**2.1. Aspirin**

Aspirin or acetylsalicylic acid (**Figure 1**) is extracted from the bark of the Willow tree *Salix alba*, family *Salicaceae*. It is one of the most extensively used analgesic agents for the management of mild pain. Aspirin is considered the first nonsteroidal anti-inflammatory drug (NSAID) that inhibits the arachidonic acid pathway resulting in the synthesis of eicosanoids, which is a potent pain mediator [4]. Moreover, the inhibition of the cyclooxygenase (COX) enzymes by aspirin led to the discovery of other synthetic NSAIDs.

For instance, the study of the biochemical cascade of COX system led to the discovery of the COX-2 enzyme inhibitors. COX-2 inhibitors are believed to be safer than other NSAIDS that inhibit the COX-1 enzyme. Rofecoxib (Vioxx)® is an example of a compound that selectively targets the COX-2 enzyme, and it was voluntarily withdrawn by Merck and Co., Inc. on September 30, 2004, from the US drug market due to an increased risk of cardiovascular effects [5].

## **2.2. Opioids**

Natural opiates and synthetic opioids are potent analgesics that bind to receptors for endogenous opiates in the central nervous system (CNS). Opioid is the common name for all com-

**Figure 1.** Aspirin.

pounds acting on opioid receptor as the constituents of opium, to produce morphine-like effects. *Papaver somniferum* (family: *Papaveraceae*) is one of the oldest medicinal plants known by mankind, and abuse of its opium juice has been known before history was recorded. Opium contains about 25 alkaloids, including morphine (**Figure 2**), codeine (**Figure 3**) and thebaine (**Figure 4**) [6]. Tramadol is a synthetic analogue of codeine that acts by binding to μ (mu) opiate receptors, added to that it inhibits norepinephrine and serotonin reuptake [7]. Whereas, by modifying the chemical structure of thebaine, a semisynthetic derivative is obtained, termed oxycodone [8]. The endogenous opioid receptor system includes four receptor subtypes designated as mu (μ), delta (δ), kappa (k) and opioid receptor like (ORL-1) receptors. These receptors are widely disseminated in the mammalian system and have been found in all vertebrates. Opioid receptors are highly distributed in the CNS, including the brain and spinal cord, but they are also found in the gastrointestinal system and in the cells of immune system [9].

Lately, newly discovered chemical structures have appeared in the literatures that interact either with opioid receptors directly or through some other mechanism of controlling opioid receptor signalling. These compounds are interesting from a drug design perspective as most of them do not contain nitrogen.

**Figure 2.** Morphine.

capsaicin, atropine, pilocarpine, digitalis, quinine, scopolamine and captopril are examples of

Since ancient times, many active compounds originated from natural sources have been consumed for various medical purposes including the management of pain. Opium, for example, has been used since 7000 years ago. Up to the nineteenth century, other active components derived from different natural remedies were identified, purified and utilized. Since then, analogues have been made from natural sources, and completely synthetic compounds based

Aspirin or acetylsalicylic acid (**Figure 1**) is extracted from the bark of the Willow tree *Salix alba*, family *Salicaceae*. It is one of the most extensively used analgesic agents for the management of mild pain. Aspirin is considered the first nonsteroidal anti-inflammatory drug (NSAID) that inhibits the arachidonic acid pathway resulting in the synthesis of eicosanoids, which is a potent pain mediator [4]. Moreover, the inhibition of the cyclooxygenase (COX)

For instance, the study of the biochemical cascade of COX system led to the discovery of the COX-2 enzyme inhibitors. COX-2 inhibitors are believed to be safer than other NSAIDS that inhibit the COX-1 enzyme. Rofecoxib (Vioxx)® is an example of a compound that selectively targets the COX-2 enzyme, and it was voluntarily withdrawn by Merck and Co., Inc. on September 30, 2004, from the US drug market due to an increased risk of cardiovas-

Natural opiates and synthetic opioids are potent analgesics that bind to receptors for endogenous opiates in the central nervous system (CNS). Opioid is the common name for all com-

**2. Active compounds derived from natural sources possessing** 

on natural pharmacophores have been introduced into the market [3].

enzymes by aspirin led to the discovery of other synthetic NSAIDs.

drugs derived from natural sources [1, 2].

278 Pain Relief - From Analgesics to Alternative Therapies

**analgesic properties**

**2.1. Aspirin**

cular effects [5].

**2.2. Opioids**

**Figure 1.** Aspirin.

**Figure 3.** Codeine.

**Figure 4.** Thebaine.

### *2.2.1. Morphine*

In the 1850s, morphine began to be used for chronic pain, in minor surgical operations and after surgery. Morphine is the most abundant opiate obtained from opium. It is the dried latex obtained by shallow slicing of the unripe seedpods of *Papaver somniferum*. Meperidine was the first synthetic opioid analgesic, with a completely different structure from that of morphine, and its analgesic properties were identified in 1939. Far ahead in 1942, nalorphine was obtained, as the first opioid receptor antagonist, by replacing the substituent group on the nitrogen atom. By replacing the allyl group with the methyl group, nalorphine (**Figure 5**) is obtained from morphine, and naloxone is obtained from oxymorphine (**Figure 6**) [10, 11].

Nalorphine acts as an antagonist at the μ and δ receptors, but it acts as a weak agonist at the k receptor, and thus gives slight analgesia. However, nalorphine has hallucinogenic side effects. Whereas, naloxone is an antagonist at the three opioid receptors (μ, δ and k receptors). This compound is used to elucidate the possible roles of opioids in response to stress [11, 12].

In spite of the remarkable efforts by researchers to discover safe, effective and nonaddictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine [13].

**Figure 6.** Naloxone.

*2.2.1. Morphine*

**Figure 4.** Thebaine.

280 Pain Relief - From Analgesics to Alternative Therapies

(**Figure 6**) [10, 11].

[11, 12].

medicine [13].

**Figure 5.** Nalorphine.

In the 1850s, morphine began to be used for chronic pain, in minor surgical operations and after surgery. Morphine is the most abundant opiate obtained from opium. It is the dried latex obtained by shallow slicing of the unripe seedpods of *Papaver somniferum*. Meperidine was the first synthetic opioid analgesic, with a completely different structure from that of morphine, and its analgesic properties were identified in 1939. Far ahead in 1942, nalorphine was obtained, as the first opioid receptor antagonist, by replacing the substituent group on the nitrogen atom. By replacing the allyl group with the methyl group, nalorphine (**Figure 5**) is obtained from morphine, and naloxone is obtained from oxymorphine

Nalorphine acts as an antagonist at the μ and δ receptors, but it acts as a weak agonist at the k receptor, and thus gives slight analgesia. However, nalorphine has hallucinogenic side effects. Whereas, naloxone is an antagonist at the three opioid receptors (μ, δ and k receptors). This compound is used to elucidate the possible roles of opioids in response to stress

In spite of the remarkable efforts by researchers to discover safe, effective and nonaddictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary The pharmacological properties of morphine are somewhat complex and varying according to the dose, site of action, route of administration and animal species. Morphine is mostly considered as pain perception modifier, resulting in an increase in the threshold of painful stimuli. Nowadays, analgesia induced by morphine is known to be mediated via activation of membrane opioid receptors, and consequently, it can be inhibited by opioid receptor antagonists, as naloxone. Furthermore, certain undesirable side effects of morphine as euphorogenic effect, inhibition of gastrointestinal transit time, constipation, loss of appetite, hypothermia, bradycardia and retention of urine seem to involve receptormediated actions [14].

As more chemical components of traditionally used plants for the treatment of pain are explicated, there is a great potential for the development of novel drug treatments acting through opioid receptors. Indeed, some newly discovered chemical structures have been published in the literatures that interact either directly with opioid receptors or through some other mechanisms of controlling opioid receptor signalling. In the next section, examples of some of those chemical structures will be reviewed.

#### *2.2.2. Menthol*

Menthol (**Figure 7**) is isolated from peppermint (*Menthapiperita*, family: *Lamiaceae*). For many centuries, menthol was utilized as an antipruritic, antiseptic and a coolant in topical preparations as it causes a feeling of coolness due to stimulation of 'cold' receptors by inhibiting Ca2+ currents of neuronal membranes. It has also been reported that modulation of Ca2+ currents is involved in the regulation of pain threshold. Indeed, the inhibition of Ca2+ currents by administration of voltage-sensitive Ca2+ channel blockers can produce antinociception in laboratory animals. Lately, it was evaluated in the hot plate and acetic acid writhing tests where it revealed potent activity through interaction with opioid receptors, and more selectively, kappa opioid receptors activation [15].

#### *2.2.3. Salvinorin A*

Salvinorin A (**Figure 8**), isolated from *Salvia divinorium* (*Lamiaceae*, formerly *Labiatae*), was first described in nonnitrogenous selective kappa opioid receptor ligand. Salvinorin A acts as k opioid receptors agonist in spinally mediated pain. There is a great attention for k opioid

**Figure 7.** Menthol.

**Figure 8.** Salvinorin A.

receptor agonists among the pharmaceutical industry field [3, 16]. The ethnopharmacological uses of *Salvia divinorium* extract leaves being used to relief headaches, as a sedative, and for the treatment of some gastrointestinal disorders since the anatomical location of k opioid receptors in brain, spinal cord, GI tract, etc [17].

Unfortunately, k opioid receptor agonists produce unwanted side effects; thus, they are not commonly prescribed as analgesics. In this consent, salvinorin A has been reported to cause dysphoric hallucination when administered in human [18, 19]. Nonetheless, it is still listed as a chemical of concern by the United States Drug Enforcement Agency and is currently allowed to be marketed as alternative to other illegal hallucinogens.

#### *2.2.4. Mitragynine*

Mitragynine is a nitrogen-containing compound with a unique structure. It is derived from the traditional Thai herb *Mitragyna speciosa* (*Rubiaceae*). The herb has been used for many years in Thailand as a replacement for opium and used by drug addicts seeking for relief during opioid withdrawal stage. However, the use of *M. speciosa* is currently illegal in Thailand, Malaysia, South Korea and Australia, but widely available in the United States and UK [20–22].

At least two compounds have been identified in *M. speciosa* by Takayama ''in Ref. [23]", both having opioid receptor activity. The first compound termed mitragynine (**Figure 9**) is one of the

**Figure 9.** Mitragynine.

major alkaloidal components. It is a corynanthe based acting as a partial opioid receptor agonist, with about 26% the activity of morphine. The other and the more interesting compound is 7-hydroxymitragynine (mitragynine hydroxyindolenine) (**Figure 10**), with activity of 1000 times or more than that of morphine.

Mitragynine is ingested orally by chewing fresh leaves or by drinking a tea brewed with the substance. The medicinal properties of this plant had been previously described in combating fatigue and to tolerate hard work, due to its opium-like effect at high doses and cocain-like stimulant effect at low doses. However, death was reported as a result of mitragynine abuse [24, 25].

#### **2.3. Capsaicin**

receptor agonists among the pharmaceutical industry field [3, 16]. The ethnopharmacological uses of *Salvia divinorium* extract leaves being used to relief headaches, as a sedative, and for the treatment of some gastrointestinal disorders since the anatomical location of k opioid

Unfortunately, k opioid receptor agonists produce unwanted side effects; thus, they are not commonly prescribed as analgesics. In this consent, salvinorin A has been reported to cause dysphoric hallucination when administered in human [18, 19]. Nonetheless, it is still listed as a chemical of concern by the United States Drug Enforcement Agency and is currently

Mitragynine is a nitrogen-containing compound with a unique structure. It is derived from the traditional Thai herb *Mitragyna speciosa* (*Rubiaceae*). The herb has been used for many years in Thailand as a replacement for opium and used by drug addicts seeking for relief during opioid withdrawal stage. However, the use of *M. speciosa* is currently illegal in Thailand, Malaysia, South Korea and Australia, but widely available in the United States and UK [20–22]. At least two compounds have been identified in *M. speciosa* by Takayama ''in Ref. [23]", both having opioid receptor activity. The first compound termed mitragynine (**Figure 9**) is one of the

receptors in brain, spinal cord, GI tract, etc [17].

*2.2.4. Mitragynine*

**Figure 8.** Salvinorin A.

**Figure 7.** Menthol.

282 Pain Relief - From Analgesics to Alternative Therapies

allowed to be marketed as alternative to other illegal hallucinogens.

Capsicum genus, which produces both chilli peppers and bell peppers, belong to the family of *Solanaceae*. Capsicum is originated in Central and South America and has more than 20 species that are widely spread around the world. Indeed, only five species are widely cultivated including: *C. annuum, C. chinense, C. frutescens, C. pendulum* and *C. pubescens* [26].

It seems that capsicum species are among the oldest cultivated plants in the world (5200–3400 BC). Scientists have found an evidence of people who consumed peppers in Mexico as early as 7000 BC; this was the oldest document of capsicum use [27]. Högyes (1878) was the first to make evident that the alcoholic extract of paprika (*Capsicum annuum*) resulted in hypothermia when administered systemically [28].

**Figure 10.** Mitragynine hydroxyindolenine.

Interestingly, the study of pungent principles began in the 1810s using the names "capsicol", "capsicin", "capsacutin", etc. Later, capsaicin is the active principle isolated from Capsicum species by Thresh in 1846 [29] (**Figure 11**). The exact chemical structure of capsaicin was identified after half a century by Nelson in 1919 [30]. Capsaicin is considered as the most prominent component in plants belonging to Capsicum species, with about 70% of the total pungent acid amides and 30% or less constituting dihydrocapsaicin, an analogue of capsaicin (capsaicinoid) [14, 31].

Despite the unwanted primary irritant effect of capsaicin to the mucous membranes and the eyes, it is used clinically for the management of neuropathic pain syndromes and arthritis [1, 3]. The Native Americans used Capsicum to treat cramps, diarrhoea and indigestion. Other folk medicinal uses of capsaicin include enhancement of appetite, treatment of gastric ulcers, rheumatism and restoration of hair growth [32].

The biological effects of capsaicin (8-methyl-*N*-vanillyl-6-nonenamide) are biphasic: first by the excitation of the primary afferents and the second phase involves desensitization or inactivation of neurons [33]. Capsaicin stimulates the afferent sensory neurons that conduct the nociceptive information to the central nervous system (CNS), precisely the C and Aδ fibres. The stimulatory effect is mainly through calcium influx, the release of several neuropeptides including tachykinins, calcitonin gene-related peptide (CGRP) and somatostatin. It also blocks the intra-axonal transport of macromolecules, such as the neural growth factor (NGF) [27]. Additionally, capsaicin is a vanilloid receptor -1 (VR1) agonist. It is known to have an inhibitory effect on nitric oxide (NOx) production in macrophages; this effect clarifies its implications in the pathogenesis of inflammatory diseases [3, 34].

#### **2.4. Aconitum alkaloids**

Aconitum species, family *Ranunculaceae*, known by different names such as aconite, monkshood, wolf's bane, women's bane, Devil's helmet or blue rocket. Aconitum plants (mainly *A. japonicum* Thunberg and *A. carmichaeli Debeaux*) have been used from the time of historic civilizations in Ayurvedic, Chinese, Tibetan and Greco-Roman medicines for their various

**Figure 11.** Capsaicin.

pharmacological effects. Plants of *Aconitum* genus were familiar in the European countries' medicine in the nineteenth century [35].

Leaves and roots of Aconitum plant were used to relieve neuralgic pain, particularly in the face to relieve the pain of sciatica. The root is extremely bitter; its paste is applied in acute rheumatism also on cuts and wounds as an anti-inflammatory and antiseptic agent [36].

There are two groups of Aconitum alkaloids revealing strong to moderate analgesic properties. The first group includes aconitine-like diester alkaloids with strong analgesic activity: aconitine (**Figure 12**), hypaconitine, mesaconitine, 3-acetylaconitine, bulleyaconitine, and yunaconitine. The second group involves less-toxic alkaloids having moderate analgesic effect. One of them, lappaconitine (**Figure 13**), it is believed that lappaconitine and its deacetylated analogue have lower toxicity than aconitine and, consequently, it is assumed to be safely used as analgesic or anaesthetic agents [35].

Aconitine, 3-acetylaconitine and hypaconitine revealed high affinity Na<sup>+</sup> channel ligands, thus having antinociceptive, strong arrhythmogenic effects and high acute toxicity, and induce a blockade of neuronal conduction by a permanent cell depolarization. In contrast, lappaconitine has lower affinity for Na<sup>+</sup> channel and thereafter has lesser antinociceptive and lesser cardiotoxic activity, acting as a local anaesthetic. Other alkaloids with lower Na+ channel affinity such as lappaconidine and oxydelcorine have no antinociceptive effect

**Figure 12.** Aconitine.

Interestingly, the study of pungent principles began in the 1810s using the names "capsicol", "capsicin", "capsacutin", etc. Later, capsaicin is the active principle isolated from Capsicum species by Thresh in 1846 [29] (**Figure 11**). The exact chemical structure of capsaicin was identified after half a century by Nelson in 1919 [30]. Capsaicin is considered as the most prominent component in plants belonging to Capsicum species, with about 70% of the total pungent acid amides and 30% or less constituting dihydrocapsaicin, an analogue of capsaicin

Despite the unwanted primary irritant effect of capsaicin to the mucous membranes and the eyes, it is used clinically for the management of neuropathic pain syndromes and arthritis [1, 3]. The Native Americans used Capsicum to treat cramps, diarrhoea and indigestion. Other folk medicinal uses of capsaicin include enhancement of appetite, treatment of gastric ulcers,

The biological effects of capsaicin (8-methyl-*N*-vanillyl-6-nonenamide) are biphasic: first by the excitation of the primary afferents and the second phase involves desensitization or inactivation of neurons [33]. Capsaicin stimulates the afferent sensory neurons that conduct the nociceptive information to the central nervous system (CNS), precisely the C and Aδ fibres. The stimulatory effect is mainly through calcium influx, the release of several neuropeptides including tachykinins, calcitonin gene-related peptide (CGRP) and somatostatin. It also blocks the intra-axonal transport of macromolecules, such as the neural growth factor (NGF) [27]. Additionally, capsaicin is a vanilloid receptor -1 (VR1) agonist. It is known to have an inhibitory effect on nitric oxide (NOx) production in macrophages; this effect clarifies its

Aconitum species, family *Ranunculaceae*, known by different names such as aconite, monkshood, wolf's bane, women's bane, Devil's helmet or blue rocket. Aconitum plants (mainly *A. japonicum* Thunberg and *A. carmichaeli Debeaux*) have been used from the time of historic civilizations in Ayurvedic, Chinese, Tibetan and Greco-Roman medicines for their various

(capsaicinoid) [14, 31].

284 Pain Relief - From Analgesics to Alternative Therapies

**2.4. Aconitum alkaloids**

**Figure 11.** Capsaicin.

rheumatism and restoration of hair growth [32].

implications in the pathogenesis of inflammatory diseases [3, 34].

**Figure 13.** Lappaconitine.

[37]. Despite the large number of alkaloids isolated and identified from Aconitum sp. with antinociceptive effect, their cardiotoxic actions hindered their clinical use as analgesics [14].

#### **2.5. Polygodial sesquiterpenes**

Polygodial sesquiterpene is the major constituent present in the bark of *Drymis winteri* (*Winteraceae*) and related species, a well-known medicinal plant found in some South American countries such as Brazil. *Drymis winteri* is commonly used in folk medicine as an anti-inflammatory and for the treatment of asthma and allergy [38]. Phytochemical investigations of *D. winteri* demonstrated the occurrence of sesquiterpenes, lactones and flavonoids [39, 40].

As well, previous studies [40–42] indicated that a mixture of at least three sesquiterpenes, identified as being polygodial (**Figure 14**), 1-β-(ρ-methoxycinnamoyl polygodial and drimanial (**Figure 15**), appear to be the main constituents present in the park of plant *D. winteri* that are accountable for the marked antinociceptive, anti-inflammatory and anti-allergic effects of the crude extract. With regard to the relatively high concentrations of polygodial and to a lesser extent, drimanial in the park of *D. winteri*, it can be proposed that the two sesquiterpenes are the most relevant active compounds and are responsible for the major pharmacological activities of the plant.

**Figure 14.** Polygodial.

**Figure 15.** Drimanial.

The precise site of action by which polygodial induces antinociception is still under investigation. The modulatory role of polygodials as antinociceptives as proposed to be via the interaction with an opiate-like system through k and δ receptors, the α1-adrenergic receptor, the serotoninergic system, and an interaction with a Gi/o protein pertussis toxin-sensitive mechanism. Thus, polygodial or its derivatives might be concerned in the development of new analgesic drugs for controlling neurogenic pain [40, 43].
