Open access peer-reviewed chapter

Analgesic Potential of Monoterpenes from Citrus Essential Oils

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Ines Banjari, Jelena Balkić and Viduranga Yashasvi Waisundara

Submitted: May 18th, 2020 Reviewed: June 25th, 2020 Published: July 22nd, 2020

DOI: 10.5772/intechopen.93265

From the Edited Volume

Pain Management

Edited by Viduranga Yashasvi Waisundara, Ines Banjari and Jelena Balkić

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Chronic pain is a noteworthy health issue with immense impact on global healthcare systems. Although this issue has not come into the limelight as other noncommunicable diseases, it should be highlighted that modern medicine still has no efficient treatment to curb chronic pain. In this aspect, essential oils have been used for the prevention of several disease conditions including pain management. These odorous products, obtained from botanically defined raw material, have a variable and complex composition. Their composition largely depends on the extraction technique used, from simple hydro-distillation, to supercritical or microwave-assisted extraction. Monoterpenoids are some of the most biologically active and highly researched compounds when it comes to antinociceptive effects. They are volatile oils, primarily composed of two isoprene units with highly distinctive aromas and flavors. More than 90% of the essential oils of medicinal plants consist of monoterpenoids like limonene, myrcene, α-terpineol, linalool, pinene, p-cymene, and nerol. Besides strong anti-inflammatory effect, all essential oils with high D-limonene content pose a significant free radical scavenging effect, predominantly disabling the production of reactive oxygen species. Further studies in humans are encouraged to determine the real long-term potential in treating chronic pain.


  • chronic pain
  • essential oils
  • citruses
  • monoterpenes
  • limonene

1. Introduction

Chronic pain is defined as a long-term pain lasting 3–6 months after the normal healing period, and is described as continuous or recurrent [1]. The European Pain Federation (EFIC) in its Declaration on Pain identifies chronic pain as a distinct health issue, which has an immense financial impact on healthcare systems around the world [2]. In Europe, 20% of adults or one in five suffer from chronic pain, and about 34% of them describe their chronic pain as severe [3]. In the U.S., estimated prevalence among adults ranges from 11 to 40% [4]. Estimated total cost of the consequences of chronic pain across Europe is €300 billion [3], while the annual healthcare cost for back pain only was estimated to be £13.44 billion in Germany and £1 billion in UK [5].

Chronic pain alters all aspects of a patient’s life inducing severe physical, psychological, and social impairments, while increasing consumption of opiates and analgesics. It eventually deteriorates an individual’s quality of life [1, 3, 5]. The most common sites affected, according to a UK population study, are the lower back [30%], hip [25%], neck and shoulder (25%), and knee (24%) [6]. The underlying pathophysiology of chronic pain is usually complex, and can be explained by the presence of typical inflammation and neuropathy [7].

Modern medicine still has no efficient treatment to deal with chronic pain. Essential oils have been used to prevent and treat diseases for many centuries [8] and have been proven to pose antibacterial, antifungal, antiproliferative, anti-inflammatory, antioxidant, and anesthetic properties, although the exact mechanisms of action are still elusive [8, 9]. Recent meta-analysis by Lakhan et al. [10] found a significant positive effect of aromatherapy [compared with placebo or treatments as usual controls] in reducing pain intensity, with the strongest evidence for nociceptive and acute pain, unlike inflammatory and chronic pain. The aim of this chapter is to summarize the existing evidence on the effectiveness of Citrus essential oils, that is, their monoterpenes and especially limonene, for the treatment of chronic pain.


2. Essential oils

One of the modalities where plants have been put to use is aromatherapy, where they can be diffused aromatically, consumed internally, or applied topically to the skin [8, 11]. In general, the respiratory tract offers the most rapid way of entry of oils followed by the dermal pathway [12]. The main beneficial constituents present in essential oils are the monoterpenes, sesquiterpenes, and phenylpropanoids [9]. Citrus essential oils have been used for millennia to treat anxiety, agitation, stress, challenging behaviors, fatigue, and insomnia [11]. Composition of selected essential Citrus oils is given in Table 1, along with their beneficial health effects. The composition of a specific essential oil will vary significantly depending on the extraction technique used.

Table 1.

Composition of selected essential Citrus oils and observed health effects.


3. Extraction techniques of essential oils

There are several extraction techniques that are commonly used for the isolation and purification of bioactives from herbs used as pain medications. A summary of these techniques is shown in Figure 1. Most of these bioactives are extracted together with the essential oils of the herbs. It is important that the selected extraction technique is compatible with the bioactives as well as the herb, and is efficient in obtaining as much quantity as possible while preserving the functionality.

Figure 1.

Common extraction techniques used for the preparation of essential oils and their bioactives.

Techniques commonly employed for extracting essential oils include hydro-distillation, steam distillation, solvent extraction, head space analysis, and liquid CO2 extraction [37]. Head space analysis is a potentially rapid method, which is used to extract essential oils and requires very little plant material, but a complete recovery may occur only for highly volatile materials. Conventional methods such as steam distillation and solvent extraction may result in severe losses of volatile materials because the liquid in which the oil is collected should be subsequently removed by evaporation. Application of heat in this instance is a disadvantage.

Ultrasound has been recently applied to improve the extraction of polysaccharides and essential oils from plant material that is used for pain medication, mainly through the phenomenon of cavitation [38, 39, 40, 41]. Chemat et al. [41] prepared hexane extracts of two caraway seeds focusing on the carvone and limonene contents which were isolated in the process. The study demonstrated that the carvone yield and plant extract quality were better in ultrasound extraction compared with those obtained by conventional methodologies.

Supercritical extraction (SFE) of the compounds responsible for the mitigating pain contained in herbs is another favorable technique that can be used for industrial-scale yielding of the responsible bioactives [42, 43]. Microwave-assisted extraction (MAE) is another method that is typically used for the extraction of bioactives for pain medication [44]. This technique offers a rapid delivery of energy to a total volume of solvent and solid herb matrix with subsequent heating of the solvent and solid matrix, efficiently and homogeneously [40]. Accelerated solvent extraction (ASE) is a solid-liquid extraction process performed to isolate bioactives for pain medication at elevated temperatures, usually between 50 and 200°C and at pressures between 10 and 15 MPa [40]. Solvent-free microwave extraction (SFME) is considered as a green method for the extraction of essential oils from herbs for pain medication. The methodology is a combination of microwave heating and dry distillation performed at atmospheric pressure without any added solvent or water [45].


4. Bioactive components in essential oils

One of the most biologically active and best studied herbal compounds are monoterpenoids, which consist of two isoprene units, but contain a wide variety of structures. They are volatile oils with highly distinctive aromas and flavors. More than 90% of the essential oils of medicinal plants consist of monoterpenoids [46]. Most studies analyzing analgesic potential of essential oils were tested on animal models [47].

Out of all terpenoid compounds, limonene and carvone have shown to be effective in several tumors (stomach, pulmonary, and mammary) [48]. D-limonene and/or its metabolites have been found in serum, liver, lung, kidney, and other tissues such as adipose tissue and mammary glands, which may explain its positive effect on mammary gland carcinoma [49]. D-limonene is also an excellent solvent of cholesterol; so, it is used clinically to dissolve cholesterol-containing gallstones [49]. Because of its gastric acid neutralizing effect and its support of normal gastrointestinal motility, it has also been used for relief of heartburn [49].


5. Essential oils monoterpenes

5.1 Limonene

Limonene is a colorless liquid hydrocarbon classified as a monocyclic terpene [30], one of the main constituents found in essential oils extracted from citrus peels [50]. Out of the two isomers, D- and L-limonene, D-isomer is more common and possesses a strong orange odor [30, 50, 51], which is the reason for its wide application as a flavor and fragrance additive [49]. Health benefits of limonene include antioxidant, anti-inflammatory, vasorelaxant, anticarcinogenic, chemopreventive, and chemotherapeutic potentials [13, 52, 53, 54].

The analgesic effect is helpful in relieving headaches and stomach ache, relaxing the muscles, and preventing muscle stiffness. It also helps to overcome fatigue and it plays a vital role in relaxing and stabilizing the nervous system and, therefore, is used as a sedative [50, 52].

Yoon et al. [55] carried out a study to verify the pharmacological and biological effects of limonene on the production of pro-inflammatory cytokines and inflammatory mediators in RAW 264.7 macrophages and concluded that limonene effectively inhibited lipopolysaccharide-induced nitric oxide (NO) and prostaglandin E2 production that included dose-dependent decreases in the expression of inducible nitric synthase (iNOS) and cyclooxygenase-2 (COX-2) proteins. The same study also showed inhibition of macrophage-cytokine production [55]. A beneficial antioxidant effect via increased iNOS and COX-2 protein expression was found in ulcerative colitis rat models [53]. Moreover, systemic application of limonene reduced nociceptive behaviors via H2O2-induced TRPA1 activation, and this effect is related to the inflammatory pain [51]. Myrcene and limonene inhibit IL-1β-induced responses found in osteoarthritis [56].

In conclusion, D-Limonene presented significant antinociception in different models of nociception without opioid receptor stimulation [57]. Instead, it is more likely related to the appreciable anti-inflammatory activity of this compound [58].

5.2 Myrcene

Myrcene or β-myrcene is a monoterpene polyunsaturated acyclic found in nature, originally isolated from lemon grass oil (Cymbopogon citratus) [58]. Besides its effect on both central and peripheral sites through endogenous opioids and α2-adrenoreceptors, it was also shown to inhibit lipopolysaccharide [LPS]-induced inflammation including cell migration and production of NO, along with significant inhibition of c-interferon and IL-4 production [58, 59].

5.3 α-Terpineol

α-Terpineol is a volatile monoterpene alcohol, relatively nontoxic, and one of the major components of the essential oils of various plant species, being a nonirritant at 1–15%, and non-phototoxic [13]. There are three isomers, α-, β-, and γ-terpene, with the latter two differing only by the location of the double bond [51]. It is the third most representative monoterpene in citrus species [60]. It has insecticidal, antimicrobial, antispasmodic, anticonvulsant [47], antinociceptive, and immunostimulant properties, and it increases the skin’s permeability to soluble compounds [60].

Studies have found that α-terpineol possesses peripheral and central analgesic properties [7]. A research conducted on mice, using carrageenan and TNF-α induced hypernociception, showed increase of the mechanical threshold of hypernociceptive behavior by α-terpineol, probably by the inhibition of inflammatory mediators (inhibiting the release of substance P and other inflammatory molecules such as serotonin, histamine, bradykinin, and prostaglandins) [60]. α-Terpineol showed an antioxidant activity as it was able to suppress the superoxide production by agonist-stimulated monocytes [7]. Moreover, α-terpineol showed higher COX-2 activity inhibition than aspirin, the most popular NSAID, and most potently inhibited the expression of pro-inflammatory cytokines and NF-κB activation [7, 61]. α-Terpineol also showed antinociceptive effect in the capsaicin (neurogenic origin), glutamate, and formalin-induced orofacial nociception tests [51, 62, 63].

Anti-inflammatory effects that α-terpineol from orange juice demonstrated in vitro (suppressed IL-6 and increased IL-10) were further analyzed by ex vivo experiments, and results have shown anti-inflammatory action in macrophages after incubation of human blood with α-terpineol [61]. Described effects were attributed to α-terpineol, while linalool and limonene had no significant action [61]. On the other hand, a research conducted on morphine-tolerant mice showed inhibitory effect of α-terpineol in low dosages on the induction of dependence on morphine and attenuated the signs of withdrawal syndrome without antinociceptive effect [46].

5.4 Linalool

Linalool is an acyclic oxygenated monoterpene reported to be the major volatile component of the essential oils of several aromatic species, including the Rutaceae family, with sedative, antidepressant, anticancer, antifungal, and pesticidal properties [13]. It is the most studied monoterpene in various painful conditions [58]. A research on adult female Swiss mice treated with a single intraperitoneal injection of (−)-linalool (50 or 200 mg/kg) or multiple treatments given chronically (twice daily for 10 days; 50 mg/kg, i.p.) showed that (−)-linalool significantly reduced CFA-induced mechanical hypersensitivity (complete Freund’s adjuvant) and produced effective reduction in CFA-induced paw edema following the acute treatment [61, 64]. Following intraperitoneal administration in mice, linalool was found to produce antinociceptive and antihyperalgesic effects in different animal models in addition to its anti-inflammatory properties [65]. (−)-Linalool acts as analgesic on several receptors, including opioids, adenosine A1 and A2, cholinergic M2, and produces changes in K+ channels, thus exerting analgesic-like activity [58, 66].

Some recent studies demonstrate that (−)-linalool inhibits transient receptor potential A1 (TRPA1) and N-Methyl-D-aspartate (NMDA) channels and decreases the nociception induced by cinnamaldehyde or capsaicin [58, 67].

It is neither toxic nor irritable to skin and presents an extremely low risk of skin sensitization [13]. However, due to poor oral availability, despite the biological properties of (−)-linalool, its use in the treatment of painful and inflammatory disorders is still limited [51]. Nascimento et al. [68] used pure 95% linalool, complexed and noncomplexed in β-cyclodextrin (used to increase aqueous solubility and bioavailability of monoterpenes), in an animal model of fibromyalgia. They found that both formulations had an anti-hyperalgesic effect, with the complexed form being more effective and producing a longer lasting effect (for 24 h after administration) [68]. Analgesic effect of linalool on acute central nociception (hot plate), visceral (acetic acid), and chronic pain models of neuropathic origin, and the opioid and glutamatergic systems are probably involved in this action [51, 62, 67, 69]. One preclinical trial showed that linalool from rosewood was able to reduce the action potential amplitude assessed using an isolated nerve in the single sucrose gap technique, showing it blocked neuronal excitability [70].

5.5 Pinene

α-Pinene is an organic compound of the terpene class, one of two isomers of pinene, the other being β [30]. The effects of Ugni myricoides (Kunth) O. Berg essential oil and its major constituent, α-pinene [52.1%], were analyzed in inflammatory and neuropathic models of hypernociception in mice, and the results showed that the oil significantly prevented mechanical hypernociception induced by carrageenan or complete Freund’s adjuvant (CFA), and those effects were attributed to α-pinene, which clearly has a potential role for the management of 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 human chondrocytes [56].

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 effect of naloxone [58].

5.6 p-cymene

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 effects through improved bioavailability [72].

5.7 Nerol

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].


6. Analgesic potential of some essential oils

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 cellular functions [8].


7. Safety

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, and noncarcinogenic, meaning that sweet orange, bitter orange, neroli, petitgrain, lemon, lime (both distilled and expressed), bergamot, and grapefruit oils have GRAS status [74].

However, a mixture of two optic isomers of limonene present in the essential oils of citrus fruits was shown to be hepatotoxic, have a sedative muscular relaxing effect in mice and be nephrotoxic only in male rats, cause small-scale irritation in rabbits, and be carcinogenic and teratogenic [75].

The fast metabolism and short half-life of active compounds have led to the belief that there is a minimum risk of accumulation in body tissues [12]. In humans, ingestion of D-limonene resulted in an excretion of 52–83% of the dose in the urine within 48 hours [49]. However, limonene at 20 g caused diarrhea and transient proteinuria in healthy volunteers [75]. Vapor inhalation caused respiratory disorders coupled with a decrease in vital capacity [75]. No neurological disorders occurred, but chronic exposure can induce irritation and allergy; therefore, it must be mentioned in the list of “ingredients” of cosmetics [75]. It is not acutely toxic, nephrotoxic, or carcinogenic for humans, but the oxidized D-limonene may carry some toxicity, hence, citrus oils should be stored in dark at 4°C [13]. Nevertheless, unoxidized D-limonene is listed as an allergen by the EU, and moderately allergenic in Germany [13].


8. Conclusions

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.


Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


  1. 1. Treede RD, Rief W, Barke A, Aziz Q , Bennett MI, Benoliel R, et al. A classification of chronic pain for ICD-11. Pain. 2015;156:1003-1007. DOI: 10.1097/j.pain.0000000000000160
  2. 2. European Pain Federation [EFIC]. Declaration on Pain. Available from: [Accessed: 08 June 2018]
  3. 3. PAE. Survey on chronic pain. 2017. Available from:
  4. 4. Dahlhamer J, Lucas J, Carla Zelaya C, Nahin R, Mackey S, De Bar L, et al. Prevalence of chronic pain and high-impact chronic pain among adults — United States, 2016. CDC. 2018;67(36):1001-1006. DOI: 10.15585/mmwr.mm6736a2
  5. 5. Phillips CJ. The cost and burden of chronic pain. Pain Reviews. 2009;3(1):2-5. DOI: 10.1177/204946370900300102
  6. 6. Macfarlane GJ, Beasley M, Smith BH, Jones GT, Macfarlane TV. Can large surveys conducted on highly selected populations provide valid information on the epidemiology of common health conditions? An analysis of UK biobank data on musculoskeletal pain. British Journal of Pain. 2015;9:203-212. DOI: 10.1177/2049463715569806
  7. 7. Khaleel C, Tabanca N, Buchbauer G. α-Terpineol, a natural monoterpene: A review of its biological properties. Open Chemistry. 2018;16:349-361. DOI: 10.1515/chem-2018-0040
  8. 8. Han X, Parker TL, Dorsett J. An essential oil blend significantly modulates immune responses and the cell cycle in human cell cultures. Cogent Biology. 2017;3:1340112. DOI: 10.1080/23312025.2017.1340112
  9. 9. Sarmento-Neto JF, Nascimento LG, Bezerra Felipe CF, de Sousa DP. Analgesic potential of essential oils. Molecules. 2016;21(1):E20. DOI: 10.3390/molecules21010020
  10. 10. Lakhan SE, Sheafer H, Tepper D. The effectiveness of aromatherapy in reducing pain: A systematic review and meta-analysis. Pain Research and Treatment. 2016;2016:8158693. DOI: 10.1155/2016/8158693
  11. 11. Ali B, Al-Wabel NA, Shams S, Ahamad A, Khan SA, Anwar F. Essential oils used in aromatherapy: A systemic review. Asian Pacific Journal of Tropical Biomedicine. 2015;5(8):601-611. DOI: 10.1016/j.apjtb.2015.05.007
  12. 12. Djilani A, Dicko A. The therapeutic benefits of essential oils. Nutrition, well-being and health. In: Bouayed J, editor. Nutrition, Well-Being and Health. Rijeka, Croatia: IntechOpen; 2012. pp. 155-178. DOI: 10.5772/25344
  13. 13. Dosoky NS, Setzer WN. Biological activities and safety of citrus spp. essential oils. International Journal of Molecular Sciences. 2018;19:1966. DOI: 10.3390/ijms19071966
  14. 14. Kamal GM, Anwar F, Hussain AI, Sarri N, Ashraf MY. Yield and chemical composition of citrus essential oils as affected by drying pretreatment of peels. International Food Research Journal. 2011;18(4):1275-1282
  15. 15. Kamal GM, Ashraf MY, Hussain AI, Shahzadi A, Chughtai MI. Antioxidant potential of peel essential oils of three Pakistani citrus species: Citrus reticulata, Citrus sinensis and Citrus paradisii. Pakistan Journal of Botany. 2013;45(4):1449-1454
  16. 16. Ahmad MM, Rehman SU, Iqbal Z, Anjum FM, Sultan JI. Genetic variability to essential oil composition in four citrus fruit species. Pakistan Journal of Botany. 2006;38(2):319-324
  17. 17. Egharevba HO, Oladosun P, Izebe KS. Chemical composition and anti-tubercular activity of the essential oil of orange [Citrus sinensis L.] peel from North Central Nigeria. International Journal of Pharmacognosy and Phytochemical Research. 2016;8(1):91-94
  18. 18. Radan M, Parčina A, Burčul F. Chemical composition and antioxidant activity of essential oil obtained from bitter orange peel [Citrus aurantium L.] using two methods. Croatica Chemica Acta. 2018;91(1):125-128. DOI: 10.5562/cca3294
  19. 19. Siddique S, Shafique M, Parveen Z, Jabeen Khan S, Khanum R. Volatile components, antioxidant and antimicrobial activity of citrus aurantium var. bitter orange peel oil. Pharmacologyonline. 2011;2:499-507
  20. 20. Bakhsha F, Yousefi Z, Aryaee M, Jafari SY, Derakhshanpoor F. Comparison effect of lavender and Citrus aurantium aroma on anxiety in female students at Golestan University of Medical Sciences. Journal of Basic Research in Medical Sciences. 2016;3(4):4-11. DOI: 10.18869/acadpub.jbrms.3.4.4
  21. 21. Carvalho-Freitas MIR, Costa M. Anxiolytic and sedative effects of extracts and essential oil from Citrus aurantium L. Biological & Pharmaceutical Bulletin. 2002;25:1629-1633
  22. 22. Sarrou E, Chatzopoulou P, Dimassi-Theriou K, Therios I. Volatile constituents and antioxidant activity of peel, flowers and leaf oils of Citrus aurantium L. growing in Greece. Molecules. 2013;18:10639-10647. DOI: 10.3390/molecules180910639
  23. 23. Khodabakhsh P, Shafaroodi H, Asgarpanah J. Analgesic and anti-inflammatory activities of Citrus aurantium L. blossoms essential oil [neroli]: Involvement of the nitric oxide/cyclic guanosine monophosphate pathway. Journal of Natural Medicines. 2015;69:324-333. DOI: 10.1007/s11418-015-0896-6
  24. 24. Mondello L, Dugo G, Dugo P, Bartle KD. Italian citrus Petitgrain oils. Part I. composition of bitter orange Petitgrain oil. Journal of Essential Oil Research. 1996;8(6):597-609. DOI: 10.1080/10412905.1996.9701026
  25. 25. Ferlazzo N, Cirmi S, Calapai G, Ventura-Spagnolo E, Gangemi S, Navarra M. Anti-inflammatory activity of Citrus bergamia derivatives: Where do we stand? Molecules. 2016;21:1273. DOI: 10.3390/molecules21101273
  26. 26. Mannucci C, Navarra M, Calapai F, Squeri R, Gangemi S, Calapai G. Clinical pharmacology of Citrus bergamia: A systematic review. Phytotherapy Research. 2017;31:27-39. DOI: 10.1002/ptr.5734
  27. 27. Lauro F, Ilari S, Giancotti LA, Morabito C, Malafoglia V, Gliozzi M, et al. The protective role of bergamot polyphenolic fraction on several animal models of pain. PharmaNutrition. 2016;4S:35-40
  28. 28. Navarra M, Mannucci C, Delbò M, Calapai G. Citrus bergamia essential oil: From basic research to clinical application. Frontiers in Pharmacology. 2015;6:36. DOI: 10.3389/fphar.2015.00036
  29. 29. Campêlo LML, Almeida AAC, Freitas RLM, Cerqueira GS, Sousa GF, Saldanha GB, et al. Antioxidant and antinociceptive effects of citrus Limon essential oil in mice. Journal of Biomedicine & Biotechnology. 2011:678673. DOI: 10.1155/2011/678673
  30. 30. Gobato R, Gobato A, Fedrigo DFG. Molecular electrostatic potential of the main monoterpenoids compounds found in oil lemon Tahiti – [citrus Latifolia Var Tahiti]. Parana Journal of Science and Education. 2015;1:1-10
  31. 31. Md Othman S, Hassan M, Nahar L, Basar N, Jamil S, Sarker S. Essential oils from the Malaysian citrus [Rutaceae] medicinal plants. Medicine. 2016;3:13. DOI: 10.3390/medicines3020013
  32. 32. Amorim JL, Simas DL, Pinheiro MM, Moreno DS, Alviano CS, da Silva AJ, et al. Anti-inflammatory properties and chemical characterization of the essential oils of four citrus species. PLoS One. 2016;11(4):e0153643. DOI: 10.1371/journal.pone.0153643
  33. 33. Javed S, Ahmad R, Shahzad K, Nawaz S, Saeed S, Saleem Y. Chemical constituents, antimicrobial and antioxidant activity of essential oil of Citrus limetta var. Mitha [sweet lime] peel in Pakistan. African Journal of Microbiology Research. 2013;7(24):3071-3077. DOI: 10.5897/AJMR12.1254
  34. 34. El Kamali HH, Burham BO, El-Egami AA. Essential oil composition of internal fruit Peel of Citrus paradisi from Sudan. AM Research. 2015;1(9):2079-2085. DOI: 10.6084/m9.figshare.1480470
  35. 35. Lan-Phi NT, Shimamura T, Ukeda H, Sawamura M. Chemical and aroma profiles of yuzu [citrus junos] peel oils of different cultivars. Food Chemistry. 2009;115(3):1042-1047
  36. 36. Vasudeva N, Sharma T. Chemical composition and antimicrobial activity of essential oil of citrus limettioides Tanaka. Journal of Pharmaceutical Technology and Drug Research. 2012:1-7. DOI: 10.7243/2050-120X-1-2
  37. 37. Charles DJ, Simon JE. Comparison of extraction methods for the rapid determination of essential oil content and composition of basil. Journal of the American Society for Horticultural Science. 1990;115(3):458-462
  38. 38. Mason TJ. Ultrasound in synthetic organic chemistry. Chemical Society Reviews. 1997;26:443-451. DOI: 10.1039/CS9972600443
  39. 39. Vinatoru M, Toma M, Mason TJ. Ultrasound-assisted extraction of bioactive principles from plants and their constituents. Advances in Sonochemistry. 1999;5:209-247
  40. 40. Wang L, Weller CL. Recent advances in extraction of nutraceuticals from plants. Trends in Food Science and Technology. 2006;17:300-312. DOI: 10.1016/j.tifs.2005.12.004
  41. 41. Chemat S, Lagha A, AitAmar H, Bartels PV, Chemat F. Comparison of conventional and ultrasound-assisted extraction of carvone and limonene from caraway seeds. Flavour and Fragrance Journal. 2004;19:188-195. DOI: 10.1002/ffj.1339
  42. 42. Reverchon E. Supercritical fluid extraction and fractionation of essential oils and related products. Journal of Supercritical Fluids. 1997;10(1997):1-37. DOI: 10.1016/S0896-8446[97]00014-4
  43. 43. Fornari F, Vincente G, Vazquez E, Garcia-Risco MR, Reglero G. Isolation of essential oil from different plants and herbs by supercritical fluid extraction. Journal of Chromatography. A. 2012;1250:34-48. DOI: 10.1016/j.chroma.2012.04.051
  44. 44. Kaufmann B, Christen P. Recent extraction techniques for natural products: Microwave-assisted extraction and pressurized solvent extraction. Phytochemical Analysis. 2002;13:105-113. DOI: 10.1002/pca.631
  45. 45. Filly A, Fernandez X, Minuti M, Visinoni F, Cravotto G, Chemat F. Solvent-free microwave extraction of essential oil from aromatic herbs: From laboratory to pilot and industrial scale. Food Chemistry. 2014;150:193-198. DOI: 10.1016/j.foodchem.2013.10.139
  46. 46. Parvardeh S, Moghimi M, Eslami P, Masoudi AR. α-Terpineol attenuates morphine-induced physical dependence and tolerance in mice: Role of nitric oxide. Iranian Journal of Basic Medical Sciences. 2016;19:201-208
  47. 47. De Sousa DP, Quintans L, de Almeida RN. Evolution of the anticonvulsant activity of α-terpineol. Pharmaceutical Biology. 2007;45(1):69-70. DOI: 10.1080/13880200601028388
  48. 48. Raphael TJ, Kuttan G. Immunomodulatory activity of naturally occurring monoterpenes carvone, limonene, and perillic acid. Immunopharmacology and Immunotoxicology. 2003;25(2):285-294. DOI: 10.1081/IPH-120020476
  49. 49. Sun J. D-limonene: Safety and clinical applications. Alternative Medicine Review. 2007;12(3):259-264
  50. 50. Chhikara N, Kour R, Jaglan S, Gupta P, Gata Y, Panghal A. Citrus medica: Nutritional, phytochemical composition and health benefits – A review. Food & Function. 2018;9:1978. DOI: 10.1039/c7fo02035j
  51. 51. De Cássia da Silveira e Sá R, Cardoso Lima T, da Nóbrega FR, Medeiros de Brito AE, de Sousa DP. Analgesic-like activity of essential oil constituents: An update. International Journal of Molecular Sciences. 2017;18:2392. DOI: 10.3390/ijms18122392
  52. 52. Nogueira de Melo GA, Grespan R, Fonseca JP, Farinha TO, Silva EL, Romero AL, et al. Rosmarinus officinalis L. essential oil inhibits in vivo and in vitro leukocyte migration. Journal of Medicinal Food. 2011;14:944-946. DOI: 10.1089/jmf.2010.0159
  53. 53. Yu L, Yan J, Sun Z. D-limonene exhibits anti-inflammatory and antioxidant properties in an ulcerative colitis rat model via regulation of iNOS, COX-2, PGE2 and ERK signaling pathways. Molecular Medicine Reports. 2017;15:2339-2346. DOI: 10.3892/mmr.2017.6241
  54. 54. Lima TC, Mota MM, Barbosa-Filho JM, Dos Santos MRV, De Sousa DP. Structural relationships and vasorelaxant activity of monoterpenes. Daru. 2012;20:23. DOI: 10.1186/2008-2231-20-23
  55. 55. Yoon WJ, Lee NH, Hyun CG. Limonene Supresses lipopolysaccharide-induced production of nitric oxide, prostaglandin E2, and pro-inflammatory cytokines in RAW 246.7 macrophages. Journal of Oleo Science. 2010;59(8):415-421
  56. 56. Rufino AT, Ribeiro M, Sousa C, Judas F, Salgueiro L, Cavaleiro C, et al. Evaluation of the anti-inflammatory, anti-catabolic and pro anabolic effects of E caryophyllene, myrcene and limonene in a cell model of osteoarthritis. European Journal of Pharmacology. 2015;750:141-150. DOI: 10.1016/j.ejphar.2015.01.018
  57. 57. Do Amaral JF, Silva MIG, Neto MRA, Neto PFT, Moura BA, de Melo CTV, et al. Antinociceptive effect of the monoterpene R-[+]-limonene in mice. Biological & Pharmaceutical Bulletin. 2007;30:1217-1220
  58. 58. Guimarães AG, Quintans JSS, Quintans-Júnior LJ. Monoterpenes with analgesic activity—A systematic review. Phytotherapy Research. 2013;27:1-15. DOI: 10.1002/ptr.4686
  59. 59. Souza MC, Siani AC, Ramos MF, Menezes-de-Lima OJ, Henriques MG. Evaluation of anti-inflammatory activity of essential oils from two Asteraceae species. Pharmazie. 2003;58:582-586
  60. 60. De Oliveira MG, Marques RB, de Santana MF, Santos AB, Brito FA, Barreto EO, et al. α-Terpineol reduces mechanical hypernociception and inflammatory response. Basic & Clinical Pharmacology & Toxicology. 2012;111:120-125. DOI: 10.1111/j.1742-7843.2012.00875.x
  61. 61. De Cássia da Silveira e Sá R, Nalone Andrade L, Pergentino de Sousa D. A review on anti-inflammatory activity of monoterpenes. Molecules. 2013;18:1227-1254. DOI: 10.3390/molecules18011227
  62. 62. Brito RG, Santos PL, Oliveira MA, Pina LTS, Antoniolli AR, da Silva Almeida JRG, et al. Natural Products as Promising Pharmacological Tools for the Management of Fibromyalgia Symptoms – A Review in Discussions of Unusual Topics in Fibromyalgia, Chapter 4. 2018:57-78. DOI: 10.5772/intechopen.70016
  63. 63. Quintans-Júnior LJ, Oliveira MGB, Santana MF, Santana MT, Guimarães AG, Siqueira JS, et al. α-Terpineol reduces nociceptive behavior in mice. Pharmaceutical Biology. 2011;49(6):583-586. DOI: 10.3109/13880209.2010.529616
  64. 64. Katsuyama SK, Towa AO, Amio SK, Ato KS, Agi TY, Ishikawa YK, et al. Effect of plantar subcutaneous administration of bergamot essential oil and linalool on formalin-induced nociceptive behavior in mice. Biomedical Research. 2015;36(1):47-54. DOI: 10.2220/biomedres.36.47
  65. 65. Sakurada T, Kuwahata H, Katsuyama S, Komatsu T, Morrone LA, Corasaniti MT, et al. Intraplantar injection of bergamot essential oil into the mouse Hindpaw: Effects on capsaicin-induced nociceptive behaviors. International Review of Neurobiology. 2009;85:237-248. DOI: 10.1016/S0074-7742[09]85018-6
  66. 66. De Sousa DP. Analgesic-like activity of essential oils constituents. Molecules. 2011;16:2233-2252. DOI: 10.3390/molecules16032233
  67. 67. Batista PA, de Paula Werner MF, Oliveira EC, Burgos L, Pereira P, da Silva Brum LF. The antinociceptive effect of [−]-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice. The Journal of Pain. 2010;11(11):1222-1229. DOI: 10.1016/j.jpain.2010.02.022
  68. 68. Nascimento SS, Camargo EA, DeSantana JM, Araújo AAS, Menezes PP, Lucca-Júnior W, et al. Linalool and linalool complexed in β-cyclodextrin produce anti-hyperalgesic activity and increase Fos protein expression in animal model for fibromyalgia. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2014;387(10):935-942. DOI: 10.1007/s00210-014-1007-z
  69. 69. Quintans-Júnior LJ, Barreto RSS, Menezes PP, Almeida JRGS, Viana AFSC, Oliveira RCM, et al. β-Cyclodextrin-complexed [−]-linalool produces antinociceptive effect superior to that of [−]-linalool in experimental pain protocols. Basic & Clinical Pharmacology & Toxicology. 2013;113:167-172. DOI: 10.1111/bcpt.12087
  70. 70. De Almeida RN, Araújo DAM, Gonçalves JCR, Montenegro FC, de Sousa DP, Leite JR, et al. Rosewood oil induces sedation and inhibits compound action potential in rodents. Journal of Ethnopharmacology. 2009;124(3):440-443. DOI: 10.1016/j.jep.2009.05.044
  71. 71. Santana MF, Quintans-Júnior LJ, Cavalcanti SCH, Oliveira MGB, Guimarães AG, Cunha ES, et al. p-cymene reduces orofacial nociceptive response in mice. Revista Brasileira de Farmacognosia. 2011;21(6):1138-1143. DOI: 10.1590/S0102-695X2011005000156
  72. 72. Quintans-Júnior SS, Menezesa PP, Santosa MRV, Bonjardima LR, Almeidab JRGS, Gelainc DP, et al. Improvement of p-cymene antinociceptive and anti-inflammatory effects by inclusion in β-cyclodextrin. Phytomedicine. 2013;20:436-440. DOI: 10.1016/j.phymed.2012.12.009
  73. 73. González-Ramírez AE, González-Trujano ME, Orozco-Suárez SA, Alvarado-Vásquez N, López-Muñoz FJ. Nerol alleviates pathologic markers in the oxazolone-induced colitis model. European Journal of Pharmacology. 2016;776:81-89. DOI: 10.1016/j.ejphar.2016.02.036
  74. 74. Food and Drug Administration, Table of substances generally recognized as safe. 1998. Available from: // [Accessed: 28 November 2018]
  75. 75. Vigan M. Essential oils: Renewal of interest and toxicity. European Journal of Dermatology. 2010;20(6):685-692. DOI: 10.1684/ejd.2010.1066

Written By

Ines Banjari, Jelena Balkić and Viduranga Yashasvi Waisundara

Submitted: May 18th, 2020 Reviewed: June 25th, 2020 Published: July 22nd, 2020