**7. Vitamins**

Vegetarian diets seem to alleviate some symptoms of FM due to a low content of fat and proteins, high levels of fiber, vitamin C, beta-carotenes, minerals (magnesium, potassium, zinc, and selenium), and antioxidants [49].

In the first controlled pilot study to establish the safety and feasibility of intravenous treatment of micronutrients based on water-soluble vitamins and minerals in FM (Myer's cocktail), the authors reported that the majority of subjects experienced alleviation compared to baseline symptomatology, but they did not observe significant differences between the therapy and the placebo, considering the relationship uncertain between the placebo and micronutrients in FM [84]. According to the Brazilian Society of Rheumatology, the ingestion of sugar, salt, fat, and alcohol should be reduced, and the ingestion of fiber, fruits, vegetables, and fluids increased, in order to avoid the appearance of chronic degenerative illnesses and obesity [85]. Specific micronutrients like calcium (Ca) and magnesium (Mg) are important for proper muscular contraction, and the increase in tryptophan intake can be beneficial in the synthesis of serotonin [86]. The combination of vitamins and minerals can reduce the doses of analgesics and improve the sensation of pain in patients with FM [87]. In the majority of subjects with FM, an inadequate intake of vitamin C is observed. In 2003, Richard et al. demonstrated that the prolonged use of analgesics can augment the excretion of potassium and vitamin C causing anemia from iron deficiency [88]. In the study by Sakarya et al., the authors evaluated blood levels of antioxidant vitamins and Mg in FM patients, and they correlated them with clinical parameters without finding a correlation between the levels of vitamins A, C, E, and Mg with pain severity, functional capacity, and depression. The authors suggest that based on the results, the poor intake of these nutrients does not necessarily signify low blood levels [89]. Folate and vitamin B12 are essential for the regulation of the central nervous system, and their deficiency can result in peripheral neuropathic pain. Vitamin C deficiency can cause myalgia and bone pain, and a deficiency of vitamin D can cause muscle-skeletal pain [90]. The fatigue present in FM seems to have similarities to the manifestations of mild thiamine deficiency [91]. Various similarities have been reported between FM and thiamine deficiency, which include irritability, frequent headache, fatigue, muscular weakness, irritable bowel syndrome, and sleep disturbances. Studies have been published where anomalies in thiamine metabolism have been demonstrated in FM, and investigating thiamine deficiency together with the consumption of alcohol has been suggested in FM patients [92]. The administration of large quantities of oral thiamine increases the blood concentration to levels where the passive transport restores the normal glucose metabolism, and then the normal glucose metabolism of all the organs returns to normal values and symptoms are reduced. It is recommended to prescribe the permanent use of high doses of thiamine in FM [93]. Vitamins A, E, and C are potent nonenzymatic antioxidants [94]. Vitamins A and E are essential fat-soluble vitamins, are the primary chain antioxidants in body tissues, are considered the first line of defense against LPO, they protect the cell membranes early on when the activity of free radicals increases [95]. Vitamin C is the main water-soluble vitamin and is a free radical purifier that transforms vitamin E to its active form [96]. Magnesium (Mg) is a mineral that plays an important role in ATP synthesis and functions in adequate muscle metabolism [97]. Serum levels of Mg have been investigated in FM to reveal etiopathology [98]. Vitamin C is capable of accelerating the degradation of intra- and extracellular proteins targeting lysosomal lumen by autophagic and heterophagic pathways. Vitamin C decreased and stabilized the intra-lysosomal acid pH at values that resulted in maximal activation of the lysosomal hydrolases [99].

#### **7.1. Vitamin D**

mechanism involved in the regulation of dysfunctional pain [77]. There have been reports of studies which suggest that melatonin increases the effect of the descending pain inhibitory system, which involves anatomical connections between cortical regions and the brainstem in the human brain [78]. Therefore, the restoration of melatonin could be an additional mechanism to explain the discrepancy of its effect compared to amitriptyline. In a phase II randomized controlled clinical trial, it was demonstrated that the exogenous administration of 10 mg every 24 h of melatonin augmented the endogenous inhibitory system of pain regulation, evaluated by a numerical scale (0–10), and demonstrated that the association between melatonin with amitriptyline gave better results than the amitriptyline alone, as determined by the visual analog pain scale [79]. Another randomized trial demonstrated that the administration of melatonin alone or in combination with fluoxetine (3–5 mg/day) was efficient in treating FM [80]. However, clear and conclusive evidence from clinical trials or prospective cohorts with prolonged follow-up on the effect of melatonin in patients suffering from FM is still lacking. Melatonin behaves as a free radical scavenger and therefore as a potent antioxidant. Melatonin has physical–chemical advantages over other antioxidant molecules. It is a hormone that is found naturally in the body. Melatonin molecules enter all subcellular organs and compartments. Melatonin detoxifies up to 10 Free Radicals [81]. Compared with other antioxidants, melatonin has equal or better efficacy in the protection of tissues from oxidative lesions such as vitamin C and E. Another inherent feature of melatonin is mitochondrial membrane selectivity and may be the most interesting advantage of pineal hormone [82]. Even melatonin is an effective antioxidant in the prevention of hepatotoxicity induced by

Vegetarian diets seem to alleviate some symptoms of FM due to a low content of fat and proteins, high levels of fiber, vitamin C, beta-carotenes, minerals (magnesium, potassium, zinc,

In the first controlled pilot study to establish the safety and feasibility of intravenous treatment of micronutrients based on water-soluble vitamins and minerals in FM (Myer's cocktail), the authors reported that the majority of subjects experienced alleviation compared to baseline symptomatology, but they did not observe significant differences between the therapy and the placebo, considering the relationship uncertain between the placebo and micronutrients in FM [84]. According to the Brazilian Society of Rheumatology, the ingestion of sugar, salt, fat, and alcohol should be reduced, and the ingestion of fiber, fruits, vegetables, and fluids increased, in order to avoid the appearance of chronic degenerative illnesses and obesity [85]. Specific micronutrients like calcium (Ca) and magnesium (Mg) are important for proper muscular contraction, and the increase in tryptophan intake can be beneficial in the synthesis of serotonin [86]. The combination of vitamins and minerals can reduce the doses of analgesics and improve the sensation of pain in patients with FM [87]. In the majority of subjects with FM, an inadequate intake of vitamin C is observed. In 2003, Richard et al. demonstrated that the prolonged use of analgesics can augment the excretion of potassium and

amitriptyline [83].

22 Discussions of Unusual Topics in Fibromyalgia

**7. Vitamins**

and selenium), and antioxidants [49].

Vitamin D is a hormone essential for maintaining homeostasis of the muscle-skeletal system. Vitamin D deficiency has been proposed as a factor associated with generalized chronic pain. The majority of vitamin D is produced naturally in the skin after exposure to ultraviolet B light (UVB) producing 25-hydroxyvitamin D (25-OHD). Vitamin D undergoes hydroxylation of the active form 1,25-dihydroxyvitamin D (1,25-OHD) in the liver and kidneys. Age, latitude, time of day, season, skin pigmentation, adiposity, smoking, and amount of exposure to sunlight directly affect the production of vitamin D in the skin [100]. People who are at risk of vitamin D deficiency include people with dark skin, obesity, the elderly, those with chronic degenerative illnesses, or those with disabilities who have little exposure to sunlight [101]. The active form of vitamin D, 1,25-OHD, acts in the cell nucleus (genomic effects caused by gene over-regulation) and the cell membranes (nongenomic effects that cause rapid response) in more than 30 tissues and organs [102]. The muscles are a target organ for the metabolites of vitamin D because they contain receptors for vitamin D identified in the muscle tissues in humans and animals on producing genomic effects that alter calcium, phosphate, and the metabolism of phospholipids [103]. These changes are important for the normal, functional development of the skeletal musculature. There is evidence that the ingestion of vitamin D improves muscle strength and functional capacity. It should be considered that vitamin D decreases in elderly populations, and supplementation is necessary [104]. Recent studies have centered on the potential therapeutic implications of vitamin D and its deficiency, in the regulation of chronic pain processing in FM, through the interactions of central and peripheral complexes. The primary functional scenario of the interaction is based on the presence of the vitamin D receptor and the 1α-hydroxylase (enzyme that converts the 25-hydroxyvitamin D by hydroxylation to the active 1,25 di-hydroxyl-vitamin D (1,25 (OH) 2D3) in many areas of the human central nervous system, among which are: the prefrontal cortex, the amygdala, the raphe, the gelatinous substance, the cerebellum, the hippocampus, the cingulate cortex, the substance *nigra*, the thalamus, and the hypothalamus [105]. Both the receptor and the enzyme have been found in neuronal and glial cells [106]. The general characteristics of hypovitaminosis D are body pain, especially in the shoulder, the thoracic cavity, and lumbar and pelvic regions. The biological relationship between generalized chronic pain and vitamin D deficiency continues to be an interesting investigative topic. Patients with FM could have vitamin D deficiencies due to the characteristics of their pain, poor mobility, or the associated depression that decreases free time exposed to sunlight, or by the increase in adiposity that favors the decrease in vitamin D synthesis. Therefore, the participation of the 1,25-OHD in the regulation of the immune system could be involved in vitamin D deficiency and muscular pain [107]. A systematic review that sought evidence of an association between FM and vitamin D deficiency was inconclusive, without finding improvement in muscular pain after supplementation. However, patients with concurrent risk factors between FM and other pathologies like osteoporosis should be tested in case a vitamin D deficiency is found that would favor muscle strength [108]. The search between vitamin D deficiency and the presence of FM remains an inconclusive matter.

**Author details**

**References**

Alejandra Guillermina Miranda-Díaz\* and Simón Quetzalcóatl Rodríguez-Lara

Health Sciences Centre, University of Guadalajara, Guadalajara, Jalisco, México

with fibromyalgia. BMC Musculoskeletal Disorders. 2007;**8**:27

Department of Physiology, Institute of Clinical and Experimental Therapeutics, University

The Role of Oxidants/Antioxidants, Mitochondrial Dysfunction, and Autophagy in Fibromyalgia

http://dx.doi.org/10.5772/intechopen.70695

25

[1] Gerdle B, Björk J, Cöster L, Henriksson K, Henriksson C, Bengtsson A. Prevalence of widespread pain and associations with work status: A population study. BMC

[2] Bennett RM, Jones J, Turk DC, Russell IJ, Matallana L. An internet survey of 2,596 people

[3] Heymann RE, Paiva Edos S, Helfenstein M Jr, Pollak DF, Martinez JE, Provenza JR, Paula AP, Althoff AC, Souza EJ, Neubarth F, Lage LV, Rezende MC, de Assis MR, Lopes ML, Jennings F, Araújo RL, Cristo VV, Costa ED, Kaziyama HH, Yeng LT, Iamamura M, Saron TR, Nascimento OJ, Kimura LK, Leite VM, Oliveira J, de Araújo GT, Fonseca MC. Brazilian consensus on the treatment of fibromyalgia. Revista Brasileira de

[4] Tornero MJ, Sanmartí SR, Rodríguez VV, Martín ME, Marenco-de la Fuente JL, González AI, Muñoz FS, Gómez-Reino CJ, Carreño PL, Batlle GE, Balsa CA, Andreu JL, Alvaro-Gracia JM, LJA M, Loza SE. Update of the consensus statement of the Spanish Society of Rheumatology on the management of biologic therapies in rheumatoid arthritis.

[5] Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis and Rheumatism. 1995;**38**:19-28

[6] Wolfe F, Smythe HA, Yunus MB, Bennett RM, Bombardier C, Goldenberg DL, Tugwell P, Campbell SM, Abeles M, Clark P, Fam AG, Farber SJ, Fiechtner JJ, Franklin CM, Gatter RA, Hamaty D, Lessard J, Lichtbroun AS, Masi AT, Mccain GA, Reynolds WJ, Romano TJ, Russell IJ, Sheon RP. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis and

[7] Bellato E, Marini E, Castoldi F, Barbasetti N, Mattei L, Bonasia DE, Blonna D. Fibromyalgia syndrome: Etiology, pathogenesis, diagnosis, and treatment. Pain Research and Treatment.

[8] Gavi MB, Vassalo DV, Amaral FT, Macedo DC, Gava PL, Dantas EM, Valim V. Strengthening exercises improve symptoms and quality of life but do not change autonomic modulation in fibromyalgia: A randomized clinical trial. PloS One. 2014;**9**(3):e90767

\*Address all correspondence to: kindalex1@outlook.com

Musculoskeletal Disorders. 2008;**9**:102

Reumatologia. 2010;**50**:56-66

Rheumatism. 1990;**33**:160-172

2012;**2012**:426130

Reumatologia Clinica. 2010;**6**(1):23-36

### **8. Conclusion**

In conclusion, oxidative stress, mitochondrial dysfunction, autophagy, multivitamin deficiencies, and the imbalance between oxidants and antioxidants are an intriguing and clinically attractive topic to elucidate the state and progression of FM. Pharmacological treatment alone is insufficient for the majority of patients who suffer from FM syndrome. It is recommended to approach treatment in a multidisciplinary way in clinical practice. Moderate physical activity and the supplementation/ingestion of antioxidants could be beneficial in regulating the oxidative state.
