**6. Antioxidants**

**5.1. Amitriptyline in fibromyalgia**

20 Discussions of Unusual Topics in Fibromyalgia

Amitriptyline is a tricyclic antidepressant known to inhibit the reuptake of serotonin and norepinephrine, and it has been used for a long period of time in the management of neuropathic pain and FM [56]. Amitriptyline is the pharmacological treatment with the most solid evidence in FM management, although exhaustive follow-up for secondary effects is recommended [57]. The administration of the medication is recommended for short periods to control pain. It was previously reported that the administration of 50 mg/day of amitriptyline at bedtime, for 9 weeks, in patients with FM, significantly improved pain, muscle rigidity, and sleep, compared to patients treated with placebo [58]. In another study, 62 patients with FM received 25 mg/day of amitriptyline at bedtime with an additional 500 mg of naproxen x2 daily, or a placebo for 6 weeks. Those who received amitriptyline had significant improvements in pain, sleep disturbances, and fatigue on waking, compared to those who received placebo. The authors did not find significant differences in improvement of pain among patients who only received amitriptyline or amitriptyline with naproxen [59]. The guidelines of the European League Against Rheumatism (EULAR) suggest that the management of FM with low doses of amitriptyline of 25 mg/day improves pain, sleep, and fatigue at 6–8 weeks without finding evidence that the use of 50 mg/day was superior [60]. However, the toxicity induced by amitriptyline implies the early activation of the mitofagia that subsequently changes to apoptosis. Amitriptyline induces mitochondrial dysfunction and oxidative stress in HepG2 cells. Amitriptyline specifically inhibits mitochondrial complex III activity that is associated with decreased mitochondrial membrane potential (ΔΨm) and increased ROS production. Transmission electron microscopy studies revealed structurally abnormal mitochondria that were engulfed by double membrane structures resembling autophagosomes. Pharmacological or genetic inhibition of autophagy exacerbated the deleterious effects of amitriptyline on hepatoma cells and leads to increased apoptosis. These results suggest that mitophagy acts as a mechanism of initial adaptation of cell survival. However, persistent mitochondrial damage induces extensive and lethal mitophagy, autophagic stress, and

autophagic permeabilization leading to cell death by apoptosis [61].

The postsynaptic NMDA receptors can alter the presynaptic transport of the vesicles that contain neurotransmitters through the NO pathway that diffuses to the presynaptic membrane

The CoQ10, a small lipophilic molecule located in the internal mitochondrial membrane, transfers reducing equivalents of the complexes I and II to the complex III of the mitochondrial respiratory chain. The CoQ10 is crucial for the efficiency of the mitochondrial chain, and there is existing evidence that reports CoQ10 as affecting the expression of genes involved in the inflammatory pathways [62]. The presence of mitochondrial dysfunction has been proposed as a relevant fact in the pathogenesis of FM [63]. The mitochondria generate energy primarily in the form of an electrochemical proton gradient that fuels the production of ATP,

**5.2. Pregabalin**

and alters traffic of the vesicles [67].

**5.3. Co-enzyme Q10 (CoQ10)**

Antioxidants, like the superoxide dismutase (SOD), catalase, and the glutathione peroxidase (GPx), are enzymes of the defense system that work to prevent oxidative stress through inactivation of the ROS. The SOD enzyme eliminates the damaging effects of the free radicals through the conversion of the radical O2.− into hydrogen peroxide (H2 O2 ), and the GPx converts H2 O2 into oxygen and water [67]. The principle intracellular antioxidant enzymes, copper, zinc-SOD (Cu-Zn-SOD) in the cytoplasm, and the manganese-SOD (MnSOD) in the mitochondria, specifically reduce the O2.− radicals to H2 O2 . Normally, there is an equilibrium between the ROS and the antioxidants in the cell, in the membranes, and in the extracellular space. However, the antioxidants are overwhelmed by the excessive production of ROS. The ROS attack the polyunsaturated fatty acids of the membrane producing LPO, resulting in alteration to the membrane permeability and changes to the membrane potential. The measurement of thiobarbituric acid reactive substances (TBARS), MDA, or 4-hydroxynonenal is the most common method applied to measure LPO [68]. The central nervous system is especially sensitive to ROS due to its high content of lipids compared to other areas of the body (**Figure 1**) [34].

#### **6.1. Melatonin**

Pain is a dynamic phenomenon resultant of the activity of the endogenous system of excitation and inhibition of pain. The efficiency of the system in FM has been related to the quality of sleep [69]. The relationship between pain and quality of sleep is supported on a neurobiological basis by the neurotransmitters involved: norepinephrine, serotonin, and dopamine [70]. The effect of melatonin on pain has been demonstrated in studies on inflammatory pain in experimental animals with neuropathic pain [71, 72] and in acute and chronic pain in clinical studies [73, 74]. Since the most frequent complaints in patients with FM are sleep alterations, fatigue, and chronic pain, these symptoms could be a consequence of the disruption of melatonin secretion [75]. Additionally, there is information that the serum levels of the precursors to melatonin (tryptophan and serotonin) are diminished in patients with FM [76]. The deficiency of melatonin in FM could explain the lack of reparative sleep and could be a 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 amitriptyline [83].

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].

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

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

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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

**7.1. Vitamin D**
