Fibromyalgia syndrome (FMS) is a condition characterised by chronic widespread pain, alongside fatigue, disturbed sleep and a combination of poor memory and poor concentration [1
]. There is also a high prevalence of many co-morbidities [2
], including: anxiety, depression [3
], temporomandibular joint disorder (TMJ) [4
], chronic fatigue syndrome (CFS) [5
], migraines [6
] and/or headaches [7
], and irritable bowel syndrome (IBS) [8
]. The exact combination of and severity of symptoms and comorbidities varies substantially between individuals. The aetiology and pathophysiology of FMS remains unclear; however, current literature supports the hypothesis of central sensitisation to be involved whereby pain signals and subsequent sensations are amplified within the pathways of the central nervous system (CNS). This often leads to many of the aforementioned symptoms and comorbidities found in FMS [9
]. Regardless, fibromyalgia is a complex and multifaceted condition affecting each individual in a unique manner, with pain at the forefront. The experienced pain not only reduces overall quality of life but also has a significant impact on basic functions such as sleep and cognitive ability. This in turn exacerbates pain severity, leading to a “vicious-circle” of symptomatology and mental health problems, and a key feature of conditions characterised by central sensitisation [10
There is no gold standard diagnostic process for fibromyalgia. Individuals are instead diagnosed with FMS if they meet the classification criteria drawn up by the American College of Rheumatology (ACR), first conceived in 1990 [12
] and with three revisions; in 2010 [13
], 2011 [14
], and 2016 [15
]: Prevalence, therefore, depends on which diagnostic criteria was used at the time [16
]. Compared to the 1990 ACR criteria, the 2010 and 2016 revisions had a sensitivity of 86% and 89.5% respectively [15
]. The most recent estimate of worldwide prevalence of FMS is 1.78%, with a mean prevalence of 3.98% in women and 0.01% in men [17
]. FMS thus appears to be more prevalent in women, and, with age, those with low socioeconomic status, low education levels, and, those who live in rural areas [18
There is also no gold standard treatment for FMS. Treatment regimens can and should vary significantly from person to person depending on their symptoms [19
]. Despite this variability, individuals typically receive a combination of pharmacology, physiotherapy and cognitive behavioural therapy (CBT) [20
]. Patients rarely experience full remission of symptoms, with only 25% noting any long-term improvements [21
]. This may contribute to findings that individuals with FMS, routinely seek complimentary or alternative methods to control their symptoms [22
]. Nutritional interventions or dietary changes are commonly used as alternative treatment approaches across many illnesses, including chronic pain conditions such as rheumatoid arthritis [23
]. Despite a lack of research relating to the effect of dietary interventions or supplements, individuals with FMS frequently make dietary changes in an attempt to control their symptoms [24
Dietary interventions may allow individuals with FMS to have an active role in the management of their condition and may fall within the scope of dieticians or nutritionists. Dietary intake as a whole, influences many physiological systems and processes, therefore, clinicians and patients alike should be aware of the dangers of following anecdotal evidence in regards to dietary interventions. Even if such changes positively influence fibromyalgia and its underlying mechanisms, it may negatively influence other physiology. Regardless, the ability for certain elements of nutrition to directly or indirectly affect the pathophysiology or symptoms of FMS, should not be ignored. There exist a number of potential mechanisms by which nutrition could be beneficial including but not limited to: oxidative status or damage; dysfunction of pro-inflammatory or anti-inflammatory modulation; dysfunction of energy production; or, dysfunction of the neuromodulation within the peripheral or central nervous systems. To recommend any nutritional intervention, will require extensive randomised, controlled, human trials. These will lead to informed and evidence-based choices and will therefor protect both the individual’s health and financial status. Currently there is a lack of conclusive data on any nutritional interventions. This paper aims to systematically review the existing literature and to explore dietary changes—including the use of nutritional supplements—as an intervention in the treatment of FMS as a whole and its many symptoms.
This review of 22 nutritional intervention studies provided conflicting results across a multitude of outcome measures. Pain which is often regarded as the characterising symptom of FMS was significantly improved after the consumption of: Chlorella green algae, vegan diet, coenzyme Q10, acetyl-l-carnitine; a low-FODMAP diet; and, a combination of vitamin C, E and Nigella sativa seeds.
The baseline characteristics of participants recruited within the studies are in keeping with other fibromyalgia intervention studies and in keeping with the typical characteristics in the wider population of individuals with fibromyalgia [54
]. Participant numbers were generally quite low (mean = 37). Sample sizes of the studies included in this review ranged from eight to 75, however, only six of the 22 studies justified their sample size [33
] based on power calculations or previously published fibromyalgia intervention studies therefor, the significant findings found among many of the included studies should therefore be interpreted with caution [55
]. Further research in nutritional intervention studies should not only seek to recruit larger samples, but also ensure it is statistically sound in terms of being sufficiently powered. Otherwise, the ‘significant’ findings as found within this review, may not be significant at all when applied to the wider demographic.
Dosage and duration of any intervention can have a significant impact on their efficacy. Due to the heterogeneity of the specific interventions across this review, there was some variability in terms of the exact dosage and duration, even within the same intervention. The use of nutritional interventions in alleviating symptoms that the nutrient is not primarily associated with contributes to the difficulty in analysing efficacy. For example, the pathophysiology of how vitamin D regulates calcium absorption is very well understood, which allows researchers to carefully look at specific biomarkers and dosage, in determining the effect that dietary intake of vitamin D may have. Conversely, the pathophysiological understanding of how vitamin D may affect pain is poorly understood, thus determining dosage and duration of intervention studies for pain is much more difficult. A common approach is to refer to recommended intakes and/or nutritional status. In some instances, however, it may not always be possible to target a specific measure of nutritional status for the corresponding intervention, such as the vegan diet included within this review [45
]. A dietary protocol such as that described simply involves the exclusion of animal products and there were no restrictions on the ‘dosages’ of the food(s) the participants were permitted to consume. The recording of the nutritional status of the specific nutrients being investigated is of paramount importance when analysing the effect of nutritional interventions [56
]. Researchers need to demonstrate if their chosen demographic present with deficiencies in the nutrient being investigated and ensure that their chosen dosage results in, first and foremost a meaningful change in nutritional status, and, that this change is maintained until the subjects nutritional status meets the recommended concentrations. Unfortunately, these methods are not commonly implemented, again suggesting caution when interpreting results. Interventions such as soy [34
], olive oil [37
], tart cherry juice [45
] or the phytonutrient regimens [29
] included within this review contain many nutrients and fall short of being able to accurately measure any one particular nutrient to ascertain pre and post nutritional status. Finally, several of the studies included within this current review involved elimination diets [31
], eliminating FODMAPs, glutamate and aspartame; of which none documented pre and post nutritional status of these substances.
There was evidence of selection/recruitment bias across several of the included studies with others having no information at all with regards to the recruitment/sampling process. Seven studies recruited directly from active treatment groups within their geographical area [34
One of the biggest limitations of this review was the heterogeneity among studies, especially with regards to outcome measures. Fibromyalgia as a condition incorporates a myriad of symptoms and comorbidities which can vary significantly among sufferers. In particular, individuals with fibromyalgia have been known to report significant variability in pain, mood and fatigue [57
]. The outcome measures used to record pain levels varied significantly with the Visual Analogue Scale (VAS) for example was used in 63.64% of the included studies. The main benefit of the VAS is the speed of which it can be implemented however it has a key limitation in that it requires specific context when put towards a participant e.g., current pain level, pain level in the last 24 h, low back pain or headache pain. As pain manifests itself in many different ways, one could argue that a multidimensional scale such as the McGill Pain Questionnaire [58
] may be more appropriate.
Unless investigating specific nutrients or ingredients, blinding of participants in dietary or nutritional intervention studies, using sufficient control measures is challenging. This is made more difficult if the intervention involves an overarching dietary principle such as those in this systematic review: vegan diet [45
], low-FODMAP diet [43
], or elimination diets [29
]. The majority of studies which did
facilitate blinding or randomisation of participants, lacked specific details as to how this was achieved. Volunteer bias existed in several studies; in particular, the individuals who chose the vegan dietary intervention being studied, had significantly higher levels of pain [45
]. This may indicate that those with more severe symptoms are more likely to seek complementary or alternative forms of treatment.
The theory of treating a condition like fibromyalgia using nutritional interventions is complex. There is a lack of understanding as to how the intervention may affect the underlying pathophysiology. Understanding of the mechanisms involved is made more difficult as at least some symptoms and comorbidities appear to directly influence each other and thus may lead to unnecessary or frivolous attempts at treating the condition [59
]. Additionally, having fibromyalgia does not exclude an individual from also developing other conditions; making it difficult for patients and clinicians to differentiate what can be attributed to fibromyalgia, thus providing further confusion in regards to treatment. For example, an individual who has fibromyalgia, may also receive a diagnosis of osteoarthritis (OA) and/or rheumatoid arthritis (RA). There is some evidence that n-3 long chain polyunsaturated fatty acids (LCPUFA) may reduce pain in those diagnosed with both OA and RA [60
]. Currently it would be difficult for a sufferer of both these conditions to differentiate between these, and fibromyalgia; therefore attributing the treatment effect of a nutritional intervention would be equally as difficult.
The majority of studies included within this review lack a full understanding as to how their proposed nutritional intervention may influence pathophysiology. Despite this, there are several hypothetical pathways in which the interventions reviewed may influence the pathophysiology and/or symptomology of fibromyalgia. These include: amelioration of oxidative stress, reduction of inflammatory markers; amelioration of mitochondrial dysfunction and, removal of dietary “toxins.” Several interventions cross over a number of these. Table 4
identifies the interventions included within this review and their hypothesised mechanisms and physiological benefit. When results were analysed in terms of each of these hypothesised mechanisms, no one mechanism appeared to be any more or any less promising. Without investigating corresponding biomarkers for each of these mechanisms it would be speculative to suggest any one mechanism supersedes the rest.
Individuals with FMS have been found to have significantly higher levels lipid perioxidation in their skin [63
] and significantly higher total oxidant status and serum prolidase in fasting blood samples [64
] which are also positively correlated with VAS-Pain and VAS-Fatigue. Oxidative stress also plays a pathophysiological role within the neuropathic pain of diabetic neuropathy [65
] and chemotherapy-induced neuropathy [66
]. There is also evidence that oxidative stress correlates significantly with specific inflammatory biomarkers such as Tumour Necrosis Factor Alpha (TNF-α) and C-Reactive Protein (CRP) in individuals with rheumatoid arthritis [67
Significant positive correlations were also noted with markers of oxidative stress and inflammatory cytokine interleukin (IL)-6 in patients with Major Depressive Disorder [68
]. CRP and TNF-α have also been found to be significantly higher in individuals with fibromyalgia compared to healthy controls [69
] and have been found to correlate positively with pain and fatigue [71
]. The relationship between oxidative stress and inflammatory changes is complex with both mechanisms being interdependent. A pathology manifesting as a primary oxidative stress condition will eventually lead to inflammation which further exacerbates levels of oxidative stress and vice versa [72
]. For optimum outcomes it is proposed that chronic patients may benefit from the treatment of both.
More specifically, oxidative stress has also been shown to exacerbate neuroinflammatory
changes as evidenced in neurodegenerative disorders [73
] and may have a similar effect within fibromyalgia. Evidence does exist of systemic inflammation, and specifically, central neuroinflammation in individuals with fibromyalgia [74
]. Animal models have shown that oxidative stress leads to the activation of spinal microglial cells leading to the overexpression of TNF-α, IL-1β and IL-6 [75
]. Furthermore, brain glial activation has been noted in both fMRI and PET imaging in individuals with fibromyalgia [76
]. This may in part account for the aforementioned central neuroinflammation in humans. Such inflammatory changes could hypothetically lead to increased phosphorylation of N-methyl-D-aspartic receptors in spinal dorsal horns thus playing a role in the central sensitization of fibromyalgia [75
]. Diets high in consumption of fruit and vegetables have been shown to reduce oxidative stress [77
]. Furthermore, dietary interventions such as soy protein, n-3 LCPUFA, low-fat-low-carbohydrate diet and grape polyphenols have been successful in reducing inflammatory biomarkers including TNF-α and CRP [78
]. Consumption of a Mediterranean diet resulted in significantly lower IL-6 and CRP concentrations individuals with metabolic syndrome when compared to controls [79
]. Individuals who consume a diet high in fruits, vegetables, whole grains, white meat, tomato, legumes, tea and fruit juices were significantly and inversely related to markers of systemic inflammation even after controlling for BMI and waist circumference. Conversely, diets rich in refined grains, red meat, butter, processed meat, high-fat dairy, sweets, desserts, pizza, potatoes, eggs, hydrogenated fats and soft drinks were found to be significantly and positively correlated to markers of systemic inflammation [80
]. This may account for the positive changes noted within this review from the vegan diet [45
], chlorella green algae [35
] or extra-virgin olive oil [37
Individuals with FMS have also been shown to present with mitochondrial dysfunction [63
] and significantly reduced coenzyme Q10 concentrations [82
]. Further evidence suggests that levels of oxidative stress and mitochondrial dysfunction, through coenzyme Q10 levels are correlated with fibromyalgia symptoms [84
]. Supplementation of coenzyme Q10 has been shown within this review to improve these markers and the symptoms of FMS [38
]. Animal models [85
] have demonstrated a significant improvement in oxidative status and inflammatory markers after the consumption of acetyl-l
-carnitine. L-Carnitine is routinely converted to acetyl-l
-carnitine and back again depending on the cells’ requirements. Supplementation of L-carnitine has demonstrated significant improvements in oxidative status of human participants [86
]. Future nutritional intervention studies should account for the lack of physiological understanding and facilitate ways in which to measure the appropriate biomarkers to either support or negate their hypothesis.
This review concludes that there is insufficient evidence to recommend any one particular dietary intervention in the management of FMS symptoms. Most studies lack power calculations and have a small number of participants. Widespread heterogeneity exists across study methodology, particularly with regards to intervention protocol and outcome measures making comparisons between studies very difficult. Study quality was relatively good across the included studies; however, the majority had a high risk of bias, with several also lacking blinding and/or randomisation. Finally, several papers did not publish specific values for outcome measures making comparisons with other interventions difficult. Because of these limitations, the statistically significant findings should be interpreted with caution, especially in terms of their clinical significance. These findings are in keeping with a recent systematic review by Silva and colleagues [87
Conventional therapies in the treatment of fibromyalgia. Despite these substantial limitations, a reduction in pain and overall severity of fibromyalgia was observed in those studies who supplemented with Chlorella green algae, coenzyme Q10, acetyl-l-carnitine, a vegan diet, extra-virgin olive oil, a low-FODMAP diet, a combination of vitamin C, E and Nigella sativa seeds. Each of these interventions have been shown to be involved in improving oxidative status, energy production and inflammatory markers. Coenzyme Q10, in particular, appears promising as it has been associated with benefits to oxidative stress, energy metabolism and in regulating inflammation. Further research is required across each of the interventions within this review, with statistically sound sampling methodologies and measurements of oxidative stress and inflammatory biomarkers to further bolster pathophysiological understanding. Further research may also benefit from investigating certain combinations of nutritional modalities. For example, a nutritional intervention grounded in an anti-oxidative mechanism combined with one with an anti-inflammatory mechanism, versus anti-oxidative or anti-inflammatory alone. This may demonstrate the interplay within and between such systems and how this may or may not affect the pathophysiology of fibromyalgia. If these interventions show further promise in well-designed clinical trials if may provide an active treatment protocol to use with or without.