**5. Managing fibromyalgia**

present symptomatology characterized by muscle weakness, pain, fatigue, and exercise intolerance that progressively worsen over time, similar to what happens in patients with FM [34]. Defects in any part of the cycle in the generation of ATP by the mitochondria can alter mitochondrial energy production and cause symptoms [35]. Oxidative stress is implicated in the pathogenesis of FM, which indicates that mitochondrial dysfunction can be associated with FM [36]. In fact, a decrease in the quantity of mitochondrial mass and the coenzyme Q10 (CoQ10) in the production of mitochondrial ROS in mononuclear blood cells has been detected in patients who suffer from FM [37]. Reports of muscle biopsies from the trapezius muscle have shown inflammatory markers, abnormal mitochondria, accumulation of sub-sarcolemma mitochondria, higher incidence of irregular red fibers, and defects of the cytochrome-c oxidase (Complex IV of oxidative phosphorylation) [38]. In addition, the implication of mitochondrial oxidative stress in peripheral nociception described as a predominant symptom mediated by the inflammatory state in FM has been previously reported [39].

Autophagy is the process of cellular recycling that promotes energy efficiency through the generation of ATP and mediates damage control through the elimination of organelles and nonfunctional proteins, in regulating the degradation of cytosolic components by the liposomes [40]. Autophagy is the main catabolic pathway through which macromolecules and organelles of the eukaryotic cells are degraded and recycled. This pathway is activated under conditions of environmental stress and during the development of diverse pathologic situations. Autophagy plays an essential role in the cellular differentiation, development, and response to stress. It is activated during amino acid deprivation and is associated with neurodegenerative illnesses, cancer, pathogenic infections, and myopathies [41]. Autophagy can be induced by diverse causes: mitochondrial dysfunctions, infections of intracellular pathogens, and intrinsic cellular signals. Folded or damaged proteins, the organelles, and the intracellular pathogens are isolated by double membrane vesicles forming autophagosomes, which, on fusing with the lysosomes, convert into autolysosomes to be degraded [42]. Autophagy is an active process that plays the role of cleansing in maintaining the integrity of the intracellular organelles and proteins; however, autophagy is strongly induced by starvation, as in the case of cellular hypoxia, and is a key component in the adaptive response of the cells and organisms to the lack of nutrients, in order to promote cellular survival until the nutrients are made available once more [43]. Thirty-two different genes have been identified in relation to autophagy, obtained by genetic screening in yeasts. Many of these genes can be found in mold, plants, worms, flies, and in mammals, emphasizing, through phylogeny, the importance of the autophagy process in response to starvation [44]. Three types of autophagy that promote proteolytic degradation of the cytosolic components in lysosomes have been defined: **a.** *Macroautophagy:* the cytoplasmic load is given to the lysosomes through a vesicle with a double-layered membrane called an autophagosome, which fuses with the lysosome to form the autolysosome. Macroautophagy is capable of engulfing large structures through

**4. Autophagy**

18 Discussions of Unusual Topics in Fibromyalgia

selective and nonselective mechanisms.

Treatment for FM is a challenge and often requires nonpharmacological and pharmacological treatment [53]. The dietary habits of FM patients are important, and diverse studies have demonstrated improvement of symptoms with the ingestion of healthy, balanced diets [54]. However, the heterogeneity of symptoms that presents in FM deserves individualized treatment. Therapy should include physiotherapy, psychotherapy, pharmacotherapy, and educate the patient on the pathology of FM [55].

#### **5.1. Amitriptyline 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].

ion transport, and metabolism. The mitochondria are the primary sources of ROS in the complexes I and III, together with CoQ10 [64]. Management with CoQ10 could be useful as an alternative treatment in FM; however, more studies are needed to confirm whether the beneficial effect is real. More detailed studies through analysis in double blind placebo-controlled clinical trials are required on the effect of CoQ10 in bodily fluids and/or muscle biopsies [65]. In a study by Alcocer-Gomez E et al. included four patients with FM who measured the visual analogue scale (pain, fatigue and sleep), the Generalized Pain Index, the symptom severity scale and the Scl-90-R using the FM Impact Questionnaire High-performance liquid chromatography the CoQ10 content of patients with FM, and the authors found that CoQ10 in the four patients had defiecincy before the treatment, and after the treatment with CoQ10 patients

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

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 radi-

copper, zinc-SOD (Cu-Zn-SOD) in the cytoplasm, and the manganese-SOD (MnSOD) in the

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

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

into oxygen and water [67]. The principle intracellular antioxidant enzymes,

O2

O2

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

21

. Normally, there is an equilibrium

), and the GPx

cals through the conversion of the radical O2.− into hydrogen peroxide (H2

showed significant improvement in clinical symptoms [66].

mitochondria, specifically reduce the O2.− radicals to H2

**6. Antioxidants**

converts H2

(**Figure 1**) [34].

**6.1. Melatonin**

O2

#### **5.2. Pregabalin**

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 and alters traffic of the vesicles [67].

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

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, ion transport, and metabolism. The mitochondria are the primary sources of ROS in the complexes I and III, together with CoQ10 [64]. Management with CoQ10 could be useful as an alternative treatment in FM; however, more studies are needed to confirm whether the beneficial effect is real. More detailed studies through analysis in double blind placebo-controlled clinical trials are required on the effect of CoQ10 in bodily fluids and/or muscle biopsies [65]. In a study by Alcocer-Gomez E et al. included four patients with FM who measured the visual analogue scale (pain, fatigue and sleep), the Generalized Pain Index, the symptom severity scale and the Scl-90-R using the FM Impact Questionnaire High-performance liquid chromatography the CoQ10 content of patients with FM, and the authors found that CoQ10 in the four patients had defiecincy before the treatment, and after the treatment with CoQ10 patients showed significant improvement in clinical symptoms [66].
