Bergamot Essential Oil- for Reduction of Pain and Inflammation

Citrus bergamia Risso, an alternative therapy to reduce pain and inflammation
Margo R. Flanagan
American College of Healthcare Sciences

Abstract
Chronic pain and chronic inflammation disorders are the most common reasons patients seek care and treatment by physicians in the United States. Given an opioid crisis and increasing numbers of patients with autoimmune diseases, alternative forms of therapy that do not have addictive nor significant side effects are needed for long term treatment of chronic symptoms. Inflammation, while a precursor to pain is also linked to the development of certain types of cancers. Understanding the pathways of inflammation on a cellular level helps find different avenues and approaches to halting the process through natural means. Research on complementary and alternative methods to reduce pain and inflammation has increased over the last decade to not only to educate patients on symptom management but to decrease the healthcare cost burden. Citrus bergamia Risso (Bergamot) fruit from the southwest region of Italy is mainly produced for its intense fragrance and highly valued within the cosmetics industry for its aroma. Bergamot essential oil (BEO) procured from cold pressing of the fruit’s rind contains terpens and furanocoumarins in the chemical constituents. These constituents break down further into limonene, linalool, linalyl acetate and bergamottin. Bergamot Juice extract (Bje), produced from squeezing the fruit’s endocarp once considered a by-product was found to contain high amounts of flavonoids. Together BEO and BJe have shown antiproliferative, antioxidant, anti-inflammatory and anti-cancer effects in vitro and in some cases in vivo. This reviews seeks to evaluate the derivatives of Citrus bergamia Risso as an alternative therapy to reduce pain and inflammation.

Keywords: chronic pain, chronic inflammation, bergamot essential oil, bergamot juice extract, anti-inflammatory, Citrus bergamia Risso, limonene, linalool

Introduction
Citrus bergamia Risso et Poiteau is a fruit resembling a cross between a lime and bitter orange belonging to the Rutacae family growing almost exclusively in the Calabria region in southwest Italy (Navarra, Mannucci, Delbo & Calapai, 2015). The fruit of C.bergamia is not generally eaten rather its derivatives are widely used within the commercial industry. Bergamot essential oil (BEO) is obtained by cold pressing the fruit’s rind producing a yellow to greenish brown colored oil with an intense sweet citrusy odor highly prized in the perfume industry as a product top note (Balchin, 2006). BEO is comprised of both volatile and non volatile parts. The volatile fractions of BEO that exert therapeutic activity include the monoterpene hydrocarbon d-limonene, sesquiterpenes and oxygenated derivatives linalool, linalyl acetate, delta terpinene and beta-pinene (Navarra, Mannucci, Delbo & Calapai, 2015). Steam distillation is sometimes used in order to extract the toxic furocoumarins but the resulting oil is not considered a “true essential oil” (Balchin, 2006). Bergamot Juice extract (Bje), squeezed from the endocarp and once considered a by-product has gained considerable attention within the scientific field for its hypolipemic, antioxidant, anti-inflammatory, anti-proliferative and anti-cancer properties found mainly in the flavonoids (Impellizzeri et al., 2016).
According to the National Center for Complementary and Integrative Health, chronic pain affects millions of adults in the United States. A 2012 national survey showed 11.2 % of U.S. adults had chronic pain for the prior three months and the 17.6% with severe pain required more healthcare and were more likely to be disabled (Chronic pain NIH, 2016). Complementary and alternative therapy approaches to treating pain are growing areas of research and necessary amidst a U.S. opiate crisis.
Autoimmune diseases affect up to 50 million Americans, are one of the top causes of death in women under 65 and are a category of diseases that require chronic management and treatment of symptoms where the underlying hallmark problem is inflammation (The cost burden of autoimmune disease. 2011). Chronic inflammation leads to chronic pain conditions unless the inflammation is contained at the acute phase. Current treatment options for inflammation include non-steroidal anti-inflammatory drugs and corticosteroids which can have significant side effects when used long term. Natural treatment options for reducing inflammation with little to no side effects would benefit this population.
C.bergamia and its derivatives have shown in vitro and in some in vivo studies their antiproliferative, antioxidant, anti-inflammatory and anti-cancer effects. This reviews seeks to evaluate the derivatives of Citrus bergamia Risso as an alternative therapy to reduce pain and inflammation.

Methods
The thesis question for this literature review asks, “Can Bergamot essential oil provided an alternative therapy for the reduction of pain and inflammation?” Pain and inflammation tax the healthcare system and many patients frustrated with an inability to find pain relief or with medications unable to relieve symptoms, addictive or with significant side effects are seeking out alternative and complementary therapies. Searches for this review revolved around articles that showed positive results that would further scientific research.
Initial searches were performed on PubMed using keyword Bergamot essential oil yielding 96 results. Articles selected contained information on chemical composition of BEO and clinical information or studies with free full text links to articles. Google searches for scholarly articles using keywords BEO, Citrus bergamia, inflammation, pain, limonene produced many recent full text journal articles with information directly related to pain and inflammation. Textbooks for AROMA 501 were consulted for information on Bergamot monograph.
Topic for search was broadened beyond BEO to include Bergamot Juice extract due to the valuable information found pertaining to the anti-inflammatory nature of the flavonoids and anti-cancer research of its effect on neuroblastoma cells.
Information on pain and chronic inflammatory conditions was gathered to include a report on the cost burden of Autoimmune disease.

Results
Bergamot essential oil contains approximately 40% limonene, 28% linalyl acetate, 8% linalool and small amounts of alpha-pinene all of which have anti-inflammatory effects seen in studies (Karaca et al., 2007). Folk medicine has used BEO as an antiseptic and for wound care prompting current research on its therapeutic properties. Aromatherapy and massage both use BEO and have provided much anecdotal evidence on its ability to not only calm the client but also reduce pain.
Linalool dosed at 100mg/kg s.c. was able to weaken the pain response when it was administered to rats modeling spinal nerve litigation and neuropathic pain. BEO was able to show the same response but required a higher dose of 1 mL/kg s.c. (Bagetta et al., 2010)
A study performed on human neuroblastoma cells showed that BEO and monoterpene hydrocarbons gave neuroprotective activity against cell death, reduced neuronal damage and prevented injury on death pathways (Corasaniti et al., 2007).
A review on the the anti-inflammatory activities of the the derivatives of Citrus bergamia showed positive results warranting further investigation of their use as an alternative therapy for chronic inflammatory conditions (Ferlazzo et al., 2016). BEO has the ability to modulate the release of specific neurotransmitters in rats that are responsible for pain signals in the brain as well as provide a sedative like response (Russo, Coarasaniti, Bagetta & Luigi, 2015).
Studies related to the activity of BJe on key inflammatory mediators showed positive results. Bergapten and citropten, the chemical constituents found in Bje were able to inhibit IL-8 gene expression specifically in a study on cystic fibrosis epithelial cell line (Borgatti et al., 2011). Bje was able to reduce the expression of IL-1beta, IL-6 and phosphorylation of MAPK in a study on its potential as a natural drug for neuroinflammatory diseases such as Alzheimer’s (Curro et al., 2016). BJe was able to reduce cytokine production, neutrophil infiltration and adhesion molecule expression by interfering with signaling pathways in a study on intestinal ischemia in mice (Impellizzeri, 2016).
Indirect studies on the chemical constituents that are found in BEO but contrived from other essential oil sources showed positive results. When the cellular activity of the monoterpenes linalyl acetate, linalool and alpha-pinene were tested for immunomodulating effects on natural killer cells, linalyl acetate was able to show stimulation (Andrade, de Sousa & de Cassia da Silveira e Sa, 2012). Linalool showed significant anti-inflammatory activity by reducing rat paw edema induced by intraplantar injection when given once by injection or twice daily for 10 days ( Andrade, de Sousa & de Cassia da Silveira e Sa, 2012). Limonene is able to effectively inhibit some of the key mediators of inflammation; cytokines, suppress cell chemotaxis, inactivate eosinophil migration and ROS production making it a potentially useful anti-inflammatory agent ( Andrade, de Sousa & de Cassia da Silveira e Sa, 2012). Limonene significantly reduced skin inflammation of experimental murine model and also led to rapid wound healing (D’Alessio, Menut, Lejay, Bisson & Bene, 2015)
The phototoxic effects of the furocoumarins when exposed to sunlight can be seen in
Fig 1 of the writer.

Conclusions and Recommendations
Citrus bergamia Risso and its derivatives BEO and BJe have shown anti-inflammatory activities that would largely benefit those patients suffering with chronic pain and chronic inflammatory conditions using traditional medicine in need of more support for managing symptoms. Many of the journal articles and studies strongly suggested that further studies be proposed to gather more information on the neuroprotective, anti-inflammatory and anti-proliferative of the derivatives and chemical constituents. The data reported in “Neuropharmacology of the essential oil of Bergamot” provided a substantial amount of information to provide a foundation for pharmaceutical size clinical studies so that BEO could be used in clinical setting other than alternative medicine (Bagetta et al., 2010).
Studies on the ability of Citrus bergamia Risso to alter the expression of IL-8 is an incredible breakthrough in finding a new treatment avenue for Cystic Fibrosis infections that do not respond to current therapies.
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Figure 1.

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