**1. Introduction**

Fibromyalgia (FM) is a painful syndrome caused by changes in the central nervous system. This syndrome is chronic in nature and is present in about 5% of the world population. Generalized musculoskeletal pain and changes in sensitivity, as well as fatigue in the absence of any organic disease, are presented as clinical aspects. Other important symptoms may manifest in patients with FM such as sleep disturbances and cognitive problems, as well as a variety of psychosomatic symptoms. Patients with FM often complain of tingling, numbness, burning, cutaneous hyperalgesia, momentary pain attacks, and depression [1].

Pathophysiological factors are genetic predisposition, autonomic and emotional dysfunctions, physical or environmental stresses, and neurohormonal and inflammatory dysfunctions [2]. Besides that, ischemia and muscular microtraumas, which result in pain during and after exercise, can be considered favorable for the onset of pain in FM. Elvin et al. [3] studied 10 female fibromyalgic patients and 11 female patients in the control group, using Doppler ultrasound in the infraspinatus muscle during low-intensity exercise. Experimental patients presented muscle ischemia when compared to control patients, perhaps because they evoked reflexes in the muscular sympathetic nervous activity, resulting in vasoconstriction. This may be contributed to pain in FM, which could be resulting from possible microtraumas. An abrupt increase in muscle vascularization during and after dynamic exercise was also observed for patients with FM, which did not occur with static exercise when compared to the control patients. Thus, increased muscle sympathetic nerve activity in the FM group may have resulted in imbalance between vasodilation and sympathetic vasoconstriction.

Areas of the descending pathway of pain, such as the periaqueductal gray (PAG) and rostroventromedial area (RVM), which have mainly opioid and serotonergic activation, respectively, may act in endogenous analgesia. These two areas make connections with the dorsal horn of the spinal cord, modulating the transmission of nociceptive messages [3, 4]. Changes in these areas of the central nervous system (CNS) probably occur due to a neurochemical imbalance, with the glutamatergic, 5-HTergic and opioidergic systems being important targets to control this neurotransmitter fluidity. This results in the classification of FM as a central pain syndrome, also known as "dysfunctional pain," where there are changes in sensitivity such as allodynia (pain due to a stimulus that normally does not cause pain) and hyperalgesia (increased pain of a stimulus that usually causes pain), without any tissue or nervous injury [5–7].

of NPs such as essential oils (EOs), plants extracts, terpenes, sapogenins, and alkaloids in the treatment of FM. The results have shown that natural products have an analgesic effect in different animal models of FM, probably by activation of inhibitory descending pathways, such as the periaqueductal gray and rostroventromedial medulla. Natural products and their secondary metabolites could therefore be a promising source for FM management. However, translational studies that seek to validate the preclinical studies are scarce, incipient, and lacking an approach focused on the traditional pharmaceutical

Fibromyalgia (FM) is a painful syndrome caused by changes in the central nervous system. This syndrome is chronic in nature and is present in about 5% of the world population. Generalized musculoskeletal pain and changes in sensitivity, as well as fatigue in the absence of any organic disease, are presented as clinical aspects. Other important symptoms may manifest in patients with FM such as sleep disturbances and cognitive problems, as well as a variety of psychosomatic symptoms. Patients with FM often complain of tingling, numbness, burning, cutaneous hyperalgesia, momentary pain attacks,

Pathophysiological factors are genetic predisposition, autonomic and emotional dysfunctions, physical or environmental stresses, and neurohormonal and inflammatory dysfunctions [2]. Besides that, ischemia and muscular microtraumas, which result in pain during and after exercise, can be considered favorable for the onset of pain in FM. Elvin et al. [3] studied 10 female fibromyalgic patients and 11 female patients in the control group, using Doppler ultrasound in the infraspinatus muscle during low-intensity exercise. Experimental patients presented muscle ischemia when compared to control patients, perhaps because they evoked reflexes in the muscular sympathetic nervous activity, resulting in vasoconstriction. This may be contributed to pain in FM, which could be resulting from possible microtraumas. An abrupt increase in muscle vascularization during and after dynamic exercise was also observed for patients with FM, which did not occur with static exercise when compared to the control patients. Thus, increased muscle sympathetic nerve activity in the FM group may have resulted in imbalance between vasodilation and sympathetic

Areas of the descending pathway of pain, such as the periaqueductal gray (PAG) and rostroventromedial area (RVM), which have mainly opioid and serotonergic activation, respectively, may act in endogenous analgesia. These two areas make connections with the dorsal horn of the spinal cord, modulating the transmission of nociceptive messages [3, 4]. Changes in these areas of the central nervous system (CNS) probably occur due to a neurochemical imbalance, with the glutamatergic, 5-HTergic and opioidergic systems being important

**Keywords:** natural products, muscle pain, chronic pain, fibromyalgia, pain

market.

58 Discussions of Unusual Topics in Fibromyalgia

**1. Introduction**

and depression [1].

vasoconstriction.

Due to the complexity of its pathophysiology, the treatment of FM is very difficult. Only 30% of the medicines used to treat FM have some positive effect. Some drugs have high costs (financial or in terms of side effects), being possible triggers of collateral effects such as nausea, edema, tachycardia, and with poor therapeutic efficacy [1, 2, 8–12]. In order to better understand the physiopathology as well as to investigate new treatment options for FM, animal models have been developed that mimic some symptoms of this syndrome. Scientists have used a combination of repetitive stimuli applied to the muscle, coupled with stress added to the nociceptive stimuli applied in the muscle to trigger lasting hyperalgesia, which mimics FM (**Table 1**) [13–16].

In the search for new sources of more effective drugs with fewer side effects, scientists have been focusing on the study of different pharmacological approaches including natural products (NPs) due to their promising effects on the CNS. NPs are considered the main source of new chemical entities in the search for new medicines and may be fundamental to the discovery of new drugs for diseases or syndromes that still do not respond adequately to the current available treatments. In this context, an important approach to discover new painkillers has been developed with NPs such as medicinal plants or their secondary metabolites that could modulate painful conditions, including FM [17].

Medicinal plants (MPs) are natural products that have been used in the control of several diseases by the world's population for thousands of years. Popular knowledge about the use of these plants has directed scientists to conduct new research seeking drugs that act on specific targets or multiple molecular sites such as the pathophysiology of FM usually presents [18, 19]. Many drugs that are commonly used in clinical treatment are derived directly or indirectly from MPs and include analgesics such as aspirin (antiinflammatory nonsteroidal derived from salicylic acid, which was initially extracted from *Salix alba*) and morphine (opioid analgesic derived from *Papaver somniferum*) [20]. As evidence of the importance of natural products, between 2005 and 2010, the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) approved 19 medicines derived from NPs, including trabectedin (Yondelis™) and cannabidiol (Sativex®), for cancer and pain treatment, respectively [21, 22]. Moreover, the growing number of patents to protect new formulations containing NPs demonstrates the importance of these compounds [23].

In relation to FM, some classes of bioactive compounds extracted from medicinal plants have presented analgesic activity described in the literature, such as essential oils [24–26], extracts [27, 28], monoterpenes [29–31], sesquiterpenes [32], saponins [33], and alkaloids (**Figure 1** and **Table 2**) [34].


**Natural product Dose/route Type of study Sample Molecular** 

Preclinical Male Swiss mice

**Figure 1.** General structures of different categories of bioactive plant compounds studied for the treatment of FM: alkaloids (A1 and A2); monoterpenes (B); sesquiterpenes (C); and triterpenes, saponins, and steroids (D) (adapted from

Preclinical Male Swiss mice

(*n* = 8/group)

(*n* = 8/group)

either sex

**Essential oils**

Azmir et al. [42]).

*Hyptis pectinata* 0.3 ml/mouse

*Ocimum basilicum* 25, 50, and 100

(5%); sc

mg/kg; po

O24™ Not described; to Clinical 133 subjects of

**mechanism**

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Opioid, serotoninergic, cholinergic, and reduction of SP, with involvement in the descending pain pathway

Opioid, glutamatergic, TRPV1, and reduction of SP, with involvement in the descending pain pathway

Stimulation of A-beta sensory fibers and inhibition of bradykinin, histamine, and prostaglandins

**References**

Quintans-Júnior et al. [24]

Nascimento et al. [25]

Ko et al. [26]

*Note*: CNS, central nervous system; FM, fibromyalgia.

**Table 1.** Summary of major animal models of fibromyalgia.

Natural Products as Promising Pharmacological Tools for the Management... http://dx.doi.org/10.5772/intechopen.70016 61

**Author Animal model Induction Similarities with the** 

days

An acute

inflammatory insult (carrageenan or IL-6) followed by PGE2 injection into the same muscle

Running wheel for 2 h followed by two injections of acid saline (pH 5)

Repeated administration of reserpine (1 mg/kg/ day, for 3 consecutive

days; sc)

the day

3, and 4

room (−3 to +4°C) overnight for 3 days and transfer between normal room temperature (24°C) and a cold room every 30 min during

tones of 5, 11, 15, and 19 kHz, with amplitudes between 20 and 110 dB in random times each minute, lasting from 5 to 10 s, on days 1,

Cold stress model Maintenance in cold

Sound stress model Exposure to pure

*Note*: CNS, central nervous system; FM, fibromyalgia.

**Table 1.** Summary of major animal models of fibromyalgia.

Two injections of acid saline (pH 4; im) separated by 2–5

Acid saline-induced

Hyperalgesic priming

Fatigue-enhanced muscle pain

Biogenic amine depletion model

pain

60 Discussions of Unusual Topics in Fibromyalgia

model

Sluka, Kalra, Moore [35]

Dina, Levine, Green [36]; Dina, Green, Levine [37]

Yokoyama et al. [38]

Nagakura et al. [39]

Nishiyori et al.

Khasar et al. [41]

[40]

**clinical condition**

Long duration of hyperalgesia may indicate differential processing of muscular or cutaneous pain by peripheral or central

pathways

anxiety

Muscle fatigue may increase hyperalgesia produced by lowintensity agents

Animals show signs of comorbidities as depression and

Pharmacological treatments directed to FM also have an effect in this model, with the exception of opioids, which are not effective in FM and reduce hyperalgesia in the model cited

Anxiety is developed as comorbidity

Widespread and generalized hyperalgesia including the bilateral hind limbs, muscles, paws, and viscera, and anxiety

**Limitations of the model**

It is not clear if there are comorbidities such as depression, anxiety, fatigue, or sleep disturbances, as in FM. Unlike what is observed in FM, the model is sensitive to opioids intrathecally

Pharmacological and nonpharmacological treatments for FM or comorbidities, as well as changes in the CNS, have not yet been studied

in this model

and females

not developed

and females

Comorbidities such as anxiety and depression are

All studies so far have been performed only on males. It is not known if there are differences between males

Pharmacological and non-pharmacological treatments for FM or comorbidities have not yet been determined

It is unclear how changes in the serotonergic system contribute to the maintenance of hyperalgesia. All studies so far have been performed only on males. It is not known if there are differences between males

**Figure 1.** General structures of different categories of bioactive plant compounds studied for the treatment of FM: alkaloids (A1 and A2); monoterpenes (B); sesquiterpenes (C); and triterpenes, saponins, and steroids (D) (adapted from Azmir et al. [42]).



**2. Pharmacology of bioactive compounds**

that induce pharmacological or toxic effects in humans or animals [42].

known property that can be used in the treatment of FM [43].

number two or three and usually be between 20 and 70% of the oil [45].

**2.1. Essential oils**

**2.2. Plant extracts**

Bioactive compounds, produced by plants, are designated secondary metabolites. Metabolites can be divided into primary and secondary. Primary metabolites are those involved in growth and development, such as carbohydrates, amino acids, proteins, and lipids, while secondary metabolites, which often have unusual chemical structures, are not required for primary metabolic processes and are believed to support plant survival with respect to local challenges. Thus, the production of secondary metabolites of a given species will be related to their need for survival. Among the secondary metabolites, some compounds have an effect on biological systems, being considered bioactive, which defines them as secondary metabolites of plants

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Bioactive compounds can be extracted from various parts of the plant, such as the leaves, seeds, flowers, bark, roots, and fruits [43]. These compounds form the essential oil of the plant, resin, or other plant products, which can be extracted in a concentrated form (containing secondary metabolites) or by means of solvents, such as water, ethanol, methanol, chloroform, dichloromethane, ether, and acetone [42]. The best solvent or extraction procedure will depend on the botanical material to be used as well as of the type of secondary metabolites being obtained. In addition, various substances can be isolated from the essential oil or chemical extracts, such as terpenes, flavonoids, alkaloid, and steroids that already have some

Essential oils (EOs) are derived from the secondary metabolism of aromatic plants and are mainly terpene compounds. They are volatile and usually have a strong and characteristic smell. In nature, they perform plant protection functions against predators and help attract certain animals for pollination. In industry, they are used for numerous purposes including in perfume, as antiseptics, and food preservatives but also have numerous pharmacological properties [44]. They are mixtures and may contain 20–60 compounds (or more) in varying concentrations. Usually, each EO is characterized by its major components, which may be

Although the biological effect of EOs are thought to be due to the major components which define their pharmacological profiles, synergism between the molecules present in each oil, even those that are in a smaller quantity, can modulate the effects of the major components [45].

Based on non-pharmacological studies and holistic or alternative medicine with the use of medicinal plants (and related products), several researchers have sought to evaluate the effects of materials obtained through NPs in clinical and preclinical studies. This research has been based on the popular and potentially dangerous belief given the chemical diversity of NPs that "what is natural, cannot do you harm." The innovative pharmacological effects that these products are able to produce are promising but due to possible side effects remain challenging at the same time [50–52]. One way to evaluate possible pharmacological effects

\* All preclinical studies used the chronic muscle pain model induced by acid saline.

*Note*: ATP, adenosine triphosphate; ip, intraperitoneal; po, oral administration; sc, subcutaneous; SP, substance P; to, topically; TRPV1, transient receptor potential vanilloid 1.

**Table 2.** Summary of studies involving bioatctive compounds aimed at the treatment of fibromyalgia and their main mechanisms of action.
