 to -2.88); pain (MD -6.59; 95% CI, -10.71 to -2.48); and stiffness (MD -18.34; 95% CI, -35.75 to -0.93). Muscle strength improved, on average, to 0.63 standard deviations higher than the control group, a moderate effect size. Only stiffness and muscle strength met the 15% improvement threshold for clinical significance. Aquatic exercise compared favorably to land-based programs in five studies with no statistical differences in improvements in pain, stiffness, multidimensional function, or cardiorespiratory function. However, land-based programs resulted in slightly greater muscle strength measurements. None of the outcomes of either type of exercise reached the 15% threshold for clinical significance. Dropout rates were the same for both types of exercise programs.

Alternative forms of exercise were the subject of a recent review by Mist et al.28 Sixteen studies of 832 participants were included in their meta-analysis. Interventions included yoga, tai chi, Qigong, Pilates, Biodanza, and a “body movement and perception” intervention. Several of these studies had no control group. The dropout rate was 81%, but when a control group was present, dropout rate in the treatment group did not differ from dropout rate in the control group. Study strength was considered moderately low by Jadad and modified Jadad scores. In the meta-analysis of study results, standard difference in means (effect size) was moderate to high at 0.84 and standard error was 0.07, statistically significant positive outcomes for alternative exercise studies reviewed (P = 0.00). No significant adverse events were noted in any of these studies.

Acupuncture

Acupuncture was the subject of a systematic review by Deare et al for the Cochrane database.29 Nine randomized, controlled trials were included, three using electroacupuncture and six using manual acupuncture (n = 395). All studies used “formula acupuncture” (a standard set of acupoints stimulated for each patient) except for one that used trigger points. Study quality was hampered by biases (selective reporting, attrition, performance, and detection), small sample sizes, and methodological flaws. Authors concluded from the pooled data that there is low to moderate level evidence that acupuncture improves pain compared with no treatment (MD, -22.40 points on a 100-point scale; 95% CI, -40.98 to -3.82; P = 0.02) or standard therapy (MD, -17.30 points on a 100-point scale; 95% CI, -24.13 to -10.47; P < 0.00001). Moderate level evidence suggests that acupuncture is no better than sham acupuncture in improving pain, fatigue, sleep, or overall well-being. Electroacupuncture showed slight nonsignificant improvement over manual acupuncture for all symptom outcomes reported. Limited evidence from two studies suggests that effects are not sustained. Acupuncture appears to be a safe, low-risk intervention. A different review on traditional Chinese medicine arrived at similar conclusions about acupuncture.30

Body Awareness Interventions

Courtois et al reviewed the efficacy of body awareness interventions for FM and for chronic fatigue syndrome, believed by some to be a similar clinical entity.31 Of 29 studies meeting inclusion criteria included in the review, after reviewing reported data for completeness or usefulness, only eight were included in the meta-analysis. Interventions in these 29 studies were heterogeneous and included meditation, movement therapies, massage and other manual therapies, hypnotherapy, and breathing exercises. In some studies, the control intervention could be argued to increase body awareness (yoga, progressive relaxation, massage). Only one of the studies reported body awareness as an outcome, limiting interpretation for the others that body awareness is the factor in these interventions that is correlated with clinical symptom outcomes. The heterogeneity of the studies, hampered by small sample sizes and methodological flaws, limits applicability to clinical practice decision-making, although the authors concluded that body awareness interventions appear to have an overall positive effect on pain and quality-of-life measures.

Massage

In a 2015 systematic review and meta-analysis by Yuan et al, 10 randomized and non-randomized controlled trials were included.32 The six massage interventions included Swedish massage, manual lymphatic drainage, myofascial release, shiatsu, connective tissue massage, and combination technique massage. Strong evidence does not exist to support any form of massage for FM symptoms. Moderate to low evidence supports all styles of massage reviewed for improving FM pain and quality of life except for Swedish massage. Myofascial release appeared to have the best evidence of efficacy for multiple symptom outcomes. The studies reviewed were again hampered by small sample size, design, and methodological flaws, which, along with the small number of studies, limit confidence in these results for clinical application and decision making. However, massage is a low-risk intervention and is widely accessible.

Mind-body Therapies

Theadom et al conducted a review and analysis of mind-body therapies for the Cochrane database.33 Sixty-one randomized, controlled trials with 4234 participants were included. Interventions assessed included psychological therapies, biofeedback, mindfulness, movement therapies, and relaxation. Quality of studies was low or very low and analysis was hampered by small numbers of trials for each intervention and by wide heterogeneity in the use of outcome measures. Authors concluded that current research only supports psychological therapies as effective for improving pain, physical functioning, and mood.

Spa Therapy

Spa therapy efficacy for FM symptoms was reviewed by Guidelli et al in 2012.34 Spa therapy studies encompassed not only thermal mineral baths (balneotherapy), but also mud packs, massage, relaxation, and exercise therapies. In this review, studies were of low sample size, and the trials were hampered by design and methodology flaws, such as absence of double-blinding and failure to include intention-to-treat analysis. Further, the high heterogeneity of the treatment programs and differences in the study populations made it difficult to compare studies. However, balneotherapy appeared to have lasting positive effects on FM pain and quality of life, although the authors felt that definitive conclusions were not possible.

A meta-analysis and review of balneotherapy and hydrotherapy (treatments with normal tap water) interventions in 2014 attempted to isolate the effects of these therapies for FM symptoms.35 For hydrotherapies, there was moderate-to-strong evidence for a small reduction in pain (effect size -0.42; 95% CI, -0.61 to -0.24; P < 0.00001; I2 = 0%) and moderate-to-strong evidence for a small improvement in health-related quality of life at the end of treatment (effect size -0.40; 95% CI, -0.62 to -0.18; P = 0.0004). Heterogeneity in these study analyses, as measured by I2 calculation, was low (0-15%). Five studies (n = 177) on balneotherapy showed moderate evidence for a medium-to-large size reduction in pain (effect size, -0.84; 95% CI, -1.36 to -0.31; P = 0.002). I2 analysis indicated moderate heterogeneity in these studies for this outcome. Moderate evidence was demonstrated for a medium improvement of health-related quality of life (effect size -0.78; 95% CI, -1.13 to -0.43]; P < 0.0001) with low calculated heterogeneity. The improvements for pain were maintained at 3- to 6-month follow-up, though with smaller effects.

Other Therapies

Repetitive transcranial magnetic stimulation (rTMS) was the subject of two recent reviews. This intervention involves the use of an electromagnetic field generator on the scalp to stimulate neurons in deeper brain regions with the small electrical currents produced. Galhardoni et al evaluated rTMS for several chronic pain conditions in a descriptive review of 33 randomized trials (n = 843, 166 of whom had FM).36 The FM studies all involved multiple rTMS sessions for patients and were double-blind, placebo-controlled or sham-controlled trials. Several positive outcomes were described: reductions in daily pain, improvement in quality of life, and improvement in cognition as measured by neuropsychiatric testing. One study found that positive outcomes were associated with regional brain metabolic changes.

Knijnik et al performed a meta-analysis on five studies reported on FM, which they determined were of moderate to high quality and which included four of the studies reviewed by Galhardoni above.37 Results of their analysis indicated that rTMS improved quality of life with a moderate effect size (pooled SMD = 0.472; 95% CI, 0.80-0.14). There was a trend toward reducing pain intensity, again with a moderate effect size (SMD = 0.64; 95% CI, 0.31-0.017). Depressive symptoms were not affected.

In a review of cannabinoids for the treatment of non-cancer pain, Lynch and Campbell found one randomized, placebo-controlled trial of nabilone (a synthetic cannabinoid) for FM that met inclusion criteria. This study reported statistically significant reductions in visual analog scale for pain ratings (P < 0.02) and improvements in the fibromyalgia impact questionnaire (P < 0.02) and anxiety (P < 0.02).38 Many side effects were reported. Further, nabilone can have toxic effects when abused. Another study compared FM cannabis users (n = 28) to non-users (n = 28) and noted improvement in pain scores, increased relaxation, and increased sense of well-being in cannabis users (P < 0.001).39 Because of the recent increase in states legalizing cannabis for medical and recreational use, patients may ask about these potential treatments.

Conclusions and Recommendations

Confident interpretation of research on complementary and alternative interventions for FM is still hampered by the overall low amount and quality of research. Based on recent reviews, the following therapies have demonstrated at least moderate positive effect on FM symptoms: balneotherapy and hydrotherapy for pain and quality of life, rTMS for pain and quality of life, massage (all styles studied except for Swedish) for pain and quality of life, and alternative exercise for multiple symptoms (see Table 3). All of these interventions are low risk. No optimum treatment protocols have been developed for any of these interventions for FM. Repetitive transcranial magnetic stimulation is costly ($6000-$10,000 for a 4- to 6-week treatment regimen). Patients should be encouraged to exercise and may try alternative exercise forms such as Tai Chi and yoga, which are accessible in terms of availability and cost. Patients with access to mineral springs can be encouraged to try balneotherapy. Massage is also widely accessible; many massage schools offer discounts to clients to allow their students sufficient practice toward certification, thus making this intervention less costly for patients. Acupuncture remains a popular and commonly used intervention for patients with chronic pain, including fibromyalgia. Despite the lack of evidence of efficacy, patients may wish to try a short series of treatments to assess their own individual response. In the end, however, we will have to await more and higher quality research on both conventional and alternative treatments, and patient treatment plans will have to remain highly individualized, consisting of trials of multiple modalities, balancing evidence of efficacy and safety, to arrive at optimum management of symptoms.

Table 3: Integrative Modalities Demonstrating at Least Moderate Positive
Effect on FM Symptoms

Intervention

Symptom Improvement

Balneotherapy and
hydrotherapy

Pain and quality of life

Massage (all styles except Swedish)

Pain and quality of life

Repetitive transcranial magnetic stimulation (rTMS)

Pain and quality of life

Alternative exercise (e.g., Tai Chi, Yoga, Pilates)

Multiple symptoms

 

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