**2.5. Cannabis and cannabinoids as analgesic**

Cannabis or medical marijuana is related to the use of cannabis and isolated cannabinoids to cure diseases and relieve pain [28]. In addition, cannabis and its compounds are used to treat chronic pain. The best‐known analgesic of these cannabinoids for treatment of pain is tetrahy‐ drocannabinol, or the best known as THC [29–31].

In comparison, numerous mixtures of analgesic drugs have been determined to have insuf‐ ficient effectiveness compared to similar doses of their separate mechanisms. Furthermore, these analgesic mixtures frequently result in consequences such as unintentional overdoses, often owing to misperceptions that arise from the many mentioned compounds and combi‐ nations [32]. Countless people use alternative medicine for pain relief. There are indications that some medications relieve some kind of pain more efficiently than others [33]; however, additional research would be essential to improve comprehension of the uses of many alter‐ native medicine [34].

## **2.6. Plants as new sources of pain killers**

Numerous medicinal plants and their derived phytochemicals were evaluated for their analge‐ sic and anti‐inflammatory effects. For example, extracts of bark as well as terpenoids obtained from *Combretum molle* (Combretaceae), β‐glucopyranosyl, and other isolated compounds have been documented to have an excellent potential against carrageenan‐induced paw edema in rats [7]. Similarly, *Millettia versicolor* crude extract and its isolated phytochemicals were found to inhibit 12‐*O*‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced acute ear edema and phospholipase A2 acute mouse paw edema [8]. Furthermore, chemical constituents isolated from various parts of *Millettia griffoniana*, *Erythrina addisoniae*, and *Erythrina mildbraedii* have been reported to exhibit significant anti‐inflammatory activity on induced‐paw edema and induced‐ear edema in mice [8], whereas compounds isolated from *Erythrina sigmoidea* have been shown to possess anti‐inflammatory activity against 12‐*O‐*tetradecanoylphorbol‐13‐ace‐ tate (TPA)‐induced ear edema [8]. Based on the above facts, the present chapter will focus on documenting the recent literature pertaining to medicinal plants and their phytochemicals and extracts as analgesics and in the treatment of inflammation.

## **2.7. Other natural products with analgesic properties**

Natural products play a key role for living organisms. Primary metabolites are defined by Kossel as the main components of metabolic paths that are compulsory for life. Primary metabolites are related to important cellular roles, such as energy production, assimilation of nutrients, and development/growth. Secondary metabolites, in contrast to primary, are not essential and not required for the survival of living organisms [35–38].

Interestingly, secondary metabolites possess a broad range of functions. They comprise pher‐ omones, which can act as community gesturing molecules with additional individuals of the same species [39–41]. Communication molecules entice and stimulate a symbiotic organism and agents to solubilize and transport various nutrients, including siderophores, as well as good arms such as venoms, repellants, and toxins, which are used as a prey and predators competitors [42]. It has been documented in the literature that nearly 10 million organic com‐ pounds have been discovered and many new and novel compounds are still being isolated and characterized in various parts of the world.

Regarding these compounds, one hypothesis is that they present a good benefit to the living organism which makes them. Another view says that these compounds have similarity to the immune system of living organisms, and although they have no function, yet they can afford assorted bioactive compounds which have important biological activity [42].

Naturally obtained agents such as aspirin, morphine, codeine, thebaine, and others have been reported to have analgesic activity. Aspirin derived from salicylic acid extracted from barks of the willow tree (*Salix alba*) is one of the most extensively used compounds for the manage‐ ments of mild pain. On the other hand, morphine codeine and thebaine isolated from plants are used as analgesics (**Figure 1**) [43, 44].

Different types of active phytochemicals, such as steroids, alkaloids, tannins, phenol, and polyphenols are produced by medicinal plants [45–49]. In addition, a large number of plants that have been investigated are reported to have less pharmacologically active secondary metabolites identified. Plant‐derived molecules are mainly reported for their medical impor‐ tance; this includes morphine, nicotine, quinine, steroidal, and many others [50]. A large num‐ ber of presently recommended drugs have been derived from natural medicinal plants; some characteristic examples are given in next sections.

## *2.7.1. Salicin*

**2.4. Alcohol compounds as analgesics**

342 Pain Relief - From Analgesics to Alternative Therapies

**2.5. Cannabis and cannabinoids as analgesic**

drocannabinol, or the best known as THC [29–31].

**2.6. Plants as new sources of pain killers**

of extreme drinking [27].

native medicine [34].

phospholipase A2

Alcohol compounds are also documented to treat pain [24]; however, alcohols have biologi‐ cal, mental, and social properties that affect the significance of their use for treatment of pain [25]. Although reasonable usage of alcohol can reduce certain kinds of pain under certain conditions [26], the use of alcohol to cure pain, however, is encountered by the negative effects

Cannabis or medical marijuana is related to the use of cannabis and isolated cannabinoids to cure diseases and relieve pain [28]. In addition, cannabis and its compounds are used to treat chronic pain. The best‐known analgesic of these cannabinoids for treatment of pain is tetrahy‐

In comparison, numerous mixtures of analgesic drugs have been determined to have insuf‐ ficient effectiveness compared to similar doses of their separate mechanisms. Furthermore, these analgesic mixtures frequently result in consequences such as unintentional overdoses, often owing to misperceptions that arise from the many mentioned compounds and combi‐ nations [32]. Countless people use alternative medicine for pain relief. There are indications that some medications relieve some kind of pain more efficiently than others [33]; however, additional research would be essential to improve comprehension of the uses of many alter‐

Numerous medicinal plants and their derived phytochemicals were evaluated for their analge‐ sic and anti‐inflammatory effects. For example, extracts of bark as well as terpenoids obtained from *Combretum molle* (Combretaceae), β‐glucopyranosyl, and other isolated compounds have been documented to have an excellent potential against carrageenan‐induced paw edema in rats [7]. Similarly, *Millettia versicolor* crude extract and its isolated phytochemicals were found to inhibit 12‐*O*‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced acute ear edema and

from various parts of *Millettia griffoniana*, *Erythrina addisoniae*, and *Erythrina mildbraedii* have been reported to exhibit significant anti‐inflammatory activity on induced‐paw edema and induced‐ear edema in mice [8], whereas compounds isolated from *Erythrina sigmoidea* have been shown to possess anti‐inflammatory activity against 12‐*O‐*tetradecanoylphorbol‐13‐ace‐ tate (TPA)‐induced ear edema [8]. Based on the above facts, the present chapter will focus on documenting the recent literature pertaining to medicinal plants and their phytochemicals

Natural products play a key role for living organisms. Primary metabolites are defined by Kossel as the main components of metabolic paths that are compulsory for life. Primary metabolites

and extracts as analgesics and in the treatment of inflammation.

**2.7. Other natural products with analgesic properties**

acute mouse paw edema [8]. Furthermore, chemical constituents isolated

It has been reported in the literature that extracted natural products possess analgesic activ‐ ity. The bark of willow trees has been recognized for pain‐relieving properties. It has been further reported that willow bark contains a bioactive compound, salicin, which hydrolyses into salicylic acid. As we know that derivative acetylsalicylic acid is known as aspirin and is used as a pain killer, the main mechanism of its action is inhibition of the cyclooxygenase enzyme (COX). There are two types of cyclooxygenase‐2 enzyme isozymes; COX‐1 (PTGS1) and COX‐2 (PTGS2). It is nonselective and permanently inhibits both form, but it is weakly more selective for COX‐1. COX produces prostaglandins most of them are pro‐inflammatory and thromboxanes, which promote clotting [51].

Nonsteroidal anti‐inflammatory drugs (NSAIDs) act via inhibition of cyclooxygenase enzyme (COX). Research findings suggest the opposing effects of nonsteroidal anti‐inflammatory

**Figure 1.** Chemical structures of analgesic compounds from medicinal plants.

drugs on COX. These drugs act by blocking the COX‐1 enzyme, which catalyzes the pro‐ duction of prostaglandins that are involved in numerous physiological functions, such as (a) maintenance of normal renal function in the kidneys, (b) mucosal protection in the gastroin‐ testinal tract, and (c) proaggregatory thromboxane in the platelets. However, COX‐2 expres‐ sion can be induced by cytokines and other inflammatory mediators in a number of tissues, including endothelial cells, and is believed to have a role in the mediation of pain, inflamma‐ tion, and fever. COX‐2 agents only inhibit the COX‐2 enzyme, whereas traditional NSAIDs block both versions in general [16].

After extensive acceptance of the cyclooxygenase enzyme (COX‐2) inhibitors, it was revealed that many of the drugs in this class increase the risk of cardiovascular toxicity, which led to the removal of valdecoxib and rofecoxib, and others. On the other hand, etoricoxib appears comparatively safer to that of noncoxib NSAID diclofenac [17]. It is worth mentioning here that our research group has reported that pistagremic acid, a natural product isolated from *Pistacia integerrima*, can inhibit COX‐2 enzyme owing to the hydrogen and hydrophobic con‐ tacts to significant active sites of molecule [17].

The key uses of NSAID medication are typically for joint‐ and spine‐related pain. Its mech‐ anism of action is through interaction with pro‐inflammatory cytokines interleukin (IL‐1a, IL‐1b, IL‐6) and tumor necrosis factor (TNF‐α). Increased absorption of TNF‐α is thought to produce the cardinal symptoms of inflammation. These pro‐inflammatory cytokines result in chemo‐attractants for neutrophils and help them to stick to the endothelial from migration. They also stimulate white cell phagocytosis and the production of inflammatory lipid pros‐ taglandin E2 (PGE<sup>2</sup> ). The ability of NSAIDs to interfere with the production of prostaglandin during inflammatory cascade is the major mechanism cited for success of pain of medication. In normal pain, the archidonic pathway proceeds and results in the production of highly reactive mediators that are prostaglandin, prostacycline, histamines, and many others. These mediators cause the start of pain in the body.
