**3. Preclinical studies**

and examine their use in folk medicine is to study plant extracts obtained through the use of several solvents [53–55]. The extraction of biological products using solvents is mainly used with fragile or delicate flower materials, which do not tolerate the heat of steam distillation. Examples of solvents which may be used to produce plant extracts are acetone, hexane, ether, methanol, or ethanol [43]. These extracts, in turn, can have a limited use due to their high viscosity, facilitating aggregation and precipitation, or the presence of proteins that induce false results, causing better ways of obtaining and fractionating the crude extracts to be sought

Terpenes are the largest group of secondary metabolites obtained through natural products, being made from isoprene units (five carbons (C5)). They exhibit a wide variety of structures and are the most common class of chemical compounds found in essential oils [43, 46–48]. Essential oils contain mainly monoterpenes (C10) and sesquiterpenes (C15), which are generally hydrocarbons of the general formula (C5H8)n. At a lower concentration, they are present in essential oils as diterpenes (C20), triterpenes (C30), and tetraterpenes (C40), which are larger molecules. Terpenoids are oxygen compounds that can be derived from terpenes. These compounds may present predominantly as phenols, monoterpene alcohol, sesquiter-

Although monoterpenes are smaller molecules than sesquiterpenes, the structure and functional properties of these groups are similar [43, 49]. Most monoterpenes are colorless, volatile, and lipophilic, which promote greater penetration through the membrane [49]. Among the activities already described, the antinociceptive properties of these compounds have

Triterpenoid or steroidal aglycones linked to portions of oligosaccharides are called saponins. Saponins are amphipathic because of the combination of the aglycone, having hydrophobic characteristics, and sugar molecules, with a hydrophilic profile. These compounds have been studied for use in the pharmaceutical, cosmetic, agronomic, and food industries [53]. Saponins present some therapeutic activities including powerful membrane-permeabilizing agents with hypocholesterolemic, immunostimulatory, anti-inflammatory, antimicrobial, anticarcinogenic, antiprotozoan, molluscicides, and antioxidant properties [54]. The majority of plant species-producing saponins are dicotyledonous and accumulate mainly triterpenoid saponins. The monocotyledon type mainly synthesizes saponins of the steroidal type [55].

Alkaloids are complex compounds that contain nitrogen. These compounds have been used in the production of various drugs, such as metronidazole (derived from azomycin) and bedaquiline (derived from quinolone) [56–60]. Capsaicin is an alkaloid derived from hot chili peppers from the *Capsicum*. This alkaloid interacts with afferent nociceptors by means of the

pene alcohol, aldehydes, ketones, esters, oxides, lactones, and ethers [43].

[54].

**2.3. Terpenes**

64 Discussions of Unusual Topics in Fibromyalgia

**2.4. Saponin**

**2.5. Alkaloids**

received a lot of attention [50–52].

Recently, Quintans-Júnior et al. [24] evaluated pretreatment with the EO from *Hyptis pectinata* loaded in a nanoemulsion thermoreversible gel in an animal model of noninflammatory chronic muscular pain, an experimental model for FM. This pharmaceutical formulation containing EO and Pluronic F127-based hydrogel produced a long-lasting and consistent antihyperalgesic effect for 10 days after a single subcutaneous application, which was reversed by naloxone (opioid antagonist) and methysergide (serotoninergic antagonist). In addition, the formulation produced a significant reduction in substance P (SP) levels in the spinal cord. Moreover, it was also shown to increase neuron activation, by Fos protein expression, in the periaqueductal gray (PAG), the nucleus raphe magnus (NRM), and the locus coeruleus (LC), the CNS areas reported to be involved in the descending pathway of pain, so it appears that the formulation acts by improving the endogenous analgesia mechanism (**Figure 3**). Other studies have demonstrated that *H. pectinata* essential oil exhibits antinociceptive effects, probably mediated by the opioid and cholinergic receptors [64, 65].

Nascimento et al. [25] demonstrated in the same FM animal model that *Ocimum basilicum* essential oil, rich in monoterpenes such as linalool, has an important anti-hyperalgesic profile when complexed or noncomplexed with β-cyclodextrin (β-CD). Moreover, the complexed oil produced a long-lasting anti-hyperalgesic effect when compared to the oil alone, demonstrating that the complexation process allows greater stability and bioavailability of the oil or its main compounds, such as monoterpenes. In this paper, the authors also assessed Fos protein expression in the brains of mice and found that this oil promoted the activation of the PAG, NRM, and LC, which are encephalic regions that participate in the antinociceptive effect by the activation of the pain inhibitory descending pathway.

The results obtained for the *O. basilicum* essential oil may be due to its action on the inhibition of SP or through blocking the neurokinin-1 receptor and the vanilloid receptor (TRPV1). Indeed, this oil also acts by glutamatergic system inhibition or by the inhibition of inflammatory pathways, because it was able to produce a reduction in orofacial nociception when caused by formalin, capsaicin, and glutamate in mice [66]. Furthermore, when assessed using an electrophysiological approach, this oil was able to inhibit an orthodromic response in the dentate hippocampal gyrus, similar to DNQX (a glutamatergic drug), an AMPA and kainate receptor antagonist. In addition, another study carried out by Venâncio et al. [67] demonstrated that the peripheral and central antinociceptive effects of *O. basilicum* essential oil are related to the inhibition of the biosynthesis of pain mediators, such as prostaglandins and prostacyclins, and its ability to interact with opioid receptors.

Some studies using plant extracts for the treatment of FM have been performed. Chopade and Sayyad [27] used aqueous, methanolic, hydromethanolic, and hydroethanolic extracts of the genus *Phyllanthus* in an animal model of FM induced by acid saline. It was observed that the extract was able to reduce hyperalgesia without causing tolerance. Extracts of these plants have shown an antinociceptive effect, including in the hot-plate test [68]. In addition, there are indications these extracts depressed the CNS without apparently causing nervous toxicity or altering motor coordination, which may have corroborated with the anti-hyperalgesic effect obtained in the FM animal model [69].

of HpEO, has a strong interaction with the μ-opioid receptor (**Figure 2(B)**). A more interesting aspect was that when the HpEO was incorporated in a nanoemulsion thermoreversible pluronic F127-based hydrogel, it produced a long-lasting and consistent anti-hyperalgesic effect (**Figure 2(A)**), suggesting that essential oils and their major components are promising tools

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Some studies involving the effects of monoterpenes in FM experimental models have been undertaken due to their possible molecular effects on pain (**Figure 3**) [52]. Nascimento et al. [29] used linalool (**Figure 4**), a monoterpene present in plant species of the family Lamiaceae, complexed and noncomplexed in β-CD, in an animal model of FM and observed that both

**Figure 3.** Schematic illustration of descending pain pathway and cyclodextrin complexation with monoterpenes

(adapted from Quintans-Júnior et al. [24]).

for managing FM.

The variability of the pharmacological mechanisms of terpenes and related compounds is shown in **Figure 2**, especially when incorporated into pharmaceutical formulations which improve their pharmacological properties. Moreover, β-caryophyllene, a major compound of *H. pectinata* leaf essential oil (HpEO), complexed with β-cyclodextrin decreased Fos protein expression in the superficial dorsal horn, which seems to involve the descending inhibitory pain system in an animal model of FM (**Figure 2(C)**). Germacrene D, another major component

**Figure 2.** (A) Effect of nanoemulsion pharmaceutical formulation containing *Hyptis pectinata* leaf essential oil (NE-EOH; sc), tramadol (TRM, 10 mg/kg; ip), or vehicle (sc) on mechanical sensitivity induced by acidic saline in mice. Each point represents the mean ± SEM (*n* = 8, per group) of the ipsilateral paw withdrawal threshold. \**p* < 0.05 and \*\**p* < 0.01 vs. control group (ANOVA followed by Tukey's test). (B) Hydrophobic map of germacrene D (a major compound of *Hyptis pectinata* leaf essential oil) and μ-opioid receptor (μ-OR). Blue, hydrophobic region; red, hydrophilic region. (C) Fos-positive neurons in the lumbar spinal cord lamina I. Vehicle or β-caryophyllene-β-cyclodextrin (20 mg/kg) was administered orally, and, after 90 min, the animals were perfused (adapted from Quintans-Júnior et al. [25, 33]).

of HpEO, has a strong interaction with the μ-opioid receptor (**Figure 2(B)**). A more interesting aspect was that when the HpEO was incorporated in a nanoemulsion thermoreversible pluronic F127-based hydrogel, it produced a long-lasting and consistent anti-hyperalgesic effect (**Figure 2(A)**), suggesting that essential oils and their major components are promising tools for managing FM.

Some studies using plant extracts for the treatment of FM have been performed. Chopade and Sayyad [27] used aqueous, methanolic, hydromethanolic, and hydroethanolic extracts of the genus *Phyllanthus* in an animal model of FM induced by acid saline. It was observed that the extract was able to reduce hyperalgesia without causing tolerance. Extracts of these plants have shown an antinociceptive effect, including in the hot-plate test [68]. In addition, there are indications these extracts depressed the CNS without apparently causing nervous toxicity or altering motor coordination, which may have corroborated with the anti-hyperalgesic effect

The variability of the pharmacological mechanisms of terpenes and related compounds is shown in **Figure 2**, especially when incorporated into pharmaceutical formulations which improve their pharmacological properties. Moreover, β-caryophyllene, a major compound of *H. pectinata* leaf essential oil (HpEO), complexed with β-cyclodextrin decreased Fos protein expression in the superficial dorsal horn, which seems to involve the descending inhibitory pain system in an animal model of FM (**Figure 2(C)**). Germacrene D, another major component

**Figure 2.** (A) Effect of nanoemulsion pharmaceutical formulation containing *Hyptis pectinata* leaf essential oil (NE-EOH; sc), tramadol (TRM, 10 mg/kg; ip), or vehicle (sc) on mechanical sensitivity induced by acidic saline in mice. Each point represents the mean ± SEM (*n* = 8, per group) of the ipsilateral paw withdrawal threshold. \**p* < 0.05 and \*\**p* < 0.01 vs. control group (ANOVA followed by Tukey's test). (B) Hydrophobic map of germacrene D (a major compound of *Hyptis pectinata* leaf essential oil) and μ-opioid receptor (μ-OR). Blue, hydrophobic region; red, hydrophilic region. (C) Fos-positive neurons in the lumbar spinal cord lamina I. Vehicle or β-caryophyllene-β-cyclodextrin (20 mg/kg) was administered orally, and, after 90 min, the animals were perfused (adapted from Quintans-Júnior et al. [25, 33]).

obtained in the FM animal model [69].

66 Discussions of Unusual Topics in Fibromyalgia

Some studies involving the effects of monoterpenes in FM experimental models have been undertaken due to their possible molecular effects on pain (**Figure 3**) [52]. Nascimento et al. [29] used linalool (**Figure 4**), a monoterpene present in plant species of the family Lamiaceae, complexed and noncomplexed in β-CD, in an animal model of FM and observed that both

**Figure 3.** Schematic illustration of descending pain pathway and cyclodextrin complexation with monoterpenes (adapted from Quintans-Júnior et al. [24]).

nociception tests [81], indicating other possible mechanisms of action of this monoterpene. In summary, it has been shown that monoterpenes complexed in β-cyclodextrin reduce hyperalgesia induced by chronic muscle pain, activating the descending pathway, as described in

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Sesquiterpenes occur *in nature* as hydrocarbons or in oxygenated forms including lactones, alcohols, acids, aldehydes, and ketones. Biosynthesis of sesquiterpenes can occur by the mevalonic acid and the deoxyxylulose phosphate pathway. These compounds have various pharmacological activities including antileishmanial, antimalarial, antifungal, antibacterial, antiviral, anti-inflammatory, and antinociceptive properties and the ability to inhibit the pro-

β-Caryophyllene (**Figure 4**) is a bicyclic sesquiterpene compound found in the EO of the *Eugenia caryophyllata* (cloves) and *Piper nigrum* (black pepper) plant species. In an experimental study conducted in an FM model in mice, this compound, complexed in β-CD, reduced primary and secondary hyperalgesia as well as inhibited the superficial dorsal horn of the spinal cord, possibly by activation of descending pain pathway [32]. Antagonism studies, in a capsaicin-induced nociception test, showed that the antinociceptive effect of β-caryophyllene was reversed by naloxone, β-funaltrexamine (a μ-opioid receptor antagonist), and AM630 (a CB2 receptor antagonist) [83]. In addition, in a neuropathic pain model, β-caryophyllene had an effect on thermal hyperalgesia and mechanical allodynia, reducing spinal neuroinflammation. The oral administration of β-caryophyllene was more effective than the subcutaneously

Quintans et al. [33] evaluated the effect of hecogenin acetate (HA), an acetylated steroidal saponin, complexed with β-CD in a chronic noninflammatory widespread pain model. Hecogenin is already used in the pharmaceutical industry to synthesize some oral contraceptive agents. The effect of noncomplexed or complexed HA caused an increase in the nociceptive threshold and primary and secondary hyperalgesia compared to the vehicle control group. However, the HA/β-CD complex was superior in producing an analgesic profile using lower nominal doses of the active principle (HA). In addition, the interaction of the HA with opioid receptors and a decrease in SP levels in the lumbar spinal cord were verified, which indicate participa-

The antinociceptive effect of HA was previously observed in the tail-flick test. This effect was reversed by naloxone, CTOP (μ-opioid receptor antagonist), nor-BNI (κ-opioid receptor antagonist), naltrindole (δ-opioid receptor antagonist), and glibenclamide (ATP-sensitive K (+) channel blocker). Mice pretreated with HA had increased neuronal activation in the PAG area, suggesting the participation of the endogenous analgesia pathway in the hecogenin mecha-

Some clinical studies with EOs have been developed in humans with FM. O24™ is a blend of six essential oils: aloe vera, eucalyptus, lemon/orange, camphor, rosemary, and peppermint. This mixture is marketed for the relief of pain. In a double-blinded randomized clinical trial, Ko et al. [26] demonstrated the benefits of using this oil, topically, for FM pain relief. Males and females were recruited for the study through newspapers and internet communications.

tion of this substance in the descending inhibitory pain pathway [33, 85].

duction of nitric oxide and eliminate hydroxyl radicals [82].

injected synthetic CB2 agonist JWH-133 [84].

nism of action [85].

**Figure 3**.

**Figure 4.** Structure of terpenes studied for the treatment of FM (adapted from Guimarães et al. [23, 52]).

formulations had an anti-hyperalgesic effect, with the complexed form being more effective and producing a longer-lasting effect (for 24 h after administration). Previous studies have shown the analgesic effect of linalool on acute central nociception (hot plate), visceral (acetic acid) [70] and chronic pain models of neuropathic origin [71, 72], and the opioid and glutamatergic systems probably being involved in this action [73]. Moreover, linalool was able to reduce the action potential amplitude assessed using an isolated nerve in the single sucrosegap technique, showing it blocked neuronal excitability [74].

The possible benefits of the complexation of apolar compounds (such as terpenes) with CDs have been explored by the pharmaceutical industry and by researchers seeking improvements in pharmacological properties such as increased bioavailability, efficacy, and optimization of therapeutic doses (which reduces toxicity and adverse effects) [75, 76]. Clinical and preclinical evidence has shown that the pharmacological effects of analgesic and anti-inflammatory drugs are improved when complexed with CDs [76–78].

Santos et al. [30] evaluated the effect of citronellal (**Figure 4**), a monoterpene present in *Citrus* and *Cymbopogon* plants, complexed in β-CD as a potential agent against FM symptoms. It was observed that complexation in CD improved the anti-hyperalgesic effect when compared to noncomplexed citronellal. This effect probably involves activation of descending pain pathway areas, such as the PAG and rostroventromedial (RVM) areas, with possible interaction with the glutamate receptors, investigated by a docking study. Citronellal has already presented an antinociceptive effect on capsaicin, glutamate, and formalin-induced orofacial pain, showing that this terpene may be acting via SP and TRPV1 receptors or in the glutamatergic pathway [79]. In addition, the analgesic effect of citronellal was reversed by naloxone in hotplate tests, which strongly suggests its action on the opioid receptors and its ability to reduce neuronal excitability through blocking sodium channels [51, 79].

Another study, also using the chronic noninflammatory widespread pain model in mice (an FM animal model), evaluated the effect of α-terpineol (**Figure 4**), both pure and complexed in β-CD, as CDs are useful tools in improving the pharmacological properties of terpenes [77, 80]. The authors observed an anti-hyperalgesic effect, possibly related to the action of α-terpineol on the opioid and serotonergic receptors; visualized with the use of naloxone and ondansetron antagonists; and confirmed by docking studies [31]. Similarly to citronellal, α-terpineol also showed antinociceptive effect in the capsaicin, glutamate, and formalin-induced orofacial nociception tests [81], indicating other possible mechanisms of action of this monoterpene. In summary, it has been shown that monoterpenes complexed in β-cyclodextrin reduce hyperalgesia induced by chronic muscle pain, activating the descending pathway, as described in **Figure 3**.

Sesquiterpenes occur *in nature* as hydrocarbons or in oxygenated forms including lactones, alcohols, acids, aldehydes, and ketones. Biosynthesis of sesquiterpenes can occur by the mevalonic acid and the deoxyxylulose phosphate pathway. These compounds have various pharmacological activities including antileishmanial, antimalarial, antifungal, antibacterial, antiviral, anti-inflammatory, and antinociceptive properties and the ability to inhibit the production of nitric oxide and eliminate hydroxyl radicals [82].

formulations had an anti-hyperalgesic effect, with the complexed form being more effective and producing a longer-lasting effect (for 24 h after administration). Previous studies have shown the analgesic effect of linalool on acute central nociception (hot plate), visceral (acetic acid) [70] and chronic pain models of neuropathic origin [71, 72], and the opioid and glutamatergic systems probably being involved in this action [73]. Moreover, linalool was able to reduce the action potential amplitude assessed using an isolated nerve in the single sucrose-

**Figure 4.** Structure of terpenes studied for the treatment of FM (adapted from Guimarães et al. [23, 52]).

The possible benefits of the complexation of apolar compounds (such as terpenes) with CDs have been explored by the pharmaceutical industry and by researchers seeking improvements in pharmacological properties such as increased bioavailability, efficacy, and optimization of therapeutic doses (which reduces toxicity and adverse effects) [75, 76]. Clinical and preclinical evidence has shown that the pharmacological effects of analgesic and anti-inflammatory

Santos et al. [30] evaluated the effect of citronellal (**Figure 4**), a monoterpene present in *Citrus* and *Cymbopogon* plants, complexed in β-CD as a potential agent against FM symptoms. It was observed that complexation in CD improved the anti-hyperalgesic effect when compared to noncomplexed citronellal. This effect probably involves activation of descending pain pathway areas, such as the PAG and rostroventromedial (RVM) areas, with possible interaction with the glutamate receptors, investigated by a docking study. Citronellal has already presented an antinociceptive effect on capsaicin, glutamate, and formalin-induced orofacial pain, showing that this terpene may be acting via SP and TRPV1 receptors or in the glutamatergic pathway [79]. In addition, the analgesic effect of citronellal was reversed by naloxone in hotplate tests, which strongly suggests its action on the opioid receptors and its ability to reduce

Another study, also using the chronic noninflammatory widespread pain model in mice (an FM animal model), evaluated the effect of α-terpineol (**Figure 4**), both pure and complexed in β-CD, as CDs are useful tools in improving the pharmacological properties of terpenes [77, 80]. The authors observed an anti-hyperalgesic effect, possibly related to the action of α-terpineol on the opioid and serotonergic receptors; visualized with the use of naloxone and ondansetron antagonists; and confirmed by docking studies [31]. Similarly to citronellal, α-terpineol also showed antinociceptive effect in the capsaicin, glutamate, and formalin-induced orofacial

gap technique, showing it blocked neuronal excitability [74].

68 Discussions of Unusual Topics in Fibromyalgia

drugs are improved when complexed with CDs [76–78].

neuronal excitability through blocking sodium channels [51, 79].

β-Caryophyllene (**Figure 4**) is a bicyclic sesquiterpene compound found in the EO of the *Eugenia caryophyllata* (cloves) and *Piper nigrum* (black pepper) plant species. In an experimental study conducted in an FM model in mice, this compound, complexed in β-CD, reduced primary and secondary hyperalgesia as well as inhibited the superficial dorsal horn of the spinal cord, possibly by activation of descending pain pathway [32]. Antagonism studies, in a capsaicin-induced nociception test, showed that the antinociceptive effect of β-caryophyllene was reversed by naloxone, β-funaltrexamine (a μ-opioid receptor antagonist), and AM630 (a CB2 receptor antagonist) [83]. In addition, in a neuropathic pain model, β-caryophyllene had an effect on thermal hyperalgesia and mechanical allodynia, reducing spinal neuroinflammation. The oral administration of β-caryophyllene was more effective than the subcutaneously injected synthetic CB2 agonist JWH-133 [84].

Quintans et al. [33] evaluated the effect of hecogenin acetate (HA), an acetylated steroidal saponin, complexed with β-CD in a chronic noninflammatory widespread pain model. Hecogenin is already used in the pharmaceutical industry to synthesize some oral contraceptive agents. The effect of noncomplexed or complexed HA caused an increase in the nociceptive threshold and primary and secondary hyperalgesia compared to the vehicle control group. However, the HA/β-CD complex was superior in producing an analgesic profile using lower nominal doses of the active principle (HA). In addition, the interaction of the HA with opioid receptors and a decrease in SP levels in the lumbar spinal cord were verified, which indicate participation of this substance in the descending inhibitory pain pathway [33, 85].

The antinociceptive effect of HA was previously observed in the tail-flick test. This effect was reversed by naloxone, CTOP (μ-opioid receptor antagonist), nor-BNI (κ-opioid receptor antagonist), naltrindole (δ-opioid receptor antagonist), and glibenclamide (ATP-sensitive K (+) channel blocker). Mice pretreated with HA had increased neuronal activation in the PAG area, suggesting the participation of the endogenous analgesia pathway in the hecogenin mechanism of action [85].

Some clinical studies with EOs have been developed in humans with FM. O24™ is a blend of six essential oils: aloe vera, eucalyptus, lemon/orange, camphor, rosemary, and peppermint. This mixture is marketed for the relief of pain. In a double-blinded randomized clinical trial, Ko et al. [26] demonstrated the benefits of using this oil, topically, for FM pain relief. Males and females were recruited for the study through newspapers and internet communications. FM diagnosis was confirmed before the patients enrolled in the study. The authors reveal that the main mode of action is as a counterirritant to the pain sensation. The mixture of oils promotes stimulation of A-beta sensory fibers, causing inhibition of the A-delta and C fibers. Moreover, the local effects of O24™ include the inhibition of bradykinin, histamine, and prostaglandins, which do not seem to be directly related to the analgesic effect in FM, so it is more reasonable to propose its effect indirectly in the pathways of pain modulation.

precursors, aimed at treating diseases or symptomatology that had no effective treatment. Despite of the animal models described for FM, some limitations can be observed, such as the reversion of the pain with opioid treatment and the absence of other signs and symptoms observed in humans. However, these models are the most resembled FM in humans, being tools used in the search for new treatment options. Nowadays, many natural substances have been studied, clinically and preclinically, for their analgesic potential with respect to fibromyalgia. In this context, essential oils, plant extracts, terpenes, and alkaloids

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These substances have been shown to have an analgesic effect in animal models of fibromyalgia, acting through different pathways, including activation of the descending inhibitory pain pathway—specifically the opioid, glutamatergic, cannabinoid, and serotoninergic systems; inhibition of SP in the superficial dorsal horn of the spinal cord; blockage of peripheral fibers; and antioxidant activity. In addition, clinical studies have shown the importance of NPs in the pain management of FM, improving their quality of life. The effective use of these products in the clinic, without reports of considerable adverse effects, describes the advances in the use of NPs in the treatment of FM. These finding make natural products a promising source of

This work was supported by grants from CNPq (305608/2013-4, 311721/2014-1), CAPES, and FAPITEC/SE (Chamadas Públicas PROMOB e PROEF), all from Brazil. PL Santos, RG Brito, and MA Oliveira were carrying out the master's or PhD degrees in the Graduate Program in Health Sciences (PPGCS/UFS), and LTS Pina was carrying out the master's degree in the

, Marlange Almeida Oliveira<sup>1</sup>

,

, Laurent Picot<sup>3</sup>

and Lucindo José Quintans Júnior1

,

,

, Gokhan Zengin4

\*

are major sources of natural products.

treatments for the management of chronic pain.

Graduate Program in Pharmaceutical Sciences (PPGCF/UFS).

, Priscila Laise Santos<sup>1</sup>

, Angelo Roberto Antoniolli<sup>1</sup>

1 Laboratory of Neuroscience and Pharmacological Assays (LANEF), Department of

3 Faculty of Science and Technology, University of La Rochelle, La Rochelle, France

2 Center for Studies and Research of Medicinal Plants, Federal University of San Francisco

Physiology, Federal University of Sergipe (UFS), São Cristóvão, SE, Brazil

4 Department of Biology, Science Faculty, Selcuk University, Konya, Turkey

**Acknowledgements**

**Author details**

Renan Guedes Brito<sup>1</sup>

Lícia Tairiny Santos Pina<sup>1</sup>

Jackson Roberto Guedes da Silva Almeida<sup>2</sup>

\*Address all correspondence to: lucindojr@gmail.com

Jullyana Souza Siqueira Quintans<sup>1</sup>

Valley, Petrolina, Pernambuco, Brazil

Rutledge and Jones [86] also investigated the topical effect of O24 in a double-blind randomized clinical trial associated with exercises multilevel for 12 weeks. Twenty patients with FM and 23 patients of the sham group were submitted to the study. There was no statistical difference between the groups regarding the pain and physical function, but there was improvement of the physical function, without statistical difference, when compared before and after the treatment, keeping the effect of O24 on the FM symptoms unknown. This result for O24 differs from that described by Ko et al. [26], which may result from the small sample and the type of exercise used, since some exercises may contribute to the maintenance of pain in patients with FM [3].

The effect of *Ginkgo biloba* extract and the coenzyme Q10 was evaluated in 23 fibromyalgic patients, before and after the treatment, by oral administration, for 12 weeks, with 64% of patients reporting an improvement in quality of life through the application of questionnaires. The improvement observed by these patients may be related in parts to the antioxidant activities described for both coenzyme Q10 and *Ginkgo biloba* [28].

Due to the properties attributed to capsaicin, Casanueva et al. [34] evaluated the short-term efficacy of topical capsaicin treatment in 130 patients with fibromyalgia who were already using drug therapy. Patients were randomly divided into a control group (same medical treatment that they received before randomization) and topical capsaicin group (medical treatment that they received before randomization + 0.075% capsaicin) by a computer-generated sequence. After 6 weeks, it was observed that the additional topical treatment reduced the myalgia score and improved the quality of life of these patients, showing that capsaicin was also effective in this syndrome.
