**8. Conclusions**

*Pain Management - Practices, Novel Therapies and Bioactives*

effects through improved bioavailability [72].

**6. Analgesic potential of some essential oils**

human chondrocytes [56].

effect of naloxone [58].

**5.6 p-cymene**

**5.7 Nerol**

inflammatory and neuropathic pain [61]. Furthermore, the effect on inflammatory processes were observed in studies performed *in vivo*, in which repeated treatments with α-pinene [5–50 mg/kg, p. o.] were able to abolish the mechanical sensitization induced by CFA or by the partial ligation of the sciatic nerve [58]. In addition, it has been shown that α-pinene has anti-inflammatory and anti-catabolic activities in

β-Pinene is present in high amounts [5.1–13.1%] in lime citrus oil [32]. In animal models, β-pinene showed to be effective only on acute central nociception, yet, it was able to reverse the antinociceptive effect of morphine in tests equivalent to the

Biological precursor of carvacrol, p-cymene occurs in oranges and tangerines [51, 71]. Different behavioral tests of nociception in animal models showed that it exerted both peripheral and central antinociceptive action [51]. A study investigated the antinociceptive potential of p-cymene in mice models of orofacial nociception induced by formalin, capsaicin, and glutamate, and results showed that the treatment with p-cymene at all doses reduced the nociceptive behavior in all nociception tests, suggesting an action in both neurogenic and inflammatory pain [71]. Moreover, tests conducted on Swiss mice showed decreased mechanical hypernociception, reduced leukocyte and neutrophils migration, and reduced TNF-α level [51]. Like other previously mentioned terpenic compounds, p-cymene has a relatively short pharmacological half-life and bioavailability; so, complexation with β-cyclodextrin has shown to improve its analgesic and anti-inflammatory

This acyclic monoterpene alcohol is found in many essential oils, *Citrus aurantium* among them [51]. In the oxazolone-induced colitis model, González-Ramírez et al. [73], observed antinociceptive effect of nerol [30 mg/kg], which led to a significant reduction on expression of some pro-inflammatory cytokines, like IL-13 and TNF-α, which are highly characteristic for gastrointestinal tract disorders [51].

All essential oils with high D-limonene content pose significant free radical scavenging effect, predominantly disabling production of reactive oxygen species (ROS) [13]. Essential oils of sweet orange, lemon, and bergamot are most widely used to test analgesic effects in animal models. More recently, some essential oil blends were tested in various human cell models and showed significant positive effects on inflammation, immune modulation, cell cycle regulation, and other

Bioactive compounds found in essential oils are quickly absorbed after dermal, oral, or pulmonary administration, and are excreted by the kidneys in the form of phase-II conjugates [66]. Only a small fraction is eliminated unchanged by the lungs [66]. Generally speaking, Citrus essential oils are nontoxic, non-mutagenic,

**280**

**7. Safety**

cellular functions [8].

All phytochemicals present in essential oils presented here may simultaneously target multiple mechanisms involved in chronic pain. Despite long history of therapeutic applications of essential oils for the treatment of pain, only recently more attention was given to their components and elucidating mechanisms behind their antioxidant, anti-inflammatory, and antinociceptive potential. Monoterpenes are key holders of analgesic potential in Citrus essential oils, especially D-limonene and linalool. Essential oils are generally considered as safe; however, due to low bioavailability and stability, monoterpenes are complexed with β-cyclodextrin to improve their analgesic activity [62, 69]. Further studies are encouraged to determine the analgesic potential of Citrus essential oils in managing daily activities of people with a long-term history of chronic pain.
