Chapter 23 Fibromyalgia
AETIOLOGY, EPIDEMIOLOGY AND CLASSIFICATION
The American College of Rheumatology (ACR) definition of fibromyalgia (FM) has been based on generalised pain as the primary symptom; however, many of these patients present with a wide variety of complaints including, but not limited to, increased frequency of fatigue, non-restorative sleep, IBS, headache and impaired cognition and mood.1 It is more prevalent in women, ages 20–50 years, but has also been seen in paediatric and geriatric populations. It affects 0.5% to 5.8% of the population in North America and Europe.2 The diagnosis has been based primarily on subjective reporting of widespread pain, with the absence of objective findings or a known aetiology. Research has identified biochemical and metabolic abnormalities that are common to this particular group. Presently, there is a movement to redefine this disorder to include its multisystem effect and find objective, measurable biomarkers.3
The 1990 American College of Rheumatology criteria for classification of fibromyalgia1 are widespread pain for at least 3 months, defined as the presence of all of the following:
Pain, on digital palpation, must be present in at least 11 of the following 18 tender point sites (see Figure 23.1). All sites are bilateral:
The aetiology of fibromyalgia is not fully understood, but ongoing research has been elucidating some possible mechanisms for this syndrome. Biochemical, metabolic and cellular changes have been demonstrated in multiple systems including mitochondrial dysfunction with aberrations in ATP synthesis and use, central nervous system (CNS) changes affecting cerebral blood flow, neurotransmitter synthesis and function and increased pain perception.4 HPA axis function is affected, resulting in a hyporesponsiveness of the adrenals and circadian rhythm abnormalities.5 Somatic and visceral alterations have also been demonstrated in the literature.6 The result of these changes contributes to the high incidence of comorbidities associated with this syndrome.
RISK FACTORS
There are a variety of risk factors associated with FM patients, including genetics, and comorbidities with other rheumatological conditions and chronic fatigue syndrome (see Chapter 35 on chronic fatigue syndrome). One of the most consistent findings is that the prevalence among females compared to males is as high as 9:1,2 which is also common to these comorbid conditions. Previous history of domestic violence, abuse and emotional trauma appear to be factors as evidenced by the epidemiological data.7 The presence of poverty, poor support and lower educational status may be a predisposing factor associated with the high incidence of mood disorders and decreased pain threshold.8 These triggers, when combined with the prevalence of non-restorative sleep,
Table 23.1 Predictive risks factors for developing fibromyalgia7,8
| AGE 20–50 YEARS | FEMALE > MALE (9:1) |
|---|---|
| Lower education level and socioeconomic status | Non-restorative sleep |
| Increased incidence of anxiety, depression and somatisation | Comorbidity with other rheumatic diseases, such as rheumatoid arthritis and lupus |
| History of physical, sexual, emotional abuse or trauma | Comorbidity with chronic fatigue syndrome |
| Poor social support system | High prevalence of gastrointestinal dysfunction and dysbiosis |
| Abnormal stress response | Other family members with symptoms of fibromyalgia and common enzyme defect |
predispose the FM patient to irregularities in the HPA axis that are common in this cohort.9 This spectrum of systemic changes along with aberrations in the health of the gastrointestinal tract contribute to this cascade via alterations in serotonin synthesis and use, nutritional deficiencies and immune dysfunction and must be differentiated from other disease patterns presenting with myalgias.3
CONVENTIONAL TREATMENT
A variety of allopathic medications have been used in the treatment of FM, including muscle relaxants, antidepressants, anticonvulsants and other CNS agents. The antidepressants typically prescribed are tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs) and monoamine oxidase inhibitors (MAOIs).10 NSAIDs and steroids alone have not been shown to be effective.10 Review of a meta-analysis on patients using the muscle relaxant cyclobenzaprine revealed a reduction in pain initially and improvement in sleep, but no change in tender points or fatigue.11 A recent meta-analysis representing the efficacy of different antidepressant classes on the parameters associated with fibromyalgia revealed amitriptyline and duloxetine as having the most overall effectiveness. The author’s conclusion of the meta-analysis was that, based on the data, these two medications can justifiably be recommended, in the short term, for pain and sleep disturbances.12
Table 23.2 Medication overall effect using p value∗: meta-analysis of 18 randomised controlled trials (RCTs)12
TREATMENT OF GENERAL MUSCLE TENSION AND PAIN
Due to the increased side effects of the TCAs, low doses are typically prescribed; this may account for the lack of improvement in depression. The median duration for the RCTs was 8 weeks (4 to 28 weeks). The long-term effect of the medications and posttreatment improvement has not been elucidated in-depth in the literature. Median drop-out rates did not differ between the placebo and antidepressant groups due to adverse effects. Because of the possibility of suicidal thinking, in the United States of America most medications approved for fibromyalgia carry a black box warning from the Food and Drug Administration (FDA); these include duloxetine (SNRI), milnacipran (SNRI) and pregabalin, a GABA analogue typically used to treat neuropathic pain and seizures.13,14
KEY TREATMENT PROTOCOLS
Mitochondrial and cellular changes
Metabolic changes occur at the cellular level, causing functional aberrations in FM patients. These include changes in glycolysis and isoenzyme production and reduction of energy reserves. Increased lactate production and decreased lactate dehydrogenase isoenzymes were present in the muscle tissue of FM patients.15 A small study using magnetic resonance spectroscopy revealed decreased phosphocreatine, an essential muscle energy storage form, and reduced ATP levels in the quadriceps of FM patients compared to controls during rest.16 Total oxidative capacity and phosphorylation potential was also reduced during rest and exercise.16 Another study found decreased platelet ATP, along with higher calcium and magnesium levels, implying irregularities in the calcium magnesium pump mechanisms at the cellular level.17 These biochemical aberrations contribute to the fatigue, weakness and exercise intolerance associated with FM.
The role of magnesium includes glycolysis and mitochondrial function.18 ATP biosynthesis and metabolism in FM patients are affected by a disturbance in its use.19 Inconsistencies in the levels of magnesium are evident in the various blood components. Increased platelet magnesium and calcium levels have been found, and low serum and RBC magnesium levels are noted.20,21 Reduced serum magnesium levels appear to correlate with fatigue, but not to the number of tender points.22 In a small placebo controlled trial, malic acid, a precursor to malate (an intermediary in the citric acid cycle), was combined with magnesium. The effects of a 4-week course of magnesium/malic acid 300/1200 mg were compared to those of a 600/2400 mg dosage. Significant reductions in pain and tenderness measures were seen at higher dosages given for at least 2 months.21,23 A randomised, double blind, placebo controlled 8-week study using an IV micronutrient therapy (IVMT), Myers’ cocktail (which contains magnesium), thiamine, vitamin C, calcium and B vitamins demonstrated statistically significant improvement in tender points, pain, depression and quality of life in the IVMT group at 8 weeks, while the placebo group of IV lactated Ringer’s solution showed statistically significant improvement in tender points. The dramatic response of the placebo group negated a statistical significance between the groups. The response persisted for 4 weeks posttreatment for both groups.24 An 8-week uncontrolled case study of seven previously non-responsive patients by Massey revealed a 60% decrease in pain and 80% reduction in fatigue.25
The irregularities of the calcium–magnesium pump mechanism as suggested by Bazzichi may play a role in the muscle pain attributed to fibromyalgia.16 Other aberrations in calcium absorption and use may exist in the patient presenting with widespread pain. Vitamin D in the form of 1 alpha, 25-(OH)2-vitamin D3 promotes the calcium-dependent exocytotic activities of the cell when coupled with ATP, potentiating the bone anabolic effects of this nutrient.26,27 A deficiency of vitamin D may masquerade as a generalised non-specific pain, depression and poor fibromyalgia assessment scores.28 One author proposes that the widespread pain associated with low levels of vitamin D is secondary to reduced calcium absorption, which increases PTH levels.29 Elevated PTH causes increased urinary excretion of phosphorus, resulting in low levels of circulating calcium phosphate, ultimately leading to a poorly mineralised collagen matrix. Endosteal and periosteal swelling may occur secondary to the affected collagen on the surfaces, triggering bone and muscle pain.
In multiple studies of patients presenting with persistent non-specific muscle pain as well as fibromyalgia, 25-OH vitamin D levels were frequently depressed.29,30 Supplementation of vitamin D2, 50,000 IU weekly for 8 weeks, yielded significant clinical improvement in mild to moderately (10–25 ng/mL) deficient patients, but not severely deficient patients.28 However, this regimen of supplementation has not consistently yielded pain reduction in moderately deficient patients, even after 3 months.31 Vitamin D deficiency has also been associated with decreased cognitive performance and mood disorders, especially anxiety and depression.32,33 Evaluation of 25-OH vitamin D levels and correction of low serum levels are warranted in all patients presenting with widespread pain. In addition to the possible benefit to FM, depressed levels of vitamin D have been associated with increased risk of breast cancer and osteoporosis in this primarily female population.34 The optimal level of 25-OH vitamin D remains a controversial topic and one study recommended a minimum of ≥ 40 ng/mL for breast cancer prevention.34 The optimal level for fibromyalgia patients still remains unclear.34
Phosphorylated D-ribose is a component of ATP and NADH as D-ribose-5-phosphate, and may be helpful to FM patients. A small uncontrolled trial of 41 patients with FM and/or chronic fatigue syndrome, given 5 g of ribose three times daily, revealed significant improvement in energy and wellbeing according to a visual analogue scale.35 Due to the limitations and positive results of the study, further investigation of D-ribose would be valuable.
Neurotransmitter effects
The concept of ‘somatisation’ has been associated with fibromyalgia secondary to the increased reporting of hypersensitivity to pain, cognitive dysfunction, depression, anxiety, social isolation and insomnia.36 There is an increased incidence of adverse life events and psychological distress common to this primarily female cohort.7 In addition to psychosocial stressors, the biochemical changes associated with neurotransmitter synthesis and use have been implicated and may contribute to the mental and emotional state of these patients (see Section 4 on the nervous system).
There is a genetic correlation of FM in families secondary to a defect in neurotransmitter metabolism. This polymorphic rate defect displays itself in catecholamine turnover secondary to catecholamine-O-methyl transferase enzyme and is linked to dopaminergic, adrenergic/non-adrenergic neurotransmission and the mu-opioid system.37 This aberration has been associated with increased nociceptive response to painful stimuli. In addition to dopamine and epinephrine metabolism, reduced levels of serotonin and its precursors, tryptophan and 5-hydroxytryptophan (5-HTP), are seen.38,39 Low levels of plasma and serum serotonin (5-HT) have been highlighted in the literature and pharmacological treatment has focused on the use of antidepressants, most recently SSRIs and SNRIs, for treatment of pain, sleep and mood disturbances.40 In FM patients, low levels of serotonin in combination with elevated levels of substance P, a neurotransmitter that has been associated with enhanced pain perception secondary to normal stimuli, has been considered to be a precipitating factor for the increased pain hypersensitivity found in fibromyalgia.41
The conversion of tryptophan to serotonin involves the intermediary, 5-hydroxytryptophan (5-HTP). This biochemical pathway may be inhibited by stress, insulin resistance, tetrahydrobiopterin, pyridoxal 5-phosphate and magnesium deficiency.42 Supplementation with 5-HTP alone has shown significant improvement in the number of tender points, anxiety, fatigue, pain intensity and quality of sleep during a 90-day trial of patients with primary fibromyalgia syndrome. Mild transient side effects were reported in 30% of the patients.42,43
Another metabolic pathway is the use of S-adenosyl methionine (SAMe) in the conversion of 5-HT to melatonin. It acts as a coenzyme and a methyl donor, and has been shown to be an effective antidepressant in psychiatric populations.44 In FM patients there is a correlation with depression and the number of trigger points. When patients were treated with 200 mg of injectable SAMe, both depression and the number of trigger points significantly improved.45 A 6-week trial of oral SAMe revealed improvement in fatigue, mood and morning stiffness.46 Reduction in pain, but not tender point count, occurred during week 6 of the trial and may warrant a longer investigation to realise the potential benefits.
The use of botanicals specifically for the treatment of FM has not been well documented in the scientific literature. Since combination formulas are the traditional mode of botanical dispensing, a balanced combination of botanicals would most likely best address the complex nature of a FM patient. However, single botanicals addressing the separate components of this syndrome will be presented, allowing the naturopathic practitioner to develop an individualised compound to best suit the needs of their patients (see Table 23.3).
Table 23.3 Fibromyalgia: herbal medicine actions and examples47,48
| 1. Adaptogens/tonics |
| Withania somnifera, Panax ginseng, Rhodiola rosea, Eleutherococcus senticosus |
| 2. Antispasmodics |
| Viburnum opulus, Piper methysticum, Piscidia erythrina, Scutellaria lateriflora |
| 3. Nervines |
| Scutellaria lateriflora, Passiflora incarnata, Matricaria recutita, Melissa officinalis |
| 4. Thymoleptics |
| Hypericum perforatum, Avena sativum, Lavandula angustifolia, Turnera diffusa |
| 5. Hypnotics |
| Humulus lupulus, Passiflora incarnata, Valeriana spp. |
| 6. Analgesics |
| Corydalis ambigua, Eschscholtzia californica |
| 7. Digestives (aromatics, bitters, mucilages) |
| Zingiber officinale, Taraxacum officinale, Ulmus fulva |
| 8. Circulatory stimulants |
| Zingiber officinale, Ginkgo biloba, Cinnamomum zeylanicum, Zanthoxylum spp. |
The botanical Rhodiola rosea was found to increase 5-HT levels in the hippocampus of depressive rats to normal levels using 1.5 g/kg, 3 g/kg and 6 g/kg dosages.49 A randomised placebo controlled double-blind study of Hypericum perforatum in the treatment of depressive patients with somatic complaints including depression, fatigue and disturbed sleep resulted in 70% of the patients being symptom-free after 4 weeks.50 H. perforatum administration in the unstressed rat population revealed a decrease in tryptophan, an increase in corticosterone and lower 5-HT in the hippocampus and amygdala under stressful physical conditions. Serum 5-HT levels increased more than 110%, 163% and 172% in the hypothalamus, amygdala and hippocampus respectively (p < 0.01), demonstrating an adaptive response to stress. Tryptophan and corticosterone levels did not change significantly.51 In addition, a meta-analysis, including the Cochrane database, comparing HP to key SSRIs revealed that there was a similar efficacy between the medications, but fewer side effects with the HP.52,53 The botanical Scutellaria baicalensis, which has traditionally been used as a ‘nervine’, contains a metabolite similar to hyperforin, which is found in H. perforatum and would demonstrate similar actions.54
The circadian rhythm
Dysregulated circadian rhythms, manifesting as poor sleep patterns, non-restorative sleep and chronic fatigue, have been reported in fibromyalgia patients.55 Elevation of late evening cortisol and alterations in melatonin levels may contribute to the poor sleep patterns seen in this cohort.56 Normal basal circadian rhythm is typically evidenced by a sharp rise in serotonin synthesis and a release of 5-HT in the early evening, preceding an elevation in melatonin production. There are conflicting data regarding melatonin secretion in FM patients. Decreased urinary melatonin secretion levels were found between the hours of 11 p.m. and 7 a.m.57–59 Meanwhile, in another study, plasma melatonin levels were elevated in FM patients between the hours of 11 p.m. and 6:50 a.m. compared to controls, but secretory patterns remained similar.5 This discrepancy between urinary and plasma melatonin levels was not demonstrated in normal non-depressed patients.60
