Nutritional Interventions in the Management of Fibromyalgia Syndrome

Fibromyalgia (FM) is a multifactorial syndrome of unknown etiology, characterized by widespread chronic pain and various somatic and psychological manifestations. The management of FM requires a multidisciplinary approach combining both pharmacological and nonpharmacological strategies. Among nonpharmacological strategies, growing evidence suggests a potential beneficial role for nutrition. This review summarizes the possible relationship between FM and nutrition, exploring the available evidence on the effect of dietary supplements and dietary interventions in these patients. Analysis of the literature has shown that the role of dietary supplements remains controversial, although clinical trials with vitamin D, magnesium, iron and probiotics’ supplementation show promising results. With regard to dietary interventions, the administration of olive oil, the replacement diet with ancient grains, low-calorie diets, the low FODMAPs diet, the gluten-free diet, the monosodium glutamate and aspartame-free diet, vegetarian diets as well as the Mediterranean diet all appear to be effective in reducing the FM symptoms. These results may suggest that weight loss, together with the psychosomatic component of the disease, should be taken into account. Therefore, although dietary aspects appear to be a promising complementary approach to the treatment of FM, further research is needed to provide the most effective strategies for the management of FM.


Introduction
Fibromyalgia (FM) is a complex, multifactorial syndrome characterized by widespread chronic pain and a constellation of somatic and psychological manifestations, including fatigue, joint stiffness, sleep disorders, depression, anxiety, gastrointestinal and cognitive disorders [1][2][3]. Diagnostic criteria have recently been updated by the American College of Rheumatology and, using these criteria, FM is now recognized as one of the most common chronic pain conditions and the second most common cause of visits to rheumatologists after osteoarthritis [4]. It can occur at any age with a prevalence of 2-8% in the general adult population, and is more common in women than men, with a ratio of 2:1 [5,6]. Despite progress in understanding the mechanisms involved, the etiology of FM is still unknown, and the pathophysiology uncertain. Various evidence supports the hypothesis that FM is a "central pain disorder", with alterations in central nervous system function leading to increased nociceptive processing [7,8]. Furthermore, recent evidence suggests that low-grade systemic inflammation, a preponderance of prooxidative status and an insufficient antioxidant capacity, could contribute to the development of the disease, reducing the pain threshold and inducing fatigue and mood disorders [9,10]. FM shows strong family aggregation and, although this may be due to shared environmental or behavioural influences, twin studies have revealed that genetic variants and hereditary mechanisms contribute to 50% of the risk of developing chronic pain and related conditions in FM [11][12][13]. Currently, no predisposing gene has been found, but it has been reported that several environmental factors, such as psychological and physical trauma or certain infections, can trigger development and influence the severity of FM through epigenetic mechanisms [14,15]. It is believed that there is a bidirectional temporal association between some psychological stressors and FM, with an increased risk of developing each other, suggesting a potential shared pathophysiological mechanism underlying these different conditions [16].
To date, optimal management of FM requires a timely diagnosis, together with a comprehensive assessment of pain, function and psychosocial context. Effective treatment is not available, and experts recommend nonpharmacological therapy as a first-line strategy, with the pharmacological option to be chosen only in case of lack of effect [17,18]. Among the nonpharmacological treatment options, nutrition has shown increasing interest in the literature in recent years [19][20][21]. This review aims to summarise the possible relationship between FM and nutrition, exploring the role of nutrients, foods and dietary patterns in FM syndrome.

Nutritional Supplementation and Fibromyalgia
An imbalance of dietary components, including minerals and vitamins, can play a critical role in the development of FM. A survey conducted by Arranz and colleagues [22] revealed that 73% of the subjects affected by FM are users of nutritional supplements, and 61% of these became users after the onset of the disease. A recent meta-analysis showed little evidence to support the hypothesis that vitamin and mineral deficiencies could play a significant role in the development of FM, or that the use of nutritional supplements could be effective in these patients [23]. However, some intervention studies evaluating the possible effects of nutritional supplements on FM patients have been published to date and are reviewed in Table 1.

Vitamin D
Some evidence suggests that vitamin D supplementation should be considered in the management of FM in light of the fact that about 40% of FM subjects have been reported with vitamin D deficiency [37]. In addition, several studies have suggested an association between low serum vitamin D levels and chronic pain, depression and anxiety in FM patients [38,39]. The first study investigating the effect of vitamin D supplementation on FM subjects was conducted by Arnold and colleagues in 2008 [25]. Ninety FM patients with mild to moderate vitamin D deficiency were randomly assigned to receive 50,000 units of cholecalciferol (vitamin D 3 ) per week compared with a placebo. After 8 weeks of intervention, the treated group showed a significant improvement in FM scores, in contrast to the placebo group [25]. Subsequently, other studies were performed to evaluate the effect of vitamin D supplementation in FM patients [26][27][28][29][30][31]. Although in a limited sample of participants, all of these studies reported a beneficial effect of vitamin D supplementation. Only the study by Warner et al. reported inconclusive results regarding the benefits on FM symptoms [24]. However, all authors stressed the importance of testing serum vitamin D levels and recommend supplementation when risk factors for vitamin D deficiency are present.

Vitamin C and Vitamin E
Antioxidant vitamins such as vitamin C and vitamin E can play a beneficial role in the management of certain typical symptoms of FM, since they are useful for preserving the cerebellar functions, memory, emotive responses as well as muscle function [40]. However, there are currently no consistent studies in the literature. A recent meta-analysis reported lower levels of vitamin E in FM patients than in healthy controls, although this difference disappeared when low quality studies were excluded from the analysis [23]. In addition, treatment with vitamin C and E combined with or without exercise compared to exercise only in 32 women with FM over a 12 week period did not show a statistically significant improvement in FM symptoms, although both interventions resulted in significantly higher serum levels of vitamin A, C and E [32].

Minerals
Regarding the mineral status, several studies have shown a decrease in intracellular magnesium content in FM patients [41,42]. Magnesium deficiencies were largely associated with low-grade inflammation, muscle weakness and paresthesia, which are typical symptoms of FM [21]. A recent study has shown that low dietary magnesium intake is correlated with worsening pain threshold parameters in FM patients [43]. Magnesium has always been considered the nonpharmacological supplement with the highest potential for FM [44]; however, so far, only two clinical trials have been performed in FM patients. The first study investigating the effect of magnesium combined with malic acid supplementation was performed in 1995 by Russell and colleagues, showing little or no effect on pain or depression in 24 women with FM when using low doses of supplementation [33]. However, with increased dose and a longer duration of treatment, a significant improvement in pain and tenderness was reported [33]. The second study tested the effect of treatment with magnesium citrate in combination with amitriptyline versus amitriptyline in 60 female FM subjects, showing that amitriptyline and magnesium supplementation were more effective in all measured outcomes than amitriptyline alone [34].
With regard to other minerals, some studies indicated a potential link between iron deficiency and FM [45][46][47]; however, only one study evaluated the effect of iron supplementation on FM symptoms, fatigue and iron status of 81 FM subjects, showing an overall improvement only in the treated group [35].

Probiotics
Increasing evidence suggests that FM patients may present altered microbiota, with the abundance of different taxa selectively correlated with disease-related symptoms [48]. This has led researchers to hypothesize a potential beneficial use of probiotics in the treatment of FM. A pilot study to investigate the effect of a 7 week supplementation with a multispecies probiotic showed improved cognition, particularly impulsive choice and decision-making, in 40 subjects diagnosed with FM [36]. On the other hand, no other beneficial effects were observed in self-reported pain, quality of life, depression or anxiety [36].

Other Substances
Several studies have reported an association between amino acid deficiencies such as valine, leucine, isoleucine and tryptophan and FM symptoms [49,50]. However, to date, no intervention studies have been carried out to test the effect of a supplementation with these elements. Furthermore, some studies have reported some potential benefits in FM patients from botanical or antioxidant supplements, although the evidence to support these substances is very weak. Several nutritional supplements such as Chlorella pyreinoidosa, cellfood, coenzyme Q10, Ginkgo biloba, ascorbigen, L-carnitine, S-adenosylmethionine, creatine and melatonin have shown some benefits for FM patients, improving symptoms such as muscle pain, fatigue, morning stiffness and quality of life [19]. Although patients frequently experience several positive effects from supplementations, there is insufficient evidence to recommend their use in the clinical practice.

Dietary Interventions and Fibromyalgia
Several dietary approaches have been proposed with the aim of reducing the symptomatology of FM ( Table 2). The proposed nutritional strategies have been usually aimed to correct any nutritional deficiencies or to interfere with the different pathophysiological pathways supposed to be involved in the occurrence of FM.

Olive Oil
Extra-virgin olive oil (EVOO) is characterized by a high concentration of phenolic compounds. The countless health benefits of the EVOO are mainly due to its antioxidant activity, which is linked to its ability to protect DNA, proteins and lipids from damage caused by exposure to reactive oxygen species (ROS), which in turn are increased in FM patients [51]. A clinical trial investigated the effect of 50 mL/die of EVOO compared to refined olive oil in 23 female FM subjects. After 3 weeks of intervention, the authors reported a statistically significant improvement in protein carbonylation, lipid peroxidation, FIQ and mental health status after the intervention with EVOO [51]. Recently, the same research group reported similar beneficial effects of EVOO on several cardiovascular risk markers of 30 FM women, concluding that EVOO can protect women with FM against cardiovascular disease, thus proving to be a valuable therapeutic support in patients with FM [52].

Ancient Grain Products
In recent years, interest in ancient grains such as Khorasan wheat has been steadily increasing due to their beneficial effect on various pathological conditions [73,74]. The positive effect on health status seems to be due to the higher content of macro-and microelements, in particular magnesium, phosphorus, potassium, selenium and zinc, as well as carotenoids and polyphenols, compared to modern wheat [75]. Our group recently studied the effect of a replacement diet with cereal products based on ancient Khorasan wheat compared to the modern variety "Palesio" on the symptoms and quality of life of 20 patients with FM [53]. After 8 weeks, participants reported an overall improvement in the severity of FM-related symptoms, including widespread self-reported body pain, daytime sleepiness, fatigue and tiredness, resulting in an improvement in the impact of the disease on daily activities, with a greater positive effect after the intervention with Khorasan.

Monosodium Glutamate and Aspartame-Free Diet
Monosodium glutamate (MSG) and aspartame may act as excitotoxin molecules in organisms, acting as excitatory neurotransmitters, and may lead to neurotoxicity if used in excess [76]. Two case series on a total of 6 FM patients reported an overall improvement in FM symptoms such as chronic pain, fatigue, sleep and cognitive function after several months of aspartame-free or MSG plus aspartame-free diet [76,77]. A 30% remission of symptoms after an excitotoxin elimination diet was also observed in a sample of 46 patients with FM and irritable bowel syndrome (IBS) [54]. Interestingly, the MSG challenge led to a significant return of symptoms, a worsening of FM severity and a decrease in quality of life in almost all patients [54]. On the other hand, a total of 36 women with FM reported no significant differences in pain after a 12 week elimination of dietary MSG and aspartame, suggesting that discontinuation of dietary MSG and aspartame did not improve the symptoms of FM [55].

Gluten-Free Diet
FM patients often have gastrointestinal symptoms that significantly overlap with various gluten-related disorders such as nausea, abdominal pain, fatigue, tiredness, chronic pain and mood disturbance, suggesting a possible coexistence of noncoeliac gluten sensitivity in such patients [18]. This has led many investigators to hypothesize that a gluten-free diet could be beneficial for patients with FM. A pilot study investigating the clinical impact of a 1 year gluten-free diet in a small sample of 7 patients with coeliac disease, IBS and FM, revealed an overall improvement of pain symptoms, quality of life, cognitive function as well as of tissue transglutaminase serum levels [56]. The same research group investigated the effect of a 1 year gluten-free diet on 97 women with FM and IBS with or without lymphocytic enteritis, showing a slight but significant improvement in both IBS-related symptoms (chronic abdominal pain, changes in intestinal habit, bloating) and FM-related symptoms (chronic widespread pain, generalized tender points, fatigue and restless sleep) in the subgroup of lymphocytic enteritis [57]. Similar results were obtained in a 16.4 month gluten-free intervention on 20 FM patients without coeliac disease [58]. In addition, Slim and colleagues recently performed a 6 month intervention trial to study the effect of a gluten-free diet versus a low-calorie diet in 75 patients with FM experiencing gluten sensitivity-like symptoms [59]. Authors found that both dietary interventions resulted in beneficial effects on symptoms concluding that the gluten-free diet was not superior to the low-calorie diet in FM subjects with symptoms similar to gluten sensitivity [59].

Low-FODMAPs Diet
FODMAPs (Fermentable Oligo-Di-Mono-saccharides And Polyols) are poorly absorbed short-chain carbohydrates including lactose, free fructose, polyols, fructans and galacto-oligosaccharides. The low-FODMAPS diet has shown significant benefits in the treatment of IBS [78]. Since 70% of FM patients suffer from IBS [79], it has been hypothesized that the low-FODMAPs diet could be beneficial for FM subjects [60,61]. A 4 week intervention trial of 38 women with FM showed a significant reduction in gastrointestinal disorders and FM symptoms, including pain scores [60], as well as a reduction in body weight and waist circumference [61].

Low-Calorie Diet
It is known that high body mass index is associated with a number of disabling musculoskeletal conditions, suggesting that obesity may worsen symptoms of FM [62]. The most commonly used dietary strategy to reduce body weight is certainly the caloric restriction. In a pilot study, Shapiro and colleagues tested the effect of a low-calorie diet on 42 patients with FM, showing that after 20 weeks of intervention, participants reported a 4.4% reduction in body weight, along with an improvement in pain symptoms, body satisfaction and quality of life [62]. Similar results were obtained years later by Senna et al. [63], analyzing the effect of a 6 month hypocaloric diet on 83 FM subjects. Patients who lost weight reported lower interleukin-6 and C-reactive protein levels than controls, as well as lower depression and improved sleep and quality of life [63]. As a result, a more aggressive low-calorie diet for 12-16 weeks in 123 obese FM subjects led to improved pain symptoms, sleep pattern and depression, along with increased levels of anti-inflammatory cytokine interleukin-10 [64].

Vegetarian Diet
Vegetarian diets are characterized by large amounts of plant foods rich in fiber, vitamins, minerals and antioxidant elements, leading to the hypothesis that this dietary pattern may exert pain-relieving effects in FM patients, due to its anti-inflammatory properties and absence (or reduction) of animal proteins [80,81]. The first study testing the effect of a vegetarian diet on FM patients was performed in 1993 on a small sample of 10 FM patients [65]. After a 3 week period of vegetarian diet, participants reported an overall improvement in subjective well-being. Some years later, Kaartinen et al. tested a 3 month strict raw vegan diet on 18 FM patients, highlighting a significant improvement in pain scores, joint stiffness and sleep quality [67]. Interestingly, these beneficial effects tended to disappear immediately after shifting back to the omnivorous diet. Similar results with a raw vegan diet were obtained by Hänninen et al. on a group of 33 FM patients after a 3 month intervention period [68] and by Donaldson and colleagues on a sample of 30 FM subjects followed for 7 months [69]. On the other hand, after 6 weeks of dietary intervention with a vegetarian diet, 37 FM patients reported a significant improvement in pain symptoms, but this turned out to be smaller than in a control group of patients receiving a pharmacological treatment with amitriptyline [66]. Finally, a 4 week intervention program combining core stabilization exercises plus a lacto-vegetarian diet in 21 patients with FM who had low back pain led to pain reduction and improved body composition [70].

Mediterranean Diet
Only little evidence is available on the possible beneficial effects of the Mediterranean diet on FM. A recent cross-sectional study of 95 FM women showed that adherence to the Mediterranean diet was consistently associated with quantitative calcaneal ultrasound parameters, supporting the hypothesis that adherence to the Mediterranean diet may play a determining role in bone health in FM women [82]. Given that alterations in the intestinal bacterial flora appear to be a contributing factor in many chronic inflammatory and degenerative diseases, including rheumatic diseases such as FM, Michalsen and colleagues have tested the effect on the gut microbiota of interventions with the Mediterranean diet or a modified intermittent 8 day fasting regimen in 35 patients affected by FM [71]. Surprisingly, after 2 weeks and 3 months of follow-up, the authors found no significant changes in fecal bacteria counts following the two dietary interventions within and between groups. In addition, no significant differences appeared in the analysis of secretory immunoglobulin A or the symptomatology, suggesting that neither Mediterranean diet nor fasting treatments influenced the gut microbiota or symptoms in FM patients [71]. On the other hand, a recent study of 22 FM patients revealed that a 16 week Mediterranean diet with or without high doses of tryptophan and magnesium led to several beneficial effects on emotional processing, decreased fatigue, anxiety and depression, and reduced possible eating disorders and body image dissatisfaction, with significant greater improvements especially in the Mediterranean diet plus supplements group [72].

Conclusions
This review embraced the literature and showed that the role of dietary supplements on FM remains controversial, although clinical trials with vitamin D, magnesium, iron and probiotics' supplementation show promising results. In terms of dietary interventions, the administration of olive oil, the replacement diet with ancient cereals, low-calorie diets, vegetarian diets, the low-FODMAPs diet, the gluten-free diet, the monosodium glutamate and aspartame-free diet and the Mediterranean diet all appear to be effective in reducing the symptoms of FM. The majority of the included studies showed a significant improvement in chronic pain, anxiety, depression, cognitive function, sleep pattern and gastrointestinal symptoms. In addition, weight loss seems to be associated with both reduced inflammation and improved quality of life in FM subjects, thus suggesting that body weight could have a functional repercussion in these patients. Therefore, the fact that the improvement has been achieved through different dietary strategies may lead to the hypothesis that both weight loss and the psychosomatic component of the disease could have a major role in the disease. In addition, all of these diets are generally regarded as healthy dietary models, rich in plant foods, antioxidants or fiber, so the fact that people have experienced an improvement in symptoms after almost all dietary interventions suggests that an adequate diet could play a crucial role in the management of FM. However, these results should be interpreted with caution since the aforementioned studies present several biases that limit the robustness of the findings. First of all, most studies have a limited sample size with no possibility of blinding due to the nature of dietary intervention trials. Secondly, outcomes are often analyzed using different methodologies and without considering possible confounding factors. In addition, adherence to the assigned dietary intervention is hardly ever evaluated. Finally, a follow-up is almost never carried out to determine whether the positive effects are maintained over time or are only transient. Therefore, although dietary aspects appear to be a promising complementary approach to treat FM, further research is needed to improve the understanding of the disease and to provide the most effective strategies for managing FM syndrome.