**2.6. Caffeine**

[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].

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

**2.5. Polygodial sesquiterpenes**

286 Pain Relief - From Analgesics to Alternative Therapies

of the plant.

**Figure 14.** Polygodial.

**Figure 15.** Drimanial.

Caffeine is an alkaloid present in over 60 plant species. Caffeine (1,3,7-trimethylxanthine) is mainly in beverages derived from coffee beans, tea leaves and kola nuts (*Cola acuminate*, family: *Sterculiaceae*). Caffeine has been used medicinally together with ergotamine for migraine headaches and in combination with nonsteroidal anti-inflammatory drugs in analgesic preparations [44]. Moreover, caffeine is believed to be potentially effective cancer chemopreventive metabolite in terms of its antioxidant capacity [45].

Caffeine was isolated in 1820, but the precise structure of this methylxanthine was established in the last decade of the nineteenth century. Its properties were not fully recognized until 1981, when the stimulating properties of caffeine and its analogues by the blockade of adenosine receptors were allied [46].

Cola nut is native of West Africa, which has been introduced to the West Indies. It is used in large quantities in the soft drink industry. The active principles are caffeine (**Figure 16**) and theobromine (**Figure 17**), which are both stimulants [44].

Caffeine increases alertness, awareness and attention span, has stimulatory effects on mood and sense of wellbeing, and produces an increase in exercise tolerance. Other desirable physiologic effects involve protection of the cerebral vasculature by means of enhancing glucose metabolism. In this concern, it is believed that caffeine consumption has been associated with a reduced risk of Parkinson disease. It also constricts cerebral blood vessels, which is a highly desirable action in patients with migraine [47]. Caffeine is prescribed as a stimulant of the central nervous system and to treat postprandial hypotension and obesity, and also, it is indicated for treatment of apnoea in premature neonates [48].

**Figure 16.** Caffeine.

**Figure 17.** Theobromine.

Following oral intake, maximum plasma concentration arises between 30 min and 2 h, which may be prolonged with food ingestion. Caffeine is readily absorbed by the gastrointestinal tract, with 100% bioavailability and high solubility both in aqueous and nonpolar organic solvents. Caffeine is lipophilic with low protein binding. Its plasma protein binding—mainly albumin—is 10–35%. Caffeine rapidly crosses cell membranes, as well as the placental barrier, blood brain, producing drug levels in the brain and cerebrospinal fluid similar to those in plasma [46, 49].

In 1985, Burnstock and Kennedy cited that methylxanthines block purinergic receptors type 1 (P1) and have no effect on P2 receptors [50]. Added to that, the proposed mechanism of action of caffeine seems to be related to the blockade of peripheral and central adenosine receptors involved in the regulation of pain transmission, giving rise to its analgesic properties [14, 51].

#### **2.7. Ginsenosides**

Ginseng, the root of *Panax ginseng* (*Araliaceae*), has been reported to relieve a variety of ailments. Studies showed that ginseng saponins, which consist of various ginsenoids (**Figure 18**), are the most pharmacoactive constituent of ginseng root. Ginsenoids are believed to be involved in pain modulation as well as in opioid-induced antinociception and tolerance [52, 53].

In traditional folk medicine, ginseng has been used to relieve some types of pain such as toothache, abdominal pain, chest pain and neuralgia. A line of evidence also shows that ginseng

**Figure 18.** Ginsenosides.

saponins are responsible for relieving pain induced by chemicals or noxious heat in experimental animals [54].

Most ginseng species possess active naturally occurring constituents such as the ginsenosides, polysaccharides, peptides, polyacetylenic alcohols and fatty acids. From the ginseng saponin fraction, more than 30 triterpene ginsenoside derivatives containing sugars were isolated. Yet, there is a wide variation (2–20%) in the ginsenoside content among the different ginseng species [2].

Ginseng saponins inhibit voltage-dependent Ca2+ channels providing one possible explanation for its analgesic efficacy because sensory neurons transfer sensory information such as pain from the peripheral nervous system toward the central nervous system [55]. Furthermore, the regulation of voltage-dependent Ca2+ channels by ginseng saponins is not mediated through the inhibitory receptors such as opioids, ɑ2-adrenergic, GABAergic, nor muscarinic receptors [53].
