Sarah A. LoBisco, ND
Why Integrative Pain Management Right Under Our Noses
Olfactory processing is associated with the limbic system and has an effect on memory, emotions, and physiology. The emotional effect of odors and their relationship to pain perception are neurologically connected by the amygdala. This brain structure is intricately involved in pain processing through its associated CRF receptors and its role in the stress response. These connections make aroma alone impactful in effecting pain processing.1
In a previous article, I discussed these complex interactions between odors modulating psychological and physiological responses. Now, I will discuss how aromatic compounds, which contain secondary metabolites, can provide multimodal effects on pain more profoundly than odor alone. Specifically, I will show how combining pleasant aromatic associations and powerful secondary metabolites can entice a physiological relaxation response as they modify pain perception on a molecular level.
What Are Essential Oils?
Essential oils are aromatic secondary metabolites produced by plants in order to modulate immune function and stimulate various molecular pathways.1-8 As a result, they enhance cellular and biochemical responses and provide defense against stressors that could interfere with optimal development.1-14
In humans, essential oils favorably affect all levels of health, biochemical, physiological, and psychological. This is due to the fact that these plant compounds not only exert modulation of molecular pathways and cellular receptor interaction but also provide a profound impact on emotions through their aromatic quality.1-14 Essential oils are absorbed easily into our system through skin application, inhalation, or ingestion and excreted quickly, mostly through the kidneys. They have a low toxicity profile, when used in their proper, pure form.8,10
Essential oils are a truly holistic and mind-body medicine tool with a vast array of applications. For example, with one bottle of an essential oil, biochemistry could be altered through the presence of secondary metabolites that: inhibit unwanted microbial growth, defend against oxidative stress, modulate hormonal pathways, and balance inflammation.2-6,8,10,13 Furthermore, the aroma of essential oils could also produce a calming effect, affecting memory and focus, and affecting physiology through the olfactory response.1,11-12 In fact, the connection between aromatherapy and mitigating negative physiological stress patterns has an infinite amount of positive benefits and synergistically adds to all of their listed beneficial effects.1
Essential Oils: Physiological, Biochemical, and Psychological Effects on Pain
Probably one of the most recognized and validated applications for aromatherapy and essential oils is their ability to induce relaxation.11,12 However, the antimicrobial action of high-phenol oils, without the negative consequences of microbiota devastation, are a close second.3,15-28
The impact of essential oils on physiology, biochemistry, and psychology can be examined from two vantage points. The first is a more microscopic view, which examines an oil’s individual constituents and evaluates the biochemical and molecular pathways affected by them. The second is a macroscopic interpretation. This wider viewpoint encompasses the integrative and synergistic actions of the odor itself, along with the biological constituents’ effects on the mind and body. We will explore both and then connect these effects to pain response.
All the Tiny Wonders Inside a Bottle: The Microscopic View of Essential Oils
At the microscopic level the constituents present in essential oils are vast, and their classifications can be complex.2,10,29 These secondary metabolites can be grouped on the basis of their chemical structure composition, their solubility in various solvents, or their synthesis (e.g., phenylpropanoid, which produces tannins). For example, a common way to classify the volatile components is to organize them as either terpenoids or phenylpropanoids, or alternatively, into hydrocarbons and oxygenated compounds.10
Categorizing active constituents in essential oils based on their chemical structures can be exemplified as follows:
- terpenes (hydrocarbons resulting from several isoprene units, C5H8, synthesized in the cytoplasm of plant cells)
- terpenoids (terpenes that undergo enzymatic biochemical modification through incorporation of oxygen molecules and manipulating methyl groups)
- phenylpropenes (a subfamily of various groups of phenylpropanoids, they are synthesized from the amino acid precursor phenylalanines)
- “different degradation products originating from unsaturated fatty acids, lactones, terpenes, glycosides, and compounds that contain either sulfur or nitrogen”29
As stated in the introduction, it has been demonstrated that odor itself can have physiological effects, including the modulation of skin conduction, heart rate, blood pressure, respiratory rate, and regional cerebral blood flow.30-34 Furthermore, the psychological and memory-enhanced associations with odor can impact physiological processes and emotional state.35-40
Essential oils go further with the addition of these active constituents that modulate cellular signaling, biochemical responses, and neurotransmitter signaling independently of emotional arousal. In The Therapeutic Benefits of Essential Oils, Nutrition, Well-Being, and Health, the authors explain the three comprehensive actions of essential oils as a result of their synergistic constituents and properties. These include:
1. Biochemical (pharmacological): essential oils’ constituents interact with cellular receptors for hormones and enzymes, modulating their effects.
2. Physiological: essential oils impact specific biological functions through their various constituents that modulate molecular pathways.
3. Psychological: the “olfactory area of the brain (limbic system) undergoes an action triggered by the essential oil molecules and then, chemical and neurotransmitter messengers provide changes in the mental and emotional behavior of the person. …”10
There can be hundreds of various constituents found in one essential oil.6,8,10,29 This synergism of molecules affects and balances physiology in a more complex way than a single synthetic compound. For example, several in vitro studies have demonstrated that oils deemed estrogenic have additional components that have antitumoral properties. Furthermore, the same “estrogenic” compound exhibits other cellular responses beyond hormonal modulation.41-43
For example, one in vivo study using a methanolic extract of fennel seeds (FSME) demonstrated anticancer potential against a breast cancer cell line (MCF7) and a liver cancer cell line (Hepg-2). According to the study, FSME modulated various antioxidant activities and glutathione content. The authors concluded that it had the potential to “reduce oxidative stress and protect mouse cells from damage caused by reactive oxygen species. … FSME also exhibited an antitumor effect by modulating lipid peroxidation and augmenting the antioxidant defense system in EAC-bearing mice with or without exposure to radiation. Furthermore, it appears the concentration and dosage of essential oils may modulate estrogenic activity as well as the cellular environment.”41 When testing for active constituents of the extract, several constituents found in the volatile oil were present, which could account for creating these synergistic effects.
As stated above, the effect of a constituent can have a balancing effect of the biochemistry based on the “estrogen environment” present. Another study examined estrogenic effects of several components considered to have estrogen activity (e.g., limonene, citral [geranial and neral], geraniol, nerol, trans-anethole, and eugenol). The study consisted of testing these constituents on estrogen sensitive yeast cells expressing the human estrogen receptor, in the estrogen-responsive human cell line Ishikawa Var I, and in vivo in ovariectomized mice. Although the authors found some evidence of certain constituents showing in vitro estrogenic effects in yeast cells, there was a failure to replicate the results in the human cell line and rodents in nontoxic doses. They concluded:
At high concentrations, estrogenic activity was detected for citral (geranial and neral), geraniol, nerol and trans-anethole, while eugenol showed anti-estrogenic activity. Molecular graphics studies were undertaken to identify the possible mechanisms for the interaction of geranial, neral, geraniol, nerol and eugenol … but none of these compounds showed estrogenic or anti-estrogenic activity in the estrogen-responsive human cell line Ishikawa Var I at levels below their cytotoxic concentrations, and none showed activity in a yeast screen for androgenic and anti-androgenic activity. The potential in-vivo estrogenic effects of citral and geraniol were examined in ovariectomized mice, but neither compound showed any ability to stimulate the characteristic estrogenic responses of uterine hypertrophy or acute increase in uterine vascular permeability. These results show that very high concentrations of some commonly used essential oil constituents appear to have the potential to interact with estrogen receptors, although the biological significance of this is uncertain.43
These studies demonstrate that on the cellular level essential oils and their constituents have complex actions. The “unknown effects” discussed in the previous study could be related to these compounds acting as phytoestrogens that modulate estrogen beta, an antiproliferative receptor, verses estrogen alpha.45,35 The fascinating complexity of these natural compounds displays an “innate intelligence” that supports a truly individualized approach to balancing biochemistry through the modality itself.
Authenticity of Constituents for Different Effects
There is evidence that the chirality of the odorants found in essential oils exert an influence on their mode of action. This indicates that the composition of authentic essential oils may produce different effects than altered compounds with synthetic additives or isolated constituents.
One study examined the effects of chiral fragrances (enantiomers of limonene and carvone) on the autonomic nervous system (ANS) and on self-evaluation in 20 healthy subjects. The researchers measured skin temperature and conductance, breathing rate, pulse rate, blood oxygenation saturation, and blood pressure. Visual analog scales measuring mood, calmness, and alertness assessed for subjective experience of the fragrances, as well as a rating for pleasantness, intensity and stimulating properties. Each subject was tested at baseline, a control of continuous air, and with administration of a fragrance enantiomer. The results indicated that while inhalation of (+)−limonene and (−)−limonene increased systolic blood pressure, only (+)−limonene impacted subjective alertness and restlessness. (−)−Carvone caused increases in pulse rate, diastolic blood pressure, and subjective restlessness; whereas (+)−carvone increased both systolic and diastolic blood pressure.46,47
In another study, the authors tested how the chirality of linalool, a component in lavender, could be attributed to differing nervous system effects in 24 subjects. The effects of both R−(−) and S−(+) linalool enantiomers on various physiological parameters, which included heart rate, blood pressure, electrodermal activity, and salivary cortisol, were measured. The authors reported that although both forms were found to be relaxing, the R−(−) linalool proved to demonstrate stress-relieving effects, whereas, the S−(+) linalool acted on electrodermal activity, a measurement of sympathetic activity of the nervous system.
The study clearly indicated that odorants can modulate salivary cortisol levels, with both linalool enantiomers exerting relaxing effects. Concerning blood pressure and heart rate, S-(+)-linalool acted as an activating agent in contrast to electrodermal activity. R-(-)-linalool proved to be stress-relieving as determined by heart rate. In conclusion, the results revealed that (1) chirality crucially influences the physiological effects of odorants and that (2) odorants may act differently on certain physiological parameters.47
A plant’s growing conditions (e.g., climate, raw material use, and region), harvesting, distillation (essential oils extraction from the plant), manufacturing, and sourcing all can impact the constituents present, their qualities, and the predominant chemotype (metabolites within a certain species) of an essential oil.48,49
A 2012 article in Alternative Medicine stated the following regarding how distillation duration and temperature changed chemical composition of a specific species of frankincense:
Chemical constituents of Boswellia sacra essential oil fractions were dependent on duration and temperature of hydrodistillation. For example, when essential oils collected from 0–2 h (Fraction I), 8–10 h (Fraction II), and 11–12 h (Fraction III) at 78 °C were compared, longer distillation produced higher percentages of sesquiterpenes, between alpha-copaene and caryophyllene oxide (Table 1). All three fractions were primarily composed of monoterpenes (82.77–90.67%), including alpha-thujene, beta-pinene, and myrcene. Among the monoterpenes, alpha-pinene was the major compound present in all essential oil fractions, ranging from 65.49% to 78.45%. As anticipated, the abundance of alpha-pinene decreased with longer and higher temperature distillation due to its highly volatile nature. Compounds such as borneol, dimethyl ether or-cinol, allo-aromadendrene, gamma-cadinene, and caryophyllene oxide were only present in Fraction III essential oil…
We found that boswellic acids contents depended on hydrodistillation duration and temperature (Table 2). Essential oils prepared from longer distillation time and higher distillation temperature contained greater amounts of boswellic acids. For example, boswellic acids contents in Fractions III (19.6%) and IV (30.1%) were higher than those detected in Fraction I (0.9%) or II (0.8%) essential oil.52
In a review article on lavender essential oil and its impact on the nervous system, the authors stated their concern with the validity of the research of essential oils’ efficacy due to these quality issues, including methodological and oil identification problems:
The dried lavender flowers used in some trials were sourced from a local herb store (i.e., [62]). Although taxonomic identification was confirmed in these studies, without quantification of key constituents the quality of the herbal product may be questionable [110]. Although some studies defined the contents of lavender, it is essential that all future clinical studies specify the exact derivation of the oils used in the study and, preferably, include a profile of the liquid or the percentage composition of the major constituents. In addition, several factors, such as temperature, skin type and quality, and the size of area being treated, which may affect the level and rate of lavender absorption after massage or aromatherapy, were not considered in several investigations. Many discreet compounds in lavender oil have shown a myriad of potential therapeutic effects, and researchers continue to seek novel treatments to different ailments [2].5
Therefore, it’s important to determine the quality of the essential oil when using them for therapeutic applications, such as pain modulation. Furthermore, processed or synthetic compounds added to essential oils could have unintended effects on physiology.
Emotions and Essential Oils: To the Macroscopic Viewpoint
The use of essential oils for their aromatic influence, mood-enhancing benefits, as well as their biochemical and physiological modulation, makes them a holistic and therapeutic intervention for pain. For example, depression is a complex syndrome and is often associated with chronic pain.54-59
The complexity of factors relating to depressive symptoms is too intensive to review in this article; however, one small study examined several factors related to its symptomatology through studying various parameters following the inhalation of the essential oil clary sage (Salvia sclarea). The study consisted of 22 menopausal women in their 50s. Researchers measured changes in 5-hydroxytrypatmine (5-HT), cortisol, and thyroid stimulating hormone (TSH), as well as differences from baseline in the Korean version of Beck Depression Inventory-I (KBDI-I), KBDI-II, and Korean version of Self-rating Depression Scale after exposure to the essential oil.60
Clary sage essential oil was selected for this trial due to its reported antidepressant actions on dopamine pathways in animal studies and its suggested estrogen effects, which impact neurotransmitter levels.60,61 The study demonstrated that clary sage oil showed an “indirect depression reduction effect in terms of reduced plasma cortisol and TSH concentration and increased plasma 5-HT concentration.” The authors noted that only the KBDI-II showed significant differences in association with 5-HT and cortisol levels in normal and depressive subjects, indicating that this subjective measurement may be a more accurate reflection of the biochemical changes in depression.
The authors concluded, “When using KBDI-I and KBDI-II, 5-HT increased by 341% and 828% for the normal group and 484% and 257% for the depression tendency group, respectively. The change rate of cortisol was greater in depression tendency groups compared with normal groups, and this difference was statistically significant when using KBDI-II (31% vs. 16% reduction) and Self-rating Depression Scale inventory (36% vs. 8.3% reduction). Among three inventories, only KBDI-II differentiated normal and depression tendency groups with significantly different cortisol level.”
Limitations to this study include generalizability to males, small sample size, and heterogeneity.60 Yet, this study demonstrated that an essential oil can modulate hormonal and neurological support through physiological effects of the constituents present and the psychological responses known to occur from the odor itself.
More extensive support for the use of essential oils on various emotions and regulation of physiology in clinical, in vitro, and in vivo trials was presented in a 2006 article, “Aromatherapy in the Management of Psychiatric Disorders: Clinical and Neuropharmacological Perspectives.” The term pyschoaromatherapy was used in order to more precisely label the impact of essential oils in the more pronounced psychiatric disorders. This is due to the fact that the researchers perceived the term aromatherapy to be an incomplete portrayal of essential oils’ effects. They understood that responses to the oils aren’t necessarily related to the aroma of the volatile compounds alone.
Therefore, in this review, the dual nature of the “indirect” and “direct” effect of aroma was examined. Specifically, the authors sought to determine how the emotional aspect of the odor (direct effect) along with the effects of the biochemical constituents (indirect effect) affected psychological disorders, mood, and physiological response patterns. The article explained:
The effects of an aroma can be instantaneous and include both direct and indirect psychological effects – even thinking about a smell may have a similar effect to the smell itself. However, accumulating evidence that inhaled or dermally applied essential oils enter the blood stream and, in relevant molecular, cellular or animal models, exert measurable psychological effects, indicates that the effects are primarily pharmacological. This conclusion is supported by increasingly reported benefits of aromatherapy using specific essential oils in the management of chronic pain, depression, anxiety, and some cognitive disorders, as well as insomnia and stress-related disorders.
Within this review was a comprehensive overview of the many aspects of assessing the efficacy and mechanisms of essential oils in psychology in several ways. First, the authors presented a thorough report on the pharmacological actions and central nervous effects of the main constituents found in various essential oils, as determined by in vitro and in vivo studies. Second, chemical constituents of aromatic essential oils relevant to cerebral function were evaluated. Third, clinical trials relating to mood disorders, including comprehensive trials using essential oils for dementia, were also described. (Noteworthy were several intriguing clinical trials with Alzheimer’s patients who demonstrated behavioral improvement with the use of essential oils, e.g., lemon balm and lavender.) Finally, the importance of the difference responses of the ANS (autonomic nervous system) to essential oils (i.e.; stimulating versus calming effects) were highlighted. These final results supported anecdotal reports familiar essential oils such as lavender being relaxing and rosemary being more stimulating. The authors’ overall conclusions were:
It is concluded that aromatherapy provides a potentially effective treatment for a range of psychiatric disorders. In addition, taking into account the available information on safety, aromatherapy appears to be without the adverse effects of many conventional psychotropic drugs. Investment in further clinical and scientific research is clearly warranted.62
Due to the fact that odors can be cued stimuli producing fear and anxiety and resultant pain response, mitigating these negative aromatic effects with calming and psychologically balancing essential oils could beneficial in treating chronic pain patients.30-40 According to a summary from a 1999 article in Alternative Therapies in Health and Medicine:
Chronic pain consumes approximately $70 billion per year and affects some 80 million Americans. Increasingly, aromatherapy has been used as part of an integrated, multidisciplinary approach to pain management. This therapy is thought to enhance the parasympathetic response through the effects of touch and smell, encouraging relaxation at a deep level. Relaxation has been shown to alter perceptions of pain. Even if one ignores the possibility that essential oils have pharmacologically active ingredients – or the potential pharmacokinetic potentization of conventional drugs by essential oils – aromatherapy might possibly play a role in the management of chronic pain through relaxation.63
In one review of 16 randomized controlled clinical trials relating to the use of essential oils and anxiety, the authors stated: “Most of the studies indicated positive effects to quell anxiety. No adverse events were reported.”64
The effects of essential oils on emotion alone could constituent a series of lengthy articles. For the purpose of this article, I will now focus on some specific studies relating to the mechanism of pain modulation with essential oils as well as clinical trials. You will discover that we have come a long in explaining the relevance of “psychoaromatherapy.”
Zeroing Back in On the Microscopic Mechanisms of Essential Oils for Antinociception
A 2016 review article analyzed 31 essential oils for their antinociceptive activity in animal models of nociception. The authors assessed the botanical aspects of these aromatic plants, their mechanisms of action, and the chemical composition profiles of the essential oils. The most common chemical constituent categories of monoterpenes, sesquiterpenes, and phenylpropanoids were the focus for the authors. To enhance understanding of mechanisms involved, descriptions of the pain models used in the studies to determine analgesia were included.
Specifically, these tests, and their percentage of frequencies in the studies reviewed, included: acetic acid-induced writhing (72.2%), formalin (66.7%), hot plate (27.8%), tail flick (11.1%), and tail immersion (5.6%). Inflammatory pain was evaluated in 22.2% of the studies, as associated with the carrageenan test. Peripheral or central mechanisms involved in pain processing were determined by the pathway induced by the specific test used. Furthermore, many studies validated particular modes of action through comparison of well-known agonist and antagonist pain medications.65
For instance, the formalin model of nociception was used to discriminate pain into its central and peripheral components. This is accomplished through its two different test phases that are separated in time. In the first phase, direct formalin action is generated in the periphery through activation of nociceptive neurons. The second phase activates the ventral horn neurons at the spinal cord level.65,66 The narcotic drug morphine inhibits nociception in both phases, indicating dual action, whereas indomethacin and corticosteroids inhibit only the second phase, indicating a peripheral action. Drugs blocking prostaglandin synthesis, such as acetylsalicylic acid and paracetamol, also block only the second phase of the formalin test. Authors in the trials reviewed also concluded that mild analgesics (such as aspirin) can initiate antinociceptive activity in tonic tests (writhing and formalin tests), but lack analgesic results in thermal tests, such as the hot-plate test.66
One example of the mechanism of antinociception as determined by these pain models was described for Cymbopogon winterianus. The review authors state, “Since it has been reported that thermal and tonic tests elicit selective stimulation of A-γ fibers and C fibers, respectively [66], essential oil from the leaves of Cymbopogon winterianus may interfere with the transmission of both fibers, or a single common pathway.” Other methods to determine analgesic effects of studying Citrus limon reported that “the acetic acid-induced writhings and hot plate tests was partially reversed by naloxone (1.5 mg/Kg, i.p.), an opioid antagonist.” This indicated an opioid pathway of pain relief by this oil.66
A summary of the essential oils and their constituent(s) determined to have analgesic properties, along with their mechanism of action(s) (if specified), in this review are listed below:
1. Bunium persicum (g-terpinene): Peripheral and central
2. Citrus limon (limonene): Central mechanism
3. Cymbopogon citrates (myrcene)
4. Cymbopogon winterianus (geraniol): Peripheral and central
5. Eucalyptus citriodora (citronellal)
6. Eugenia carophyllata (eugenol): Opioid effect
7. Heracleum pesicum (hexyl butyrate)
8. Hofmeisteria schaffneri (hormeisterin III): Opioid effect
9. Hyptis fruiticosa (1-8-cineole, a-pinene): Peripheral and central
10. Hyptis pectinata (ß-caryophyllene): Peripheral and central (opioid, nitrergic, and cholinergic)
11. Illicium lanceolatum (myristicin, thymol): Peripheral
12. Lippa gracilis (carvacrol): Peripheral and central (opioid, nitregic, and cholinergic)
13. Matricaria recutita (α-bisabolol oxide): Peripheral
14. Mentha x villosa (piperitenone oxide): Peripheral
15. Nepeta crispa
16. Ocimum basilicum (linalool): Peripheral and central (opioid)
17. Ocimum gratissimum (eugenol): Central (opioid)
18. Ocimum micranthum (€-methyl cinnamate): Peripheral
19. Peperomia serpens (€-nerolidol): Peripheral
20. Pimenta psuedocaryophyllus (neral, geranial): Peripheral
21. Piper alyreanum (carophyllene oxide): Peripheral
22. Satureja hortensis (γ-terpinene): Peripheral
23. Senecio rufinervis (germacrene): Peripheral and central
24. Tetradenia riparia (14-hydroxy-9-epi-carophyllene)
25. Teucrium stocksianum (g-cadinene)
26. Ugni myricoides (α-pinene)
27. Valeriana wallichii (g-guanene): Peripheral
28. Xylopia laevigata (γ-muurolene): Peripheral
29. Vanillosmopsis arborea (α-bisabolol): Peripheral and central (TRVP1 cholinergic, adrenergic, and serotonergic)
30. Zingiber officinale (zingiberene): Peripheral
31. Zingiber zerumbet (zerumbone): Peripheral and central (opioid)65
Another mechanistic review of essential oils constituents was reported on in an article describing the various phytotherapeutic agents in cannabis, rather than tetrahydrocannabinol (THC), which has been the primary focus in research. The author’s goal for this review was to assess the pharmacology of these essential oil (EO) agents found in this plant and their possible therapeutic interactions with phytocannabinoids “that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus).” The cannabis terpenoids studied included limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol, and phytol, which are also present in various essential oils.
Phytocannabinoids and terpenoids are related in that they both synthesized from the same parent compound, geranyl pyrophosphate.67 The mevalonate pathway produces the terpenoid precursors isopentenyl diphosphate (IPP, 1) and dimethylallyl diphosphate (DMAPP, 2). In producing these compounds found in essential oils, geranyl pyrophosophate may then form limonene and other monoterpenoids in secretory cell plastids, or couple with isopentenyl pyrophosphate in the cytoplasm to form farnesyl pyrophosphate (FPP). FPP is synthesized into sesquiterpenoids.67-72 Interestingly, FPP was found to interact with transient receptor potential vanilloid receptor (TRPV) 1 in human and mice dorsal root ganglion, an endogenous ligand to date on the G-protein coupled receptor (GPR) 92. This suggests a role of this precursor compound in processing of noxious stimuli.67,73
Terpenoids are what are responsible for the aroma of cannabis and usually compromise approximately 1% of the yield in most cannabis assays. According to the article, “Terpenoids are pharmacologically versatile: they are lipophilic, interact with cell membranes, neuronal and muscle ion channels, neurotransmitter receptors, G-protein coupled (odorant) receptors, second messenger systems and enzymes. …”67
Among the terpenoids reviewed, the constituents that were found in vivo to be analgesic were myrcene, linalool, and β-caryophyllene, supporting the previous review discussed above of these compounds.65,67
In a third systematic review of essential oil constituents, the authors sought to determine what was known about the analgesic activity of monoterpenes. The authors began their search for fitting articles using the terms analgesia, anti-inflammatory, anesthetic, and antioxidant from studies published between 1990 and 2012. The authors used three databases (COPUS, PUBMED, and EMBASE). Within the 45 English-language articles selected, 27 monoterpenes were selected and explored for their potential pain-relieving properties. Studies that used the essential oils themselves were excluded.74
Similar to the review article relating the antinociceptive properties of essential oils and their active constituents in animal models, the mechanisms reported in this review were based on summaries of different testing methods and comparisons to agonist and antagonist analgesic drugs.65 Route, dosage, and animal sex were also taken into consideration. Impressively, this review also analyzed the different methodologies used, findings, and inconsistencies. In this way, the authors were able to determine the effects of dosage, animal species, sex, and study heterogeneity.
For example, when discussing myrcene, the authors reported:
In other studies, myrcene (5–405 mg/kg, p.o.) presented strong analgesic effect on the writhing induced by acetic acid or iloprost and on hyperalgesia induced by prostaglandin E2 or isoprenaline, a sympathomimetic beta adrenergic agonist. However, this monoterpene had no effect on DbcAMP [dibutyryl cyclic adenosine monophosphate]-induced hyperalgesia or in the hot-plate test (135 and 405 mg/kg, p.o.) and did not show any tolerance as compared with morphine after 5 days of consecutive oral dosing, suggesting a peripheral site of action for myrcene (Lorenzetti et al., 1991). This contradiction may be related to the administration route and hepatic first-pass effect present in the oral route (Buxton, 2006).74
The summary of the monoterpenes found to be antinociceptive, and mechanisms of action, if specified, in this review are listed by category below:74
Acyclic monoterpenes:
1. Citral – peripheral
2. Citronellal – opioid system and decreased nerve excitability
3. Citronellol – peripheral (via inhibition of TNF-a and NO synthesis) and central (via opioids)
4. (−)−Linalool – opioid, cholinergic, muscarinic, glutamatergic (iGLUr), and dopaminergic systems, adenosinergic system (A1 and A2A receptors), opening up KATP system, inhibition of TRPA1 and NMDA channels, and decreased neuronal excitability in the peripheral and central nervous system74,75
5. Linalyl acetate
6. Linalool – peripheral opioid receptors
7. Myrcene – peripheral analgesic, arginine-NO-cGMP pathway stimulation, endogenous opioid release (alpha 2-adrenoceptor stimulation)
Monocyclic monoterpenes:
8. Carvacrol – nonopioid peripheral mediators and central mechanisms inhibited, TNF-α inhibition and NO release
9. (−)−Carvone – peripheral nerve excitability decreased (not opioid system related)
10. (+)−Carvone
11. p-Cymene – opioid, peripheral, and central mechanisms
12. Hydroxydihydrocarvone – supraspinal and spinal antinociception, non-opioid-mediated, central antinociception without tolerance
13. R-(+)−limonene – inflammation inhibition (nonopioid)
14. (−)−Menthol – selective activation of κ-opioid receptors
Note: (+)−Menthol – without antinociceptive activity
15. α-Phellandrene – glutamatergic, opioid, nitrergic, cholinergic and adrenergic systems
16. (+)−Pulegone – nonopioid central mechanism
17. α-Terpineol – TNF-α production inhibition and NO release, central and peripheral action
18. Thymol (In this review, without mechanism, blockade of voltage-operated sodium channels was shown in an in vitro model.)76
19. Thymol acetate
20. Thymoquinone – indirect activation of the supraspinal μ1-opioid and κ-opioid receptor
Bicyclic monoterpenes
21. Carvone epoxide
22. 1,8-Cineol – spinal and supraspinal action, nonopioid
23. (−)−Fenchone
24. Limonene oxide
25. α-Pinene
26. β-Pinene – μ opioid receptors partial agonist
27. Rotundifolone – opioid and nonopioid mechanisms reported 74
The Macroscopic View of the Whole Oil
As noted above, analyzing the constituents of an essential oil can be helpful to determine how the constituents present modulate pain. However, the synergism of constituents of the essential oil itself can provide a more comprehensive healing response and have differing effects. In this section, I will review the studies that assessed essential oils themselves for pain relief. First, I will discuss single oils.
Eucalyptus
One in vivo study assessed the synergism of constituents found in three species of eucalyptus oil Eucalyptus citriodora (EC), Eucalyptus tereticornis (ET), and Eucalyptus globulus (EG) in relation to their effects on inflammation and pain perception in rats exposed to acetic-acid and hot plates. EC, ET, and EG all induced analgesic effects, suggesting peripheral and central mechanisms. Furthermore, anti-inflammatory effects relating to carrageenan tests were also supported. However, there were some inconsistencies regarding parameters evaluated in terms of activity and dose-response relationships.77 This reflected the complexity of the essential oils makeup and may support how the environment affects their activity, even in rodents, as previously allotted to.41
Chamomile
In an article in Medical Hypotheses the authors theorized several mechanisms that could explain the mechanism of another essential oils, topical chamomile oil, for pain migraine headache as assessed in various studies. They concluded the following77:
1) chamazulene and apigenin, which inhibit iNOS expression in activated macrophages and can lead to the prohibition of NO release and synthesis;77,78
2) chamomile flavonoids, which have a strong inhibitory effect on endogenous prostaglandin E2 (PGE2) levels in RAW 264.7 macrophages and can play the role of selective COX-2 inhibitor;
3) chamomile polyphenols, which possess anti-inflammatory effects due to the inhibition of pro-inflammatory biomarkers in THP1 macrophages and which can reduce inflammation in neurovascular units (NVU) at the site of migraine pain;
4) chamomile, which has neuroprotective effects because of reduced NO levels;
5) sesamin in sesame oil, which possesses an anti-inflammatory effect.78
Peppermint
Due to the popularity of the use of peppermint for digestive discomfort, its role on pain mediation has been studied more vastly. In fact, clinical trials have demonstrated decreased subjective pain in those with irritable bowel syndrome (IBS) using this oil.80,81 One mechanism suggested is related to the mediation of TRPM8, a transient receptor potential (TRP) cation channel, activated by menthol, a main constituent of found in peppermint essential oil. TRPM8 activation induces smooth muscle contractions inversely relational to temperature and also involves the initiation of Rho-kinase, leading to smooth muscle contraction. There is also some controversial evidence on menthol modulating intracellular calcium stores.
In one review article L-menthol was reported to potentially be involved in modulating arachidonic acid metabolism into LTB4 (leukotriene B4) and PGE2 (Prostaglandin E2), markers of the inflammatory pathways of lipoxygenase and cyclooxygenase, respectively.80
Combinations of Essential Oils
In a randomized trial that included 60 participants with a history of neck pain and a Neck Disability Index (NDI) score of 10%, the use of a 3% concentration of an essential oil cream was evaluated for efficacy in pain relief. The dose used was 2 g of the cream daily applied for four weeks. The cream consisted of four essential oils: marjoram, black pepper, lavender, and peppermint. An unscented cream was given to the control group. Measurements for effective outcomes post intervention, as compared with baseline, included a visual analogue scale (VAS), NDI, pressure pain threshold (PPT, which used a pressure meter in the midpoint between the seventh cervical vertebra and the acromion connection), and neck-joint range (via Motion Analysis System [MAS] at the occiput, C2, C7, and shoulder level).
An independent-sample t-test indicated that the groups significantly differed with regard to age only (p = 0.04). Within each group, there were nonsignificant differences in the number of pain episodes per week and intensity, duration, associated symptoms, location, and cause of pain. The study found that the VAS scores improved in both participant groups after the intervention; however, the NDI and PPT values were only improved with the experimental group. The authors stated that the VAS scores may be more of an indicator of subjective pain, whereas the NDI and PPT may be a better overall evaluation of chronic neck pain. Furthermore, neck range of motion in the experimental group with aromatherapy significantly increased following the intervention.82
Although there were some limitations in the trial, such as the short duration of the study and translation to those with more severe neck pain, the study demonstrated a significant difference in pain modulation with essential oils.
An experiment using a quasi-experimental design with a nonequivalent control group, pre- and posttest consisted of 40 subjects who were examined in regard to the role of aromatherapy in pain, depression, and life satisfaction. An essential oils blend of lavender, marjoram, eucalyptus, rosemary, and peppermint mixed with a carrier oil to a 1.5% dilution was used. The authors reported that aromatherapy significantly decreased scores for pain and depression for the experimental group compared with the control group, though there was no difference in life satisfaction reported.83 The article was in Korean, so unbiased conclusions could not be fully examined. Limitations may have included a small sample, the dilution technique of the oil, and that subjective physiological measures weren’t examined.
In another nonequivalent Korean trial with 58 terminal cancer patients, the researchers assessed for changes in anxiety, depression, and pain when using hand massage with or without essential oils. The carrier oil used for both conditions was a sweet almond oil. The almond oil was used alone in the control group. In the experimental group, almond oil was mixed in an equal ratio of bergamot, lavender, and frankincense diluted to 1.5%. The hand massage was done for 5 minutes for 7 days. The authors found that the experimental group had a more significant difference in changes in pain and depression scores than the controls. Although the trial design has limitations, including generalizability, the subjective measurements of decrease in pain as compared with controls lend support for the pain-modulating effects of essential oils.84
In a controlled, randomized, double-blind clinical trial, the use of essential oil massage was evaluated for moderating pain in 48 subjects diagnosed with primary dysmenorrhea and who had a 10-point numeric rating scales that were more than 5. The control group received a synthetic fragrance in an unscented jojoba cream, whereas the experimental group consisted of a 2:1:1 ratio blend of lavender (Lavandula officinalis), clary sage, and marjoram (Origanum majorana) diluted in unscented jojoba cream at 3% concentration.
The cream was applied daily by the participants’ massaging it on the lower abdomen starting from the end of their last menses to the beginning of the next. The dose was two 1 g spoonfuls daily. The verbal rating scale (VRS) and the numeric rating scale (NRS) were analyzed on the first to third days of the first menstrual cycle and post intervention on the same days of the second cycle.
The NRS, VRS, and duration of pain were significantly decreased in the essential oils group, whereas the control group did not experience a decrease in duration of pain after one menses cycle. The main analgesic components of the essential oils were determined to be linalyl acetate, linalool, eucalyptol, and beta-caryophyllene.85
Limitations include generalizing to other populations, the effects of massage alone on pain, and the potential estrogenic effects present in the synthetic cream (endocrine disruptors).85-88
Popular Essential Oils Categorized by Action
In a systematic review of essential oils used in aromatherapy, the authors categorized essential oil use in the following manner: cosmetic, massage, medical (treating diseases), olfactory (impacting mood and relaxation), and psychoaromatherapy (the psychological impact from aromas’ effect on memories and emotions).
Within this context of respect for the multimodal actions of essential oils, 10 common essential oils were reviewed. The following were reported by the authors to modulate pain as follows89:
1. Clary sage: reduces cortisol, assists with menstrual periods, and eases tension and muscle cramps89,90
2. Eucalyptus: regulation of the nervous system relating to neuralgia, headache, and debility, treatment for joint and muscle pains (rheumatoid arthritis), and for muscle and joint pains and aches89,91
3. Geranium: sedative properties, nerve tonic, and may help the patient in coping with the pain in cancer89
4. Lavender: for the treatment of abrasions, burns, stress, headaches, muscle pain, and primary dysmenorrhea
5. Lemon: may help with labor pain, nausea, vomiting, and ulcers89,92
6. Peppermint: relief of pain spasms, arthritic problems, digestive pain and IBS, and inflammation
7. Roman chamomile: assist with modulation of “inflammation, muscle spasms, menstrual disorders, insomnia, ulcers, wounds, gastrointestinal disorders, rheumatic pain, and hemorrhoid.”89,93
8. Rosemary: soothes menstrual cramps, contains the anti-inflammatory constituent 1-8 cineole
9. Tea tree: anti-inflammatory, and antimicrobial support in painful infections89,94
10. Ylang ylang: powerful sedative proper-ties, and useful for trauma and shock89,95
In regards to direct pain management, the authors listed the following oils:
Eucalyptus smithii (gully gum)
Lavandula angustifolia (lavender)
Matricaria recutita (German chamomile)
Leptospermum scoparium (manuka)
Origanum majorana (sweet marjoram)
Pinus mugo var. pumilio (dwarf pine)
Rosmarinus officinalis ct. camphor (rosemary)
Zingiber officinale (ginger)89
Bioindividuality in Odor Processing Experiences and Clinical Implications with Essential Oils
Due to the complexity of aromas consisting of potentially hundreds of molecules, humans tend to weave them into a conceptual whole. Specifically, the brain encodes odor stimuli and synthesizes them into a “unified perceptual experience.”96 This unique experience of smells has implications for selecting aromas for different individuals for therapeutic use.
Specifically, it has been found that perceptions and environmental conditions associated with certain scents can vary from person to person. This means that the same smell could evoke differing emotional responses from one person to the next.33,34 Furthermore, one’s internal physiology can also impact odor perception and response. This means that one’s current state at the time of stimulus presentation may determine if it is deemed pleasant or unpleasant.97,98
For example, in one study, the scent of orange syrup was considered pleasant in a subject in the fasting state; however, after ingestion of a glucose load, the olfactory stimulus was deemed “unpleasant.”97 Furthermore, personality can also bias how emotional information is processed, and people who are emotionally liable may be more reactive to unpleasant sensations.99
This means that perception does not occur in isolation based solely on the stimulus of one odorant. Rather, olfaction is intertwined into a diverse context of physiological conditions and also psychological states.97,98 All these unique factors suggest that it is important to determine emotional liability, personality, and the internal state of your patient when choosing an aromatic oil to modulate pain and other physiological effects.
Putting it more crudely, essential oils have the molecular mechanisms to modulate pain response. Do not cancel this desired response out with an olfactory stimulus that is unpleasant and could subsequently ignite the amygdala emotional responses involved in pain perception.
Gender and Pain
Another factor to be aware in response to odorant stimuli is gender. It has also been implicated in how one processes pain during states of emotional stress. Specifically, females tend to have more sensitivity to pain, respond differently to pain medication, and those with high anxiety states tend to have a lower threshold for pain stimuli.100,101
Therefore, using subjective and autobiographical memories modulated by volatile oils could be very helpful in individualized pain perception, but especially for females who are anxious.
Concluding Thoughts
In Part 1 of this article series, the complex interactions between odorants modulating emotional and physiological responses was reviewed. Specifically, the critical role of the amygdala’s response to odorant stimuli, and the interwoven neurological overlap to its pain processing functions, were discussed. How this knowledge served in treating chronic pain was also established.
In this article, the biochemical, physiological, and psychological effects of essential oils were explored. Support for the role of physiological effects from the secondary metabolites modifying biochemical pathways was explained in order for the clinician to understand that the effect of aromatherapy is inclusive. Specifically, it supports but goes well beyond the effects of olfaction alone. The term pyschoaromatherapy may more precisely portray the impact of essential oils on various perceptual states, including mood and pain perception.
Finally, the importance of environmental association patterns, gender, and internal states was also discussed as modifying responses to odors. This means that those who implement essential oils must be aware of any potential biases against the smell they or their patients may have when initiating therapy. I have found it is best to match positive associations of an essential oil’s aroma with its biochemical and stimulating or relaxing effect on the nervous system.
In conclusion, the use of essential oils is an ancient practice that is proving to be a powerful medicine. They may appear a simple tool, but these secondary metabolites are complex in medicinal actions which assist in modulating pain response. From a societal perspective, their more popularized use could help alleviate the chronic pain epidemic in a holistic and integrative manner, one whiff at a time.
This article was originally published in Townsend Letter, December 2016.
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Published January 27, 2024
About the Author
Sarah LoBisco, ND, is a graduate of the University of Bridgeport’s College of Naturopathic Medicine (UBCNM). She is licensed in Vermont as a naturopathic doctor and holds a bachelor of psychology degree from State University of New York at Geneseo. Dr. LoBisco is a speaker on integrative health, has several publications, and has earned her certification in functional medicine. Dr. LoBisco currently incorporates her training as a naturopathic doctor and functional medicine practitioner through writing, researching, private practice, and her independent contracting work for companies regarding supplements, nutraceuticals, essential oils, and medical foods. Dr. LoBisco also enjoys continuing to educate and empower her readers through her blogs and social media. Her blog can be found at www.dr-lobisco.com.