Chapter 16 Fibromyalgia
With contribution from Dr Lily Tomas and Greg de Jong
Introduction
Fibromyalgia is a functional condition typified by widespread muscle and joint pain affecting at least 2% of the general population1 and as high as 15%.2 While the American College of Rheumatology classification criteria consists of the identification of at least 11 of 18 standardised tender points, a range of symptoms also exists including fatigue, insomnia and mood disorders (anxiety and depression).3 Furthermore, demonstrated affects on cognitive function (‘fibrofog’) have been confirmed with demonstrated influences on memory and attention.4, 5 Indeed, fibromyalgia is considered a functional somatic syndrome2 rather than a disease, in that it is a diagnosis of exclusion concluded only after other musculoskeletal disorders have been ruled out.6
Significantly, fibromyalgia is frequently found to exist contemporaneously with other functional somatic syndromes.7 Two studies of the relationship between fibromyalgia and irritable bowel syndrome (IBS) identified that IBS existed in 77%8 and 70%9 of fibromyalgia patients (compared to controls in which 18% and 10% had IBS). Of patients with fibromyalgia, 70% were also found to meet the criteria of chronic fatigue syndrome (CFS); 10 33 of 60 (55%) with fibromyalgia were considered to meet the criteria of multiple chemical sensitivity.11 As a result it has been suggested that these conditions may represent different symptoms and expressions of common pathogenetic mechanisms due to their substantial overlap,8 such that specific diagnosis between functional somatic syndromes may depend considerably upon the pragmatics of the assessment rather than definitive pathology.7
Due to the debilitating nature of fibromyalgia, long-term consequences and only partial effectiveness of pharmaceutical medicines to alleviate the symptoms, let alone affect a ‘cure’, many patients explore complementary and alternative medicines (CAM). In fact a study of patients presenting to a tertiary clinic identified that 96% of patients with a diagnosis of fibromyalgia had used CAM in the prior 6 months.12 Of the most frequently used CAM therapies, 48% used exercise, 45% spiritual healing, 44% massage, 37% chiropractic, and 20% weight loss programmes.12
Organic factors
Genetic factors
Family studies of fibromyalgia patients demonstrate that the condition aggregates in families. Furthermore it is possible that mood disorders and fibromyalgia may share inherited factors.13 Inheritability appears to be of a polymorphic nature with evidence of influence amongst serotoninergic, dopaminergic and catecholaminergic systems.14, 15, 16 Furthermore it has been postulated that subgroups of fibromyalgia patients exist with genetic factors likened to the differentiation of immune cells.17 Thus emerging evidence suggests that the individual existence, variance and degree of fibromyalgia may be influenced by heterogenous genetic influences.
Muscle changes
Fibromyalgia patients demonstrate definitive muscle changes according to pathology testing. DNA fragmentation has been noted, with disorganisation of actin and myofibre filaments and accumulation of glycogen and lipids within tissues. Muscles appear ‘moth eaten’, however inflammatory changes are not noted.18 One possible explanation for such changes is vasomotor dysregulation and vasoconstriction in muscles with a resulting low level ischemia leading to metabolic consequences.19 Muscle performance and electromyography has demonstrated an inability to relax during work activity as significant in fibromyalgia patients.20 Muscle strength has also been found to be 35% less per unit.21
Results regarding muscle energy metabolism are mixed. In some instances no difference has been found between fibromyalgia patients and controls during rest, exercise or recovery according to measures of phosphocreatine, inorganic phosphate and intracellular pH.22 However, measures of pyruvate, lactate, adenosine triphosphate and muscular isoenzymes of lacticodeshydrogenase have been found to be altered suggesting biochemical abnormalities during glycolysis may exist.23 Histological studies may also indicate abnormalities of the mitochondria, reduced capillary circulation and endothelial thickness may lead to oxygen debt, impaired oxidative phosphorylation and reduced ATP synthesis.24 Mitochondrial numbers have also been found to be significantly lowered,25 however in other instances a slight increase in type 1 muscle fibres have been noted, with type II muscle fibre atrophy.26
Oxidative stress and nutrient deficiencies
Fibromyalgia patients also appear to be under oxidative stress as identified by a comparison of oxidative stress parameters with myalgic scores and associated depression.27 Total antioxidant capacity has been observed to be significantly lower and total peroxide levels higher in fibromyalgia patients when compared to normals. A significant negative correlation between total antioxidant capacity and visual analogue scale for pain was also noted.28 These findings are consistent with investigations of female fibromyalgia patients that identified increased free radical parameters and decreased antioxidant parameters (Superoxide Dismutase) leading to oxidant/antioxidant imbalances as compared to normals.28 Hence it has been hypothesised that oxidative stress and nitric oxide balance may play an important role in fibromyalgia.30
Coenzyme Q10 is both an important aspect of the mitochondrial respiratory chain and anti-oxidant and has also been found to be abnormally distributed in patients with fibromyalgia, increased reactive oxygen species being identified in mononuclear cells of fibromyalgia patients, but decreased in the presence of CoQ10.31 Vitamin A and E have been found to be significantly reduced but not Vitamin C and beta–carotene in a study that also identified raised lipid perioxidation in patients with fibromyalgia.32
Vitamin D
In a small study of 40 female fibromyalgia patients, 17 demonstrated 25-hydroxyvitamin D concentrations less than 20nmol/l as compared to 7 normals.33 In a cross-sectional study of 150 patients with non-specific musculoskeletal pain, ages ranging between 10 and 65, 28% demonstrated severe Vitamin D deficiency (<20nmol), 55% of whom were younger than 30 years. Young women and immigrants had the highest levels of deficiency, however the authors emphasised that risks extended beyond patients traditionally suspected of Vitamin D deficiency (aged, housebound, immigrant).34 Low Vitamin D levels have also been noted amongst rheumatology patients in general35 and associated with fibromyalgia patients presenting with associated anxiety and depression.36
Calcium/magnesium
Preliminary studies comparing ATP, calcium and magnesium platelet levels in fibromyalgia patients were indicative of a trend towards higher calcium concentrations and significant elevations in magnesium simultaneous with lower ATP platelet levels suggesting that abnormal calcium–magnesium flow regulation may be of relevance in fibromyalgia.37 Intracellular evaluations demonstrate similar calcium–magnesium flow abnormalities exist with a possible influence on muscle contractility in fibromyalgia patients.
Amino acid/neurotransmitter balance
It has been hypothesised that an altered tryptophan metabolism may be responsible for fibromyalgia, however investigations suggest this may only be present in a subgroup of patients.38 A study of plasma levels of amino acids indicated that patients with fibromyalgia have significantly decreased levels of the branch chain amino acids; valine, leucine and isoleucine, and phenylalanine than normals, but no difference in measures related to tryptophan uptake or serotonergic markers.39 However, in contrast a second study indicated multiple individual amino acids (taurine, alanine, tyrosine, valine, methionine, phenylalanine and threonine) and the sum total of amino acids competing with tryptophan for brain uptake were found to be lower in fibromyalgia patients, suggesting gut protein malabsorption may be indicated with subsequent potential influences on neurotransmitter balance.40
Cerebrospinal fluid analysis indicated that in patients with fibromyalgia with other overlapping conditions (as compared to normals and primary fibromyalgia), pain intensity and tender point index co-varied with concentrations of metabolites of the excitatory neurotransmitters, glutamate and asparagines, with glycine and taurine also showing covariance with tender point index measures.41 Arginine, a precursor to nitric oxide, co-varied with tender point index scores for both primary and fibromyalgia associated with other conditions. The authors concluded that an increase in excitatory amino acid release may be associated with increased nitric oxide synthesis eventually leading to increase pain in fibromyalgia patients.41
Central nervous system (CNS)
A 2008 review of literature concluded that recent studies of fibromyalgia highlight abnormalities in the CNS processing of pain leading to increased sensitivity and a lowered threshold for pain. Persistent nociceptive input may lead to plastic changes provoking central sensitisation and chronic pain states. The authors suggested that these central changes were indicative of many of the syndromes that overlap with fibromyalgia, such as IBS, low back pain, migraine and temporomandibular disorders.42
It has also been suggested that autonomic nervous system dysregulation may exist in some patients as exemplified by the common finding of postural orthostatic tachycardia.43 However, the autonomic response in fibromyalgia patients to stress tasks appears to differ within subgroups. Although patients with fibromyalgia consistently demonstrated reduced surface electromyographic (EMG) readings at baseline, subsets of fibromyalgia patients present with increased sympathetic vasomotor reactivity and reduced muscular response with or without increased sudomotor reactivity during stress tasks, while others demonstrated parasympathetic vasomotor reactivity, reduced sudomotor activity and reduced muscular response. These variant autonomous system responses to stress subsequently imply that heterogenous groups of fibromyalgia exist.44 Abnormal responses of the sympathetic nervous system may be related to exaggerated norepinephrine (noradrenaline release) that have been observed amongst female patients with fibromyalgia.45
Cortisol
A review of papers in 2001 found that in one-third of studies, cortisol at baseline was significantly low in one-third of patients while 24-hour urinary cortisol levels are frequently within the lower part of normal.46, 47 Cortisol responses to increased ACTH in stress, exercise and during hypoglycaemic events are often blunted48, 49, 50 suggestive of an impaired ability to activate the hypothalamic pituitary portion of the hypothalamic–pituitary–adrenal (HPA) axis with subsequent adrenal hypo-responsiveness leading to a relative adrenal insufficiency.47–52 A lower expression of corticosteroid receptors has also been observed which may be compounded by lower levels of anti-inflammatory mediators.53
Consistent with this clinical studies have revealed that cortisol levels at waking and 1 hour after waking have a relationship to morning pain scores in women with fibromyalgia, although this relationship does not appear relevant later in the day.54 In the late evening an elevation of cortisol levels was evident in half of all fibromyalgia patients compared to normals and tending towards being statistically lower overnight, again suggesting a loss of resilience in the basal circadian function of the HPA axis.55
Thyroid hormone
Autoimmune thyroid disease (ATD) has been identified in a subgroup of patients presenting with fibromyalgia. An examination of 56 patients with a diagnosis of ATD identified 31% could be classified as having fibromyalgia.56 A study of thyroid antibodies in 128 fibromyalgia patients demonstrated that thyroid autoimmunity existed in 34% of fibromyalgia patients as compared to 18.8% of normals, with the highest frequencies in those patients with previous psychiatric treatment, postmenopausal women and patients presenting with a frequent history of dry mouth.57 In a further study, 41% of fibromyalgia patients had thyroid antibodies despite normal basal ranges, however age and depression were not found to be significant. Frequent symptoms reported in this study included dry eyes, burning/pain with urination, allodynia, blurred vision and a sore throat.58 There is a 4.5 times calculated likelihood of detecting thyroid antibodies associated with fibromyalgia.59
Growth hormone
A physiological dysregulation of the HPA also appears to be a factor in impaired growth hormone secretion (rather than production) frequently reported in patients with fibromyalgia.60, 61 Growth hormone stimulation tests often demonstrate blunted responses suggesting the possibility of hypothalamic origin for growth hormone dysfunction.62
Sleep, melatonin and the immune system
Fibromyalgia patients commonly report early morning awakenings, feeling tired, lack of sleep, cognitive disturbances and on occasion, sleep apnoea. Poor sleep quality has been noted to parallel pain intensity. Fibromyalgia patients often demonstrate sleep abnormalities consistent with normals during sleep deprivation (alpha-delta sleep anomaly), increased stage 1, decreased delta sleep and an increase in the number of sleep arousals.63 Dysfunctional beliefs regarding sleep may also play a role in fibromyalgia.64
Melatonin is important in regulating wake–sleep cycles. Fibromyalgia sufferers appear to have significantly lower levels of melatonin than normal controls. In a study comparing total melatonin secreted between 1800hr and 0800hr and hours of darkness (2300hr to 700hr) fibromyalgia patients were observed to be 31% lower in the latter measure and peak serum levels of melatonin were also considerably lower. It was concluded that these variations in melatonin may lead to the impaired night sleep, day fatigue and altered perceptions of pain associated with fibromyalgia pain.65
Elevations in cytokine levels have also been implicated in sleep–wake dysregulation in fibromyalgia patients. These immune mediators form a link between the periphery and the neuroendocrine, autonomic, limbic and cortical areas of the CNS and have hence been found to mediate sleep, sleepiness and fatigue.66, 67 However, views and evidence appear varied on the input of the immune system and whether it is in an excited or inhibited state. While some papers suggest there is no evidence that fibromyalgia is associated with a heightened immune system response, indeed immunosuppression may be a significant factor, trials with immunotherapies risk inducing fibromyalgia like symptoms.67 Results of C-reactive protein (CRP) studies, however, have indicated raised CRP levels are often present in patients with fibromyalgia.69
Infections
Consistent with findings of immune system involvement is the preliminary evidence that viral and other infections may be present in patients with fibromyalgia. Indeed a review of tender points during acute viral infection indicates that tender points are common and transient features during acute illness.70 Patients with acute episodes of fibromyalgia have been demonstrated to have an increase in IgM antibodies to enterovirus as compared to both chronic fibromyalgia and normal controls, suggesting a variance in their immune response.71 Of fibromyalgia patients, 13% who had muscle biopsies were found to have enterovirus present within their muscle tissue. Persistence of infection was suspected as an influence on fibromyalgia by the reporters due to these associated biopsy findings.72
A study of the presence of mycoplasmal infections in patients with chronic fatigue and/or fibromyalgia indicated that single or multiple mycoplasma organism infections (fermentans, pneumonia, hominis, penetrans) were present in over 50% of these individuals. Infections with mycoplasmal species were consistent with longer symptoms of fibromyalgia.73 Furthermore, it has been hypothesised that mycoplasmal infection may be a significant factor in thyroid abnormalities noted to occur in some fibromyalgia patients.74
A statistical association also appears to exist between Human T Cell Lymphotropic Virus Type 1 infections and patients with fibromyalgia — 38% of patients with this infection experiencing fibromyalgia as compared to 3% of normals.75 There does not appear to be a relationship between fibromyalgia and either hepatitis C (HCV) or human parvovirus B19.76, 77
Lifestyle factors
Psychological
Studies of psychological and psychosocial influences on, and comorbidities with, fibromyalgia also suggest that it is not a homogenous syndrome, with mixed elements individual to each patient being significant dependent upon their psychosocial background.80 For example, a degree of somatization appears to be a significant predictive factor in the development of fibromyalgia. A prospective study of 1658 adult patients demonstrated that patients who developed widespread pain often had a prior tendency towards somatisation.81
A comparison of psychological factors of fibromyalgia when compared to rheumatoid arthritis amongst patients attending a tertiary clinic indicated a high percentage of fibromyalgia patients. Ninety percent (N = 36) had a prior psychiatric diagnosis as compared to less than 50% for rheumatoid arthritis.82 However, while the presence of anxiety and depression are common and may exist in definable subgroups, it has been shown that the degree of the psychological comorbidities of anxiety and depression varies between patients with a subgroup of patients (‘adaptive copers’) demonstrating very few comorbidities at all.80
Psychosocial
A cross-sectional study of the community observed that people with fibromyalgia and chronic widespread pain reported more health impairments than people with no pain, or regionalised pain. There was also an increased incidence of fibromyalgia amongst people of low socioeconomic status, low educational levels, low social support and a family history of chronic pain,83 and amongst employed women and housewives.
Stress
Stress-related issues also appear to be pertinent. Indeed, fibromyalgia patients commonly demonstrate clinically significant levels of post traumatic stress disorder (PTSD)-like syndromes,84 while registering greater levels of significant disability (85% vs 50%). Those fibromyalgia patients with PTSD-like symptoms reported significantly greater levels of pain, emotional distress, life interference and disability as compared to fibromyalgia patients without PTSD symptoms. Only 15% of fibromyalgia patients with PTSD syndromes were considered adaptive copers as compared to 48% without symptoms.
Consistent with this, fibromyalgia patients appear to be associated with higher levels of victimisation than other patients (control group consisted of rheumatoid arthritis patients and other rheumatology patients).85, 86 Forms of victimisation included abuse of a sexual, physical or emotional basis (neglect);87 in particular, adult physical abuse, although childhood abuse was also significant. A further study suggested this relationship (without reaching clinical significance), however, did determine with significance that frequency of abuse was a correlate with fibromyalgia,88 even if this relationship has not always been demonstrated for all forms of abuse.89 Links have also been determined with frequency of drug abuse.88 Work stress, including workplace bullying (almost 4 times as likely), high workload (twice as likely) and low decision latitude also appear pertinent associated related/causal factors.90
Tobacco
People who smoke appear to have higher pain intensities, numbness, severity and functional difficulties than non-smokers with fibromyalgia, however, no significant difference has been associated with number of tender points or fatigue levels.91, 92 Psychiatric therapy use and alcohol consumption were higher in fibromyalgia patients who smoked as was the level of un-restorative sleepiness and anxiety-depression.93 Smokers experienced fewer good days and more days of work missed per week.92
Overview of treatment evidence for fibromyalgia
A review of the multi-factorial causation and associations with fibromyalgia identifies why it is a difficult condition to treat. As a heterogenetic syndrome with multiple overlaps with other functional syndromes and conditions (IBS, chronic fatigue, mood disorders etc.) it is essential that both a multi-disciplinary yet individualised approach is undertaken for each patient with fibromyalgia. This may also explain why many treatment approaches have only a low level of evidence, given that evidential support for treatment methods that might only be successful in particular subsets of patients would be statistically blunted if applied to undifferentiated groups of fibromyalgia patients. This further infers that comprehensive assessment is essential when addressing the patient with fibromyalgia in order to establish which therapy amongst the many advocated for the condition is both pertinent and a priority to the individual.
Multidisciplinary treatment approaches
Given the multi-factorial nature of fibromyalgia, it is unsurprising that multidisciplinary programmes are often applied to fibromyalgia patients. However, while some individual studies have demonstrated improvements from multidisciplinary approaches (group behavioural therapies, stress management, relaxation plus exercise),96–99 a Cochrane review (2000) found there was little evidence that such programmes were of benefit, given the poor quality of existing studies.100 However, subsequent clinical trials continue to indicate the potential of multidisciplinary programmes101 with growing evidence to their efficacy when combinations of behavioural therapies, exercise, relaxation and other such sessions are included.102, 103
Mind–body medicine
A study of 28 fibromyalgia patients showed that cognitive behaviour therapy (CBT) was superior to pharmacological intervention (cyclobenzaprine) during treatment and follow-up.103 Small studies of electromypgraphy and electro–encephalography biofeedback also suggests that it has the potential of being effective.105, 106 Pilot and small studies of hypnosis also advocate continued investigation.107–110
Small-scale evaluation of mindfulness meditation indicated that 8 by 2.5 sessions of mindfulness-based stress reduction may reduce the depressive symptoms in women with fibromyalgia.111 A trial of meditation-based stress management during a 10-week outpatient group programme indicated effectiveness, however, identified a specific subgroup (51%) of responders who gained through better sleep, reduced fatigue and increased feelings of rejuvenation in the morning.112 A 7-week trial of qigong indicated potential benefits amongst 29 female fibromyalgia patients,113 however a combined meditation–qigong intervention was found to be only equivalent to education and support.114 The use of guided imagery focusing on pleasant imagery as a distraction from the pain of fibromyalgia was found to be effective, however the use of attention imagery was not.115 Relaxation and guided imagery was also found to be of benefit in a small trial of Hispanic patients.116
In summary, while various mind–body therapies have been recommended for fibromyalgia and pooled evidence is suggestive of benefit,117 further evidence is required before we can conclude definitive benefits for specific treatment approaches.
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