**7. Medicinal plants as potential treatment of pain: preclinical research**

#### **7.1 Animal models of pain**

*Behavioral Pharmacology - From Basic to Clinical Research*

nal ganglion and the sciatic nerve [51].

risk of having myocardial infarction [58, 59].

**6. Side effects and toxicity in pain pharmacotherapy**

NSAIDs can promote various degrees of toxicity related to their pharmacokinetic and pharmacodynamic properties [11]. Its long-term use is a leading cause of morbidity especially in patients with risk factors, such as peptic ulcer and myocardial infarction, among others. The administration of these drugs or paracetamol frequently produces adverse effects such as gastrointestinal bleeding, hypertension, risk of infarction, hepatotoxicity, and renal failure [52–55]. Up to 25% of patients treated with NSAIDs have sodium retention, resulting in weight gain and developing peripheral edema. Likewise, hypersensitivity phenomena may occur, such as fever, rash, and eosinophilia [56]. About 15% of patients treated with NSAID presented significant elevations of liver-damaging enzymes, primarily alanine transaminase (ALT) and aspartate transaminase (AST), especially when administering Diclofenac and Sulindac [11]. Also, prostaglandins have an important role in female reproduction processes; it has been demonstrated by testing in mice the inhibition of COX-2 activity given by NSAID results in ovulation failure, fertilization, and implantation. Studies in animal models have also shown that these treatments modify the correct healing and union of fractures. Studies have not been conclusive since recovery depends on the type of wound, duration, and dose of the drug [57]. An increased risk of myocardial infarction has also been found in COX-2 inhibitors, presenting effects on blood pressure and nitric oxide production. Such is the case that ibuprofen interferes with the platelet effect and increases up to 35%

On the other hand, the side effects of opioids include dry mouth [41], constipation, respiratory depression, nausea and urinary retention, motor impairment [60],

not only used as an anticonvulsant but also prescribed to the management of postherpetic neuralgia without effects in painful sciatica [45]. Carbamazepine, Lamotrigine, and Oxcarbazepine are the first choice for the medical treatment of trigeminal neuralgia [46, 47]. They act as a dependent sodium channel blocker. Because of the unexpected drug interactions caused by a reduction in the activity of various hepatic cytochrome P450 enzymes that affect drug metabolism, carbamazepine is not recommended to treat any other types of neuropathic pain [44]. The first-line drugs to neuropathic pain include tricyclic antidepressants (TCAs)

and selective serotonin-norepinephrine reuptake inhibitors (SSNRI). TCAs are recommended based on efficacy, safety, toxic effects, and cost [44]; they are efficacious for several types of neuropathic pain including diabetic peripheral neuropathy (DPN), nerve injury pain, PHN, and central post-stroke pain. The analgesic effects of TCAs are related to inhibiting the reuptake of noradrenaline and serotonin from presynaptic terminals [48]. Amitriptyline is the TCAs most prescribed in many circumstances where neuropathic pain is presented as central pain, DPN, and PHN [44]. SSNRIs, such as Venlafaxine and Duloxetine, are an effective drug in the treatment of neuropathic pain [49, 50]. They are mainly studied on painful polyneuropathy. In recent years, connexins (Cxs) have been studied as targets for the development of new analgesic drugs. Connexins are a family of proteins with 20 subtypes and function as channels, junctions between cells, and hemichannels that sample the extracellular space and release substances such as neurotransmitters. One of the Cxs, Cx43, is expressed in astrocytes at the level of the central and peripheral nervous system. This has been studied in animal models and related to the genesis and maintenance of chronic pain, so it could be a promising therapeutic target for future treatments that act as Cx43-gap junction blockers, at the level of the trigemi-

**64**

Animal experimentation has been a very important tool in elucidating the mechanism that underlies certain diseases [66] and contributes to the improvement of diagnostic and prophylactic procedures as well as the understanding of the etiology and pathogenicity of different diseases [67]. These animal models offer the advantage of their standardization, genetic, and environmental background [68].

Animal pain perception shows similarities to human pain; thus, animal models mimic the persistent pain found in the clinic, and thus, animal studies give an idea of certain aspects of human pain conditions and lead to better pain management in patients [69]. Most nociceptive assays involve a noxious stimulus that can be thermal, chemical, mechanical, or electrical to specific parts of the body, resulting in simple noxious behaviors that can be easily qualified [70]. On the other hand, neuropathic pain models involve an injury or disease that affects the somatosensory system and include spontaneous pain, painful hyperalgesia, or allodynia [71].

Although we define pain as a homogeneous sensory entity, it is important to emphasize the etiological distinction of pain, as it is one of the most important and studied to define the neurobiological mechanisms responsible and provide an idea of how different types of pain are generated [72].

Research into new treatments for pain relief and their mechanisms has justified the use of different animal models developed to better understand the progress of specific disease issues. However, one of the most important needs when implementing an experimental model is that it reflects the necessary clinical conditions, from inflammatory pain to chronic low back pain. Therefore, over time several animal

models have been standardized that can evaluate different characteristics of pain. The **Table 3** shows the most important experimental pain models [1, 73–77].

## **7.2 Effects of medicinal plants on animal models of pain**

Most often, pain is treated with allopathic or conventional pharmacological medicine, a vast pain conditions are complex to treat because of financial strains or adverse side effects. However, complementary and alternative medicine might be a novel solution because their great repertoire of techniques includes nonpharmacological remedies (massage, acupuncture, yoga, etc.) and the use of herbal medicine [5] to reduce opioid misuse, diminish avoidable costs, and improve health outcomes [78]. Therefore, herbal medicine is an important element of health systems in many developing and industrialized countries [79].

For the World Health Organization (WHO), "herbal medicines include herbs, herbal material, herbal preparations, and finished herbal products, which contain as active ingredients parts of plants, or other plant materials, or combinations of those elements" [80]. The popular use of medicinal plants in health care in many tropical and subtropical countries is widely described because of their enormous plant diversity. The consumption of medicinal plants has been important not only for the treatment of pain but also for treating diseases and metabolic disorders [81]. Therefore, the urge to gather more ethnobotanical and preclinical evidence to support the traditional uses of plants.


**67**

metabolites are shown in **Table 4**.

*Pharmaceutical and Botanical Management of Pain Associated with Psychopathology…*

**Model name Type of stimulus or injury Natural metabolites evaluated**

Four loose ligatures around

Tight ligation of one-third to half of the sciatic nerve

common peroneal nerves

Axotomy of tibial and sural

Injection of zymosan, HMG, TNF-α around the sciatic

Radiation mediated reduction in blood supply to the sciatic

Intraspinal injections of excitatory amino acids

Persistent hyperglycemiainduced changes in the nerves

ganglion chronic constriction injury to the infraorbital

Opioids and tricyclic antidepressants, calcium antagonist (Verapamil, Nifedipine), sodium channel blockers (Lidocaine, Mexiletine, Tocainide), NMDA receptor antagonist (Dextromethorphan, Ketamine, Memantine), calcium N-channel blockers (Ziconotide), Antiepileptics (Gabapentin, Topiramate, Lamotrigine,

Felbamate)

Several biological effects of extracts and purified compounds from herbal species have been tested *in vivo* and *in vitro* models. Extracts have shown antimicrobial, antiviral, and antimutagenic activity; cytotoxic activity for cancer cell lines and antinociceptive, anti-inflammatory activity; and antiatherogenic, antioxidant, and biocide for various food pests [82]. Based on the biological models of neuropathic pain, we can mention neuropathic pain induced by paclitaxel, chronic constriction injury, alcoholic neuropathy, streptozotocin-induced diabetic, partial sciatic nerve ligation, and model of sodium monoiodoacetate. Among the main secondary metabolites that have diminished pain are alkaloids, carotenes, flavonoids, phenols, and terpenes, among others [83]. Some species with analgesic profile and their

The *Pterodon pubescens* (Benth) has been described as an analgesic. Phytochemistry studies have reported the presence of a high concentration of terpenes. The analgesic properties of *Pterodon pubescens* are attributed to these compounds [103]. An experimental study conducted in mice using the model of

*DOI: http://dx.doi.org/10.5772/intechopen.91154*

Axotomy Complete sciatic nerve

Spared nerve injury Axotomy of tibial and

transection

sciatic nerve

nerves

nerve

nerve

segments

nerve

carrageenan into temporomandibular joints

and maxilla

Spinal hemisection Laminectomy of T11–T12

Trigeminal neuralgia Compression of trigeminal

Orofacial pain Injection of formalin,

Sciatic cryoneurolysis Freezing of the sciatic nerve

**Neuropathic pain models**

Chronic constriction

Partial sciatic nerve ligation (Seltzer Model)

Tibial and sural nerve transection

Sciatic inflammatory

Laser-induced sciatic nerve injury

Excitotoxic spinal cord

Diabetes-induced neuropathy

*Principal animal models of pain.*

neuritis

injury

**Table 3.**

injury

*Pharmaceutical and Botanical Management of Pain Associated with Psychopathology… DOI: http://dx.doi.org/10.5772/intechopen.91154*


#### **Table 3.**

*Behavioral Pharmacology - From Basic to Clinical Research*

developing and industrialized countries [79].

support the traditional uses of plants.

Tail flick test Thermal Tail immersion test Thermal

Formalin test Chemical

**Nociceptive pain models**

Paw/tail pressure test and

Electric stimulation of

Abdominal constriction

**Inflammatory pain models**

Complete Freund Adjuvant (CFA)

Hot plate test Hargreaves test

Von Frey Randall-Selitto

the tail

test

**7.2 Effects of medicinal plants on animal models of pain**

models have been standardized that can evaluate different characteristics of pain. The **Table 3** shows the most important experimental pain models [1, 73–77].

Most often, pain is treated with allopathic or conventional pharmacological medicine, a vast pain conditions are complex to treat because of financial strains or adverse side effects. However, complementary and alternative medicine might be a novel solution because their great repertoire of techniques includes nonpharmacological remedies (massage, acupuncture, yoga, etc.) and the use of herbal medicine [5] to reduce opioid misuse, diminish avoidable costs, and improve health outcomes [78]. Therefore, herbal medicine is an important element of health systems in many

For the World Health Organization (WHO), "herbal medicines include herbs, herbal material, herbal preparations, and finished herbal products, which contain as active ingredients parts of plants, or other plant materials, or combinations of those elements" [80]. The popular use of medicinal plants in health care in many tropical and subtropical countries is widely described because of their enormous plant diversity. The consumption of medicinal plants has been important not only for the treatment of pain but also for treating diseases and metabolic disorders [81]. Therefore, the urge to gather more ethnobotanical and preclinical evidence to

**Model Type of stimulus or injury Natural metabolites evaluated**

**Model name Kind of stimulus or injury Natural metabolites evaluated**

Injection into the tail, leg, muscle, and joints

Mechanical

Electric

Chemical

Capsaicin Injection into skin, muscles, or joints

Carrageenan Injection into the leg, muscle, and joint

Kaolin/carrageenan Injection into knee or ankle joint Zymosan Injection into knee or ankle joint

Thermal Organic compounds with possible

antiharmful activity

Saponins, among others

Substances with antiharmful properties, Flavonoids, Triterpenes, Carbohydrates, Phenols, Terpenoids, Coumarins, and

Phytochemical compounds with possible

anti-inflammatory activity Polyphenols, Flavonoids, Quercetin, Phenolic compounds, Carotenoids, Quercetin, Catechin, Kaempferol, Epicatechins, Lupeol, Triterpenes, Phytosterols, Sterols, Lignans, Anthocyanins, and Alkaloids, among

others.

**66**

*Principal animal models of pain.*

Several biological effects of extracts and purified compounds from herbal species have been tested *in vivo* and *in vitro* models. Extracts have shown antimicrobial, antiviral, and antimutagenic activity; cytotoxic activity for cancer cell lines and antinociceptive, anti-inflammatory activity; and antiatherogenic, antioxidant, and biocide for various food pests [82]. Based on the biological models of neuropathic pain, we can mention neuropathic pain induced by paclitaxel, chronic constriction injury, alcoholic neuropathy, streptozotocin-induced diabetic, partial sciatic nerve ligation, and model of sodium monoiodoacetate. Among the main secondary metabolites that have diminished pain are alkaloids, carotenes, flavonoids, phenols, and terpenes, among others [83]. Some species with analgesic profile and their metabolites are shown in **Table 4**.

The *Pterodon pubescens* (Benth) has been described as an analgesic. Phytochemistry studies have reported the presence of a high concentration of terpenes. The analgesic properties of *Pterodon pubescens* are attributed to these compounds [103]. An experimental study conducted in mice using the model of


#### **Table 4.**

*Secondary metabolites with analgesic potential.*

neuropathic pain induced by partial sciatic nerve ligation showed that the administration of ethanolic extract of *Pterodon pubescens*, at an oral dose of 300 mg/kg, was effective in exerting antinociceptive effects, revealing a possible mechanism of action associated with the significant bite suppression induced by kainate, glutamate, NMDA, and trans-ACPD. Also, the plant extract decreased the concentration of proinflammatory cytokines like TNF-α and IL-1β and the inhibition of channels of capsaicin (TRPV1) and cinnamaldehyde (TRPA1), respectively, without pharmacological tolerance. The most abundant metabolites extracted from these plants were sesquiterpenes and diterpenes, which suggest that these compounds are responsible for the therapeutic effect [104]. There is interest in the study of other plant species, including *Woodfordia fruticosa, Adhatoda vasica, Chenopodium ambrosioides, Viburnum cotinifolium, Vitex negundo, Peganum harmala,* and *Broussonetia papyrifera* because of the presence of effective alkaloids for pain treatment. The crude alkaloid extracts of all selected medicinal herbs were active at an oral dose of 1250 mg/kg of body weight in mice, where they reduced abdominal contractions

**69**

*Pharmaceutical and Botanical Management of Pain Associated with Psychopathology…*

without collateral effects like locomotor dysfunctions or sedation [106].

caused by acetic acid and increased the latency time between the licks of the legs in both phases of pain (neuropathic and inflammatory) produced with formalin. In addition, the alkaloid-specific antinociceptive response was significantly in the

Another group of plants of pharmacological interest is the genus *Polygala* and the *Lamiaceae* family that have been widely used in pain therapy [105]. *Polygala molluginifolia* has shown important antinociceptive effects in mice. An experimental study showed that the hydroalcoholic extract of this plant, administered at a dose of 1000 mg/kg, exerted analgesic effects in a model of mechanical and thermal hyperalgesia to postoperative pain in mice. The mechanism of action of the experiment revealed that the effect of the natural product might be associated with a modulation of the TRPV1 and TRPA1 channels involved in nociceptive behavior and was demonstrated that *Polygala molluginifolia* has an antinociceptive potential

The phytochemistry of the species of the genus *Agastache* (Family *Lamiaceae*) is generally similar among them and consists of two classes of major metabolites: phenylpropanoids and terpenoids. The essential oils obtained from the family that has been identified more than 50% of estragole and volatile compounds such as methyl eugenol, pulegone, menthone, isomenthone, and spathulenol. The main nonvolatile metabolites are phenolic compounds, such as those derived from caffeic acid, especially rosmarinic acid, as well as several flavones and flavone glycosides such as acacetin, tilianin, agastachoside, and agastachin. Lignans, agastenol and agastinol, were also isolated, as well as terpenoids include oleanane type (maslinic acid, oleanolic acid, and β-amirin), ursane type (ursolic acid, corosolic acid, and α-amirin), typical plant sterols, and diterpenes (agastaquinone, agastol, and others) [82]. The plants of the *Lamiaceae* family are widely used as condiments, and some popular are oregano, thyme, and rosemary, but aromatic ones such as mint, basil,

About 250 species belong to the genus *Lippia* (Family *Verbenaceae*) and are distributed throughout Central and South America, as well as in the African continent. They are usually sold for the treatment of different types of pain, including stomach pain, abdominal pain, and headache, and are used as sedatives, anxiolytics, and anticonvulsants [108]. *Lippia alba, L. multiflora, L. gracilis, L. grata, L. origanoides, L. graveolens, L. geminata, L. origanoides,* and *L. adoensis* are the species that have reports worldwide on their effect on system disorders such as central nervous, pain,

*Lippia origanoides* commonly known in Mexico as "*oregano*" and *Lippia multiflora* also known in Africa are popularly used to control fever treat gastrointestinal disorders, enteritis, and cough. Composite leaves and flowers such as p-cymene, thymol, and carvacrol [110] were isolated from which the analgesic and antipyretic properties have been attributed, evaluated in mice and rats using carrageenan-induced hind paw as model of acute inflammation, and the analgesic effects were assayed by thermal, mechanical, and chemical models of antinociception, and this was correlated with an increase in glutathione and a decrease in nitric oxide and malondialdehyde, demonstrating a decrease in the levels of nitric acid and malonyl aldehyde process mediators such as inflammatory and pain [110]. A monoterpene called carvacrol has been isolated from oregano, which has shown antinociceptive effects. This metabolite was studied in an orofacial pain model and demonstrated that when administered at a dose of 20 mg/kg, it exerts antinociceptive effects in mice; however, this effect is punctuated more effectively if the metabolite is administered concomitantly with β-cyclodextrin [111]. Carvacrol/β-cyclodextrin has also been studied in cancer-induced pain models. Administered at a dose of 50 mg/kg, they exert antinociceptive effects in rodents that have tumors implanted in their hind

*DOI: http://dx.doi.org/10.5772/intechopen.91154*

and sage are also part of this family [107].

and inflammation [109].

naloxone model [86].

*Pharmaceutical and Botanical Management of Pain Associated with Psychopathology… DOI: http://dx.doi.org/10.5772/intechopen.91154*

caused by acetic acid and increased the latency time between the licks of the legs in both phases of pain (neuropathic and inflammatory) produced with formalin. In addition, the alkaloid-specific antinociceptive response was significantly in the naloxone model [86].

Another group of plants of pharmacological interest is the genus *Polygala* and the *Lamiaceae* family that have been widely used in pain therapy [105]. *Polygala molluginifolia* has shown important antinociceptive effects in mice. An experimental study showed that the hydroalcoholic extract of this plant, administered at a dose of 1000 mg/kg, exerted analgesic effects in a model of mechanical and thermal hyperalgesia to postoperative pain in mice. The mechanism of action of the experiment revealed that the effect of the natural product might be associated with a modulation of the TRPV1 and TRPA1 channels involved in nociceptive behavior and was demonstrated that *Polygala molluginifolia* has an antinociceptive potential without collateral effects like locomotor dysfunctions or sedation [106].

The phytochemistry of the species of the genus *Agastache* (Family *Lamiaceae*) is generally similar among them and consists of two classes of major metabolites: phenylpropanoids and terpenoids. The essential oils obtained from the family that has been identified more than 50% of estragole and volatile compounds such as methyl eugenol, pulegone, menthone, isomenthone, and spathulenol. The main nonvolatile metabolites are phenolic compounds, such as those derived from caffeic acid, especially rosmarinic acid, as well as several flavones and flavone glycosides such as acacetin, tilianin, agastachoside, and agastachin. Lignans, agastenol and agastinol, were also isolated, as well as terpenoids include oleanane type (maslinic acid, oleanolic acid, and β-amirin), ursane type (ursolic acid, corosolic acid, and α-amirin), typical plant sterols, and diterpenes (agastaquinone, agastol, and others) [82]. The plants of the *Lamiaceae* family are widely used as condiments, and some popular are oregano, thyme, and rosemary, but aromatic ones such as mint, basil, and sage are also part of this family [107].

About 250 species belong to the genus *Lippia* (Family *Verbenaceae*) and are distributed throughout Central and South America, as well as in the African continent. They are usually sold for the treatment of different types of pain, including stomach pain, abdominal pain, and headache, and are used as sedatives, anxiolytics, and anticonvulsants [108]. *Lippia alba, L. multiflora, L. gracilis, L. grata, L. origanoides, L. graveolens, L. geminata, L. origanoides,* and *L. adoensis* are the species that have reports worldwide on their effect on system disorders such as central nervous, pain, and inflammation [109].

*Lippia origanoides* commonly known in Mexico as "*oregano*" and *Lippia multiflora* also known in Africa are popularly used to control fever treat gastrointestinal disorders, enteritis, and cough. Composite leaves and flowers such as p-cymene, thymol, and carvacrol [110] were isolated from which the analgesic and antipyretic properties have been attributed, evaluated in mice and rats using carrageenan-induced hind paw as model of acute inflammation, and the analgesic effects were assayed by thermal, mechanical, and chemical models of antinociception, and this was correlated with an increase in glutathione and a decrease in nitric oxide and malondialdehyde, demonstrating a decrease in the levels of nitric acid and malonyl aldehyde process mediators such as inflammatory and pain [110]. A monoterpene called carvacrol has been isolated from oregano, which has shown antinociceptive effects. This metabolite was studied in an orofacial pain model and demonstrated that when administered at a dose of 20 mg/kg, it exerts antinociceptive effects in mice; however, this effect is punctuated more effectively if the metabolite is administered concomitantly with β-cyclodextrin [111]. Carvacrol/β-cyclodextrin has also been studied in cancer-induced pain models. Administered at a dose of 50 mg/kg, they exert antinociceptive effects in rodents that have tumors implanted in their hind

*Behavioral Pharmacology - From Basic to Clinical Research*

**Plant containing the metabolite**

*Papaver somniferum Woodfordia fruticosa Peganum harmala*

*Azadirachta indica Aloe vera Allium cepa Calamus scipionum Camellia sinensis Carica papaya Psidium guajava*

*Capsicum annuum Ginkgo biloba Solanum lycopersicum Daucus carota*

*Siegesbeckia orientalis Ageratum conyzoides Mikania cordifolia Moringa oleifera Plantago altissima Plantago lanceolata*

*Hyptis pectinata Hyptis fruticosa Erythrina velutina Aniba rosaeodora Mentha piperita Daphne aurantiaca*

*Asparagus racemosus Tribulus terrestris*

*Trianthema portulacastrum* **Pharmacological effects References**

[84–86]

[87–90]

[91, 92]

[93–96]

[97, 98]

[99, 100]

[101, 102]

Antinociceptive, anti-inflammatory, and antineuropathic

Peripheral neuropathy, anti-inflammatory, and antinociceptive

Acute or chronic pain: i.e. inhibiting the release of TNF-α and stimulating IL-10 production

Antinociceptive and anti-inflammatory

Antinociceptive and anti-inflammatory

Acute or chronic pain; antinociceptive, antiinflammatory, and neuropathic

Anti-nociceptive and anti-inflammatory

**Isolated metabolite**

Codeine Thebaine Papaverine

Rutin Kaempferol Luteolin Myricetin Apigenin

Lycopene

Resorcinol Hydroquinone Phloroglucinol Vanillic acid Gallic acid

Sarsasapogenin Dioscin

Lovastatin

*Secondary metabolites with analgesic potential.*

Alkaloid Morphine

Flavonoid Quercetin

Carotene β-carotene

Phenol Catechol

Terpene Thymoquinone Linalool Menthol Eugenol Fenchone Citronella

Saponin Digitonin

Statins Atorvastatin

**Table 4.**

**Group of metabolite**

neuropathic pain induced by partial sciatic nerve ligation showed that the administration of ethanolic extract of *Pterodon pubescens*, at an oral dose of 300 mg/kg, was effective in exerting antinociceptive effects, revealing a possible mechanism of action associated with the significant bite suppression induced by kainate, glutamate, NMDA, and trans-ACPD. Also, the plant extract decreased the concentration of proinflammatory cytokines like TNF-α and IL-1β and the inhibition of channels of capsaicin (TRPV1) and cinnamaldehyde (TRPA1), respectively, without pharmacological tolerance. The most abundant metabolites extracted from these plants were sesquiterpenes and diterpenes, which suggest that these compounds are responsible for the therapeutic effect [104]. There is interest in the study of other plant species, including *Woodfordia fruticosa, Adhatoda vasica, Chenopodium ambrosioides, Viburnum cotinifolium, Vitex negundo, Peganum harmala,* and *Broussonetia papyrifera* because of the presence of effective alkaloids for pain treatment. The crude alkaloid extracts of all selected medicinal herbs were active at an oral dose of 1250 mg/kg of body weight in mice, where they reduced abdominal contractions

**68**

paw [112]. An interesting fact about carvacrol is that its analgesic effects decrease when administered alone and increase when administered with cyclodextrin. On the other hand, carvacrol and p-cymene have an analgesic effect related to the decrease of pain mediators such as proinflammatory cytokines (IL-1, TNF, IL-4, TGF and IL-17) and anti-inflammatory (IL-10) [113, 114].

Hexane, ethyl acetate, and ethanol extracts from *Agastache mexicana subsp. xolocotziana* showed an antinociceptive effect in rats and mice. The ethyl acetate extract (containing significant amounts of ursolic acid) was the most active in the formalin-induced pain model, mainly in the inflammatory (second) phase; hexanic extract (present pulegonic and oleanolic acid) decreased thermal pain. The methanolic extract (rich in flavonoids such as acacetin and tilianin) was more active in the formalin model and in the acetic acid contortion model [82].

Rosemary plant has been assessed in Diabetes Mellitus cases of pain models. A study in rats showed that rosemary extract administration at 100, 150, and 200 mg/kg doses decreased hyperalgesia through the suppression of caspase-3. In this study, the neuroprotective effect of rosemary was also demonstrated, so that the authors suggested that the mechanisms of action might be involved in the inhibition of neuronal apoptosis [115].

The *Mentha spicata* plant, popularly known as garden mint, showed significant analgesic effects at the preclinical level. Phytochemical studies have revealed the presence of metabolites such as carvone, limonene, and menthol. Basil plant (*Ocimum basilicum*) has also shown analgesic effects combined with β-cyclodextrin. Studies have been conducted from basil essential oils, which are rich in monoterpenes. A study conducted in animal models of fibromyalgia showed that essential oils administered orally, at doses of 25, 50, and 100 mg/kg, significantly reduced mechanical hyperalgesia in mice [116, 117].

In addition to the plants described above, many others have presented significant effects in pain therapy in preclinical models associated with certain metabolites (see **Table 5**). Nevertheless, further molecular studies on secondary metabolites are needed, which allow to accurately indicate the mechanisms of action, and the effects can be compared with those analgesics already in the market. Further research is required to achieve analgesic effects at the lowest possible doses to significantly reduce the number of adverse reactions in organisms, particularly because the use of natural resources has become increasingly active in recent years because of the belief that natural products lack side effects [118]. Nevertheless, herbal therapy is risky because there are effects caused by plant metabolites that may vary depending on several external factors such as pollution, conservation processes, and the presence of pesticides, among others yet to be evaluated. As a result, the use of botanical medicine requires rigorous standardization processes that guarantee safety in its use [119]. The variety of soils and climates in such countries facilitates the growth of a wide range of plants. Nevertheless, the native people use plants empirically, which had led to the lack of standards in their use in terms of effectiveness, safety, and quality [120]. This idea has triggered the worldwide development of drugs used in plants, which lead to the phytomedicine trade worldwide [118].

Phytomedicine differs from synthetized chemical-pharmaceutical drugs in their components. A chemical-pharmaceutical drug is synthesized and designed in such a way we can have a pure compound or at least a small mixture of chemical molecules. Conversely, phytomedicine is plant extracts that contain numerous and not well-known compounds. As a result, the source of the plant material requires quality production and standardization of the extracts to guarantee the identification and purification of the compounds that target pain [121]. The increased popularity of herbal medicine worldwide had led to numerous reports that support its regulation. In some countries, regulations have been legally established in order

**71**

*Pharmaceutical and Botanical Management of Pain Associated with Psychopathology…*

Male and female mice in a chronic neuropathic sciatic nerve injury model

chronic neuropathic sciatic nerve injury model.

Anti-inflammatory *in vitro* COX-1 enzyme; Swiss mouse females in the formalin test and acetic acid-induced abdominal writhing test

(12-O-tetradecanoylphorbol-13-acetate)-induced ear

Orofacial formalin test Reduce the

Morphine Male and female mice in a

TPA

edema test

Male OF-1 mouse in formalin, acetic acidinduced abdominal writhing

models; hot plate

model

test

Hot plate and acetic acidinduced abdominal writhing

Acetic acid-induced induced abdominal writhing model. Tail flick test; tail immersion

Carrageenan, acetic acid, arachidonic acid (AA) induced paw edema and writhing models. Cyclooxygenase activity.

Formalin, capsaicin and cinnamaldehyde, carrageenan-induced paw edema models; hot plate and tail flick; traumatic sciatic

nerve injury

**Animal model used Effects on pain References**

Reduce allodynia, hyperalgesia, and ultrasonic clicks

Reduce allodynia, hyperalgesia, and ultrasonic clicks but develop tolerance after 1 week

Reduce the nociceptive response

Antiinflammatory activity

Antinociceptive but not antiinflammatory effect

nociceptive response

Decrease the number of paws licking and writhing

Reduce the number of writhing. Increase latency; reduce the tail withdrawal time

Analgesic and antiinflammatory activity Inhibit the activity of COX-I/II

Antinociceptive and antiinflammatory effect; increase paw withdrawal latency and reduce mechanical allodynia

[123]

[123]

[124, 125]

[126, 127]

[128, 129]

[130, 131]

[133–135]

[136]

[137, 138]

[132]

*DOI: http://dx.doi.org/10.5772/intechopen.91154*

**metabolite involved**

Phenolic compounds and hydroxy fatty

Sesquiterpenelactones (eudesman,

Flavonoids, flavonol glycosides, and polysaccharides

Sesquiterpene and

iridoids

Flavonoids, alkaloids, triterpenoids, steroids, saponins, phenols, and glycosides

Alkaloids,

4-Hidroxybenzaldehyde 4-Hidroxybenzyl alcohol Benzyl alcohol Vanillin Vanillic acid

Alkaloids, flavonoids, tannins, and carotenoids N-alkylamides Spilanthol

flavonoids, saponins, and tannins Curcumin Demethoxycurcumin Bisdemethoxycurcumin

cadinane, germacrane, and elemane)

acids

∆9-Tetrahydrocannabinol Cannabidiol

**Plant Potential active** 

*Cannabis sativa*

*Papaver somniferum*

*Urtica dioica, Urtica urens, and Urtica circularis*

*Verbesina persicifolia*

*Costus pictus, Costus spicatus*

*Valeriana officinalis*

*Calotropis gigantea (L) R. Br.*

*Curcuma longa L.*

*Gastrodia elata*

*Spilanthes acmella, Acmella oleracea*


*Pharmaceutical and Botanical Management of Pain Associated with Psychopathology… DOI: http://dx.doi.org/10.5772/intechopen.91154*

*Behavioral Pharmacology - From Basic to Clinical Research*

IL-17) and anti-inflammatory (IL-10) [113, 114].

neuronal apoptosis [115].

mechanical hyperalgesia in mice [116, 117].

formalin model and in the acetic acid contortion model [82].

paw [112]. An interesting fact about carvacrol is that its analgesic effects decrease when administered alone and increase when administered with cyclodextrin. On the other hand, carvacrol and p-cymene have an analgesic effect related to the decrease of pain mediators such as proinflammatory cytokines (IL-1, TNF, IL-4, TGF and

Hexane, ethyl acetate, and ethanol extracts from *Agastache mexicana subsp. xolocotziana* showed an antinociceptive effect in rats and mice. The ethyl acetate extract (containing significant amounts of ursolic acid) was the most active in the formalin-induced pain model, mainly in the inflammatory (second) phase; hexanic extract (present pulegonic and oleanolic acid) decreased thermal pain. The methanolic extract (rich in flavonoids such as acacetin and tilianin) was more active in the

Rosemary plant has been assessed in Diabetes Mellitus cases of pain models. A study in rats showed that rosemary extract administration at 100, 150, and 200 mg/kg doses decreased hyperalgesia through the suppression of caspase-3. In this study, the neuroprotective effect of rosemary was also demonstrated, so that the authors suggested that the mechanisms of action might be involved in the inhibition of

The *Mentha spicata* plant, popularly known as garden mint, showed significant

In addition to the plants described above, many others have presented significant effects in pain therapy in preclinical models associated with certain metabolites (see **Table 5**). Nevertheless, further molecular studies on secondary metabolites are needed, which allow to accurately indicate the mechanisms of action, and the effects can be compared with those analgesics already in the market. Further research is required to achieve analgesic effects at the lowest possible doses to significantly reduce the number of adverse reactions in organisms, particularly because the use of natural resources has become increasingly active in recent years because of the belief that natural products lack side effects [118]. Nevertheless, herbal therapy is risky because there are effects caused by plant metabolites that may vary depending on several external factors such as pollution, conservation processes, and the presence of pesticides, among others yet to be evaluated. As a result, the use of botanical medicine requires rigorous standardization processes that guarantee safety in its use [119]. The variety of soils and climates in such countries facilitates the growth of a wide range of plants. Nevertheless, the native people use plants empirically, which had led to the lack of standards in their use in terms of effectiveness, safety, and quality [120]. This idea has triggered the worldwide development of drugs used in plants, which lead to the phytomedicine trade worldwide [118]. Phytomedicine differs from synthetized chemical-pharmaceutical drugs in their components. A chemical-pharmaceutical drug is synthesized and designed in such a way we can have a pure compound or at least a small mixture of chemical molecules. Conversely, phytomedicine is plant extracts that contain numerous and not well-known compounds. As a result, the source of the plant material requires quality production and standardization of the extracts to guarantee the identification and purification of the compounds that target pain [121]. The increased popularity of herbal medicine worldwide had led to numerous reports that support its regulation. In some countries, regulations have been legally established in order

analgesic effects at the preclinical level. Phytochemical studies have revealed the presence of metabolites such as carvone, limonene, and menthol. Basil plant (*Ocimum basilicum*) has also shown analgesic effects combined with β-cyclodextrin. Studies have been conducted from basil essential oils, which are rich in monoterpenes. A study conducted in animal models of fibromyalgia showed that essential oils administered orally, at doses of 25, 50, and 100 mg/kg, significantly reduced

**70**


#### **Table 5.**

*Active metabolites in pain relief.*

to safeguard public health, ensuring quality, efficiency, and safety. For instance, the European Union has one of the most complete regulatory systems for the use of herbal medicine [122]. Since the combination of both conventional and traditional herbal therapy has been poorly explored, it must be careful to avoid serious adverse reactions [81].

#### **8. Final comments and conclusion**

Pain is unpleasant sensory and emotional experience associated with actual or potential tissue damage, being one of the most persistent and disabling manifestations present in several conditions and diseases mentioned in this chapter, such as tissue injuries and bumps, postoperative surgery, cancer, diabetes, mood disorders, dementia, and schizophrenia, among others.

In this chapter, it was highlighted that the pain is continually reclassified due to its severity and complexity, coupled with the difficulty of describing it, despite the fact that there are currently more reliable and valid instruments. This activity is of great importance to improve the diagnosis and sure adequate therapeutic management.

Because pain is a global public health problem, there is a large class of drugs used for its treatment, such as opiates, tricyclic antidepressants, and antiepileptic drugs. As shown in this review, the prescription of this conventional painkiller depends on the type of pain, its duration, origin, and intensity. However, the side effects shown by these compounds hinder in many instances, their safe and effective use,

**73**

PPD-167).

*Pharmaceutical and Botanical Management of Pain Associated with Psychopathology…*

particularly opioids, which could promote life-threatening respiratory depression, addiction, pruritus, nausea, and constipation. Therefore, new molecules are being sought with specific mechanisms of action that act from the genesis and maintenance of pain at different levels of the nervous system, for example, on the connex-

On the other hand, in many countries, herbal medicine is used as a complementary or an alternative strategy to treat pain because it usually lowers costs, is more within reach of patients, and has an important cultural root. In this sense, species such as *Papaver somniferum, Pterodon pubescens, Capsicum annuum, Chenopodium ambrosioides, Polygala molluginifolia, Lippia alba, Agastache mexicana, Allium cepa, Moringa oleífera,* and *Hyptis pectinata,* among others described in this chapter are used due to their analgesics and anti-inflammatory properties. Secondary metabolites such as alkaloids, flavonoids, carotenes, terpenes, and other polyphenolic compounds seem to be responsible for the pharmacological effect reported, which has been demonstrated from the use of animal models, which show similar perception to chemical, thermal, electrical, and mechanical stimuli that can induce pain than in humans and that constitute one way to approach the study of new molecules

Since the combination of both conventional and traditional phytotherapy has been poorly explored, this can often lead to harmful effects rather than improving pain treatment. Meanwhile, most analgesics and herbal products for pain treatment are accessible because they do not require a prescription for sale, their consumption has been exceeded, and self-medication has led to a major concern in several countries. Not regulated herbal therapies can trigger several conditions that may further compromise the patient's well-being. Currently, research on natural products includes the use of organic synthesis for improving natural product characteristics. Some research groups synthesize analogs of natural compounds and modify its activity to improve the effectiveness of the drug lead. Since the use of natural compounds might be risky because of the multiple active molecules present in plants, mimicking the targets that produce the desired effect, such as diminish pain, it is a useful alternative and avoids the burden of isolating molecules from natural resources. In this regard, it is possible to obtain a purified compound that can be tested. Molecular biology is a powerful tool to identify receptors and proteins, so a perspective in the pharmacological treatment of pain could be the development of further research in molecular biology for studying the targets of pain and therefore for designing specific molecules that can bind

In conclusion, it is crucial that pharmaceutical, neuroscientists, and other healthcare professionals must be involved in well-designed preclinical trials to fully understand the effects of herbal medicines and phytopharmaceuticals and to study the molecular mechanisms and biological targets in which they operate. In terms of regulation, it would be important for organisms other than the Food and Drug Administration (FDA) in developing countries to establish the mechanisms such as

Special thanks to the National Council of Science and Technology (CONACyT)

for the postgraduate scholarships awarded to MFO-S (#635389), VDC-G (#927607), LSG-B (#782401), and the Program for Teacher Professional Development (PRODEP) for the financial support (#511–6/2019–2110,171/

to conduct all the preclinical trials before releasing a new drug.

*DOI: http://dx.doi.org/10.5772/intechopen.91154*

or herbal extracts with analgesic activity.

directly to pain receptors.

**Acknowledgements**

ins, which would represent an outstanding advance.

#### *Pharmaceutical and Botanical Management of Pain Associated with Psychopathology… DOI: http://dx.doi.org/10.5772/intechopen.91154*

particularly opioids, which could promote life-threatening respiratory depression, addiction, pruritus, nausea, and constipation. Therefore, new molecules are being sought with specific mechanisms of action that act from the genesis and maintenance of pain at different levels of the nervous system, for example, on the connexins, which would represent an outstanding advance.

On the other hand, in many countries, herbal medicine is used as a complementary or an alternative strategy to treat pain because it usually lowers costs, is more within reach of patients, and has an important cultural root. In this sense, species such as *Papaver somniferum, Pterodon pubescens, Capsicum annuum, Chenopodium ambrosioides, Polygala molluginifolia, Lippia alba, Agastache mexicana, Allium cepa, Moringa oleífera,* and *Hyptis pectinata,* among others described in this chapter are used due to their analgesics and anti-inflammatory properties. Secondary metabolites such as alkaloids, flavonoids, carotenes, terpenes, and other polyphenolic compounds seem to be responsible for the pharmacological effect reported, which has been demonstrated from the use of animal models, which show similar perception to chemical, thermal, electrical, and mechanical stimuli that can induce pain than in humans and that constitute one way to approach the study of new molecules or herbal extracts with analgesic activity.

Since the combination of both conventional and traditional phytotherapy has been poorly explored, this can often lead to harmful effects rather than improving pain treatment. Meanwhile, most analgesics and herbal products for pain treatment are accessible because they do not require a prescription for sale, their consumption has been exceeded, and self-medication has led to a major concern in several countries. Not regulated herbal therapies can trigger several conditions that may further compromise the patient's well-being. Currently, research on natural products includes the use of organic synthesis for improving natural product characteristics. Some research groups synthesize analogs of natural compounds and modify its activity to improve the effectiveness of the drug lead. Since the use of natural compounds might be risky because of the multiple active molecules present in plants, mimicking the targets that produce the desired effect, such as diminish pain, it is a useful alternative and avoids the burden of isolating molecules from natural resources. In this regard, it is possible to obtain a purified compound that can be tested. Molecular biology is a powerful tool to identify receptors and proteins, so a perspective in the pharmacological treatment of pain could be the development of further research in molecular biology for studying the targets of pain and therefore for designing specific molecules that can bind directly to pain receptors.

In conclusion, it is crucial that pharmaceutical, neuroscientists, and other healthcare professionals must be involved in well-designed preclinical trials to fully understand the effects of herbal medicines and phytopharmaceuticals and to study the molecular mechanisms and biological targets in which they operate. In terms of regulation, it would be important for organisms other than the Food and Drug Administration (FDA) in developing countries to establish the mechanisms such as to conduct all the preclinical trials before releasing a new drug.

### **Acknowledgements**

Special thanks to the National Council of Science and Technology (CONACyT) for the postgraduate scholarships awarded to MFO-S (#635389), VDC-G (#927607), LSG-B (#782401), and the Program for Teacher Professional Development (PRODEP) for the financial support (#511–6/2019–2110,171/ PPD-167).

*Behavioral Pharmacology - From Basic to Clinical Research*

**metabolite involved**

Alkaloid, flavonoids, and tannins

polyphenolic salicin and glycosides 2-(hydroxymethyl) phenyl-B-Dglucopyranoside Salicyl-alcohol

Furocoumarins and coumarins

Phenolic acids (caffeic, chlorogenic), flavonoids (quercetin, palutelin), sesquiterpene lactones (helenalin, dihydrohelenalin)

**Plant Potential active** 

*Salix alba* Alkaloids, tannins,

*Zingiber officinale*

*Ammi majus*

*Arnica montana*

**Table 5.**

to safeguard public health, ensuring quality, efficiency, and safety. For instance, the European Union has one of the most complete regulatory systems for the use of herbal medicine [122]. Since the combination of both conventional and traditional herbal therapy has been poorly explored, it must be careful to avoid serious adverse

Hot plate, tail flick test; acetic acid-induced pain

Formalin-induced paw edema model Enzymatic action of hyaluronidase

Hot plate; formalin, carrageenan-hind paw edema models

Hot plate; carrageenan, formalin-hind paw edema models; cytokines determination by ELISA

model

**Animal model used Effects on pain References**

Antinociceptive effects against thermally and chemically stimulus

Inhibit the paw edema

Anti-

Inhibitory actions on biochemical pathways of arachidonic acid

inflammatory and antinociceptive; inhibition of the writhing number

Inhibition of the licking, writhing, and biting response; decrease secretion of IL-6 and IL-8 proinflammatory cytokines

[139–141]

[85, 142, 143]

[144, 145]

[146, 147]

Pain is unpleasant sensory and emotional experience associated with actual or potential tissue damage, being one of the most persistent and disabling manifestations present in several conditions and diseases mentioned in this chapter, such as tissue injuries and bumps, postoperative surgery, cancer, diabetes, mood disorders,

In this chapter, it was highlighted that the pain is continually reclassified due to its severity and complexity, coupled with the difficulty of describing it, despite the fact that there are currently more reliable and valid instruments. This activity is of great importance to improve the diagnosis and sure adequate therapeutic

Because pain is a global public health problem, there is a large class of drugs used for its treatment, such as opiates, tricyclic antidepressants, and antiepileptic drugs. As shown in this review, the prescription of this conventional painkiller depends on the type of pain, its duration, origin, and intensity. However, the side effects shown by these compounds hinder in many instances, their safe and effective use,

**72**

reactions [81].

*Active metabolites in pain relief.*

management.

**8. Final comments and conclusion**

dementia, and schizophrenia, among others.

*Behavioral Pharmacology - From Basic to Clinical Research*
